Jane De Lartigue

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

Targeted therapies have revolutionized the treatment of numerous different cancer types and ushered in an era of personalized medicine, yet they can be prohibitively costly. As patent protection expires on many of the first FDA-approved monoclonal antibodies developed for oncologic indications, the doors are opened for other companies to develop their own version of these drugs, known as biosimilars. The price of biosimilars is expected to be considerably lower than the original drugs upon which they are based.

Bevacizumab-awwb, marketed as Mvasi by Amgen and Allergen, became the first such drug to receive approval by the US Food and Drug Administration for the treatment of cancer in fall last year.¹ It is a biosimilar of Genentech’s anti-angiogenesis drug, bevacizumab (Avastin), a monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A).

Targeted therapies have revolutionized the treatment of numerous different cancer types and ushered in an era of personalized medicine, yet they can be prohibitively costly. As patent protection expires on many of the first FDA-approved monoclonal antibodies developed for oncologic indications, the doors are opened for other companies to develop their own version of these drugs, known as biosimilars. The price of biosimilars is expected to be considerably lower than the original drugs upon which they are based.

Bevacizumab-awwb, marketed as Mvasi by Amgen and Allergen, became the first such drug to receive approval by the US Food and Drug Administration for the treatment of cancer in fall last year.¹ It is a biosimilar of Genentech’s anti-angiogenesis drug, bevacizumab (Avastin), a monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A).

Targeted therapies have revolutionized the treatment of numerous different cancer types and ushered in an era of personalized medicine, yet they can be prohibitively costly. As patent protection expires on many of the first FDA-approved monoclonal antibodies developed for oncologic indications, the doors are opened for other companies to develop their own version of these drugs, known as biosimilars. The price of biosimilars is expected to be considerably lower than the original drugs upon which they are based.

Bevacizumab-awwb, marketed as Mvasi by Amgen and Allergen, became the first such drug to receive approval by the US Food and Drug Administration for the treatment of cancer in fall last year.¹ It is a biosimilar of Genentech’s anti-angiogenesis drug, bevacizumab (Avastin), a monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A).

Urologic cancers are those that form in organs of the urinary and male reproductive systems, the most significant among them being cancers of the bladder, kidney, prostate, and testicles. Collectively, they are diagnosed in close to 400,000 Americans each year and are responsible for almost 60,000 deaths annually.¹ Here, we describe the most recent developments in treating these malignancies.
 

Update/related article
Atezolizumab approval marks first new treatment option for bladder cancer in more than 3 decades 

Click on the PDF icon at the top of this introduction to read the full article.

Urologic cancers are those that form in organs of the urinary and male reproductive systems, the most significant among them being cancers of the bladder, kidney, prostate, and testicles. Collectively, they are diagnosed in close to 400,000 Americans each year and are responsible for almost 60,000 deaths annually.¹ Here, we describe the most recent developments in treating these malignancies.
 

Update/related article
Atezolizumab approval marks first new treatment option for bladder cancer in more than 3 decades 

Click on the PDF icon at the top of this introduction to read the full article.

Urologic cancers are those that form in organs of the urinary and male reproductive systems, the most significant among them being cancers of the bladder, kidney, prostate, and testicles. Collectively, they are diagnosed in close to 400,000 Americans each year and are responsible for almost 60,000 deaths annually.¹ Here, we describe the most recent developments in treating these malignancies.
 

Update/related article
Atezolizumab approval marks first new treatment option for bladder cancer in more than 3 decades 

Click on the PDF icon at the top of this introduction to read the full article.

The past 5 years have witnessed a watershed moment in the management of metastatic melanoma. The successes of molecularly targeted and immune-based therapies have transformed it from an aggressively lethal malignancy into one that is readily treatable. Here, we discuss continued efforts to find new therapies and broaden the clinical impact of existing options to maintain the unprecedented momentum of improving patient outcomes.

Click on the PDF icon at the top of this introduction to read the full article.

The past 5 years have witnessed a watershed moment in the management of metastatic melanoma. The successes of molecularly targeted and immune-based therapies have transformed it from an aggressively lethal malignancy into one that is readily treatable. Here, we discuss continued efforts to find new therapies and broaden the clinical impact of existing options to maintain the unprecedented momentum of improving patient outcomes.

Click on the PDF icon at the top of this introduction to read the full article.

The past 5 years have witnessed a watershed moment in the management of metastatic melanoma. The successes of molecularly targeted and immune-based therapies have transformed it from an aggressively lethal malignancy into one that is readily treatable. Here, we discuss continued efforts to find new therapies and broaden the clinical impact of existing options to maintain the unprecedented momentum of improving patient outcomes.

Click on the PDF icon at the top of this introduction to read the full article.

CRISPR technology, a simple, yet incredibly powerful tool for genetic engineering, is not only allowing cancer researchers to screen for drug targets more efficiently, but is also opening the door for direct cancer treatment through gene interference or activation.

“The pace at which this technology is developing is astounding and almost every cancer research lab is now using some version of it in their studies,” Dr. Scott A. Armstrong, director of Memorial Sloan Kettering Leukemia Center, New York, said in an interview.

Ancient defense mechanism

While the term CRISPR is now synonymous with the editing of human genes, it actually refers to a sort of primitive immune system used by bacteria for billions of years. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, but the complex terminology belies an elegantly simple mechanism by which bacterial cells destroy invading pathogens.

The bacterial genome contains regions with short repetitive stretches of DNA that are separated by spacers. Researchers made the startling discovery that the spacers are often composed of bits of foreign DNA and it transpired that bacteria use it as a molecular memory of prior infection.

When the same pathogen is encountered again, the stretches of repeats and spacers are transcribed to form CRISPR RNAs (crRNA). Together with a transactivating RNA (tracrRNA), it forms a kind of GPS system for a series of CRISPR-associated (Cas) proteins that function like molecular scissors, destroying the target DNA sequence in the invader’s genome.

There are three CRISPR systems – type I, II, and III – that are associated with different sets of Cas proteins and each employ unique methods for achieving the same ultimate function. The type II system that pairs with Cas9 has received the most attention.

Cut and paste gene editing

The discovery that CRISPR could be exploited as a tool for genetic manipulation in mammalian cells sparked a revolution in the genome editing field. “The CRISPR-Cas9 system has been adapted to specifically edit the genomes of mammalian cells, allowing one to make targeted changes to almost any gene,” Dr. Armstrong said.

The use of CRISPR-Cas9 as a genome editing tool is simplified by joining the crRNA and tracrRNA together so they are transcribed in a single guide RNA (gRNA). The GPS coordinates of the gRNA can be preprogrammed to target a gene of interest, specifically directing the co-transcribed Cas9 protein to cut at that location, and introducing a double-strand break (DSB) in the DNA. Cells employ a number of different mechanisms to repair DSBs and these can then be exploited for genome editing purposes, allowing researchers to introduce changes to the DNA as it is repaired.

The CRISPR-Cas9 system excels in its simplicity – allowing alterations to be made to the genome much more easily, quickly, and cheaply than ever before, plagued by far fewer off-target effects. It also allows researchers to examine the function of multiple genes at once, where before they were mostly limited to a single gene.

Alisha Siegel

“Cancer genomics has identified a large number of genes that are mutated in human cancer,” Tyler Jacks, Ph.D., director of the Koch Institute for Integrative Cancer Research at MIT, Boston, said in an interview. “CRISPR allows us to study these genes in cancer cells and in whole animals much more efficiently than the methods that were in use just a few years ago.”

But the potential of the CRISPR-Cas9 system doesn’t stop there. “At the moment, a particularly exciting application is the use of this approach to inactive genes in very specific fashion to assess the function of a given protein in a cancer cell, which should speed the identification of proteins that are important for cancer cells and thus potentially aid drug discovery efforts,” Dr. Armstrong said.

CRISPR at AACR

The latest developments in the use of the CRISPR-Cas9 system were highlighted at the annual meeting of the American Association of Cancer Research. Dr. David Sabatini, professor of biology at MIT, Boston, described his own lab’s method for using CRISPR-Cas9 to seek out the essential genes involved in different types of cancers. In a study recently published in Science, he and his colleagues employed this method in chronic myelogenous leukemia and Burkitt’s lymphoma cell lines. The gRNA library targeted just over 18,000 genes and roughly 10% of these proved to be essential. Mostly, these genes were linked to key cellular processes (Science 2015;350[6264]:1096-1101).

Dr. Christopher Vakoc of Cold Spring Harbor (N.Y.) Laboratory, presented a slightly different kind of CRISPR screen for drug targets. Most commonly, CRISPR introduces edits at the start of the gene, which may or may not change the DNA enough to produce a nonfunctional protein. Dr. Vakoc’s lab has developed a system that instead edits functional protein domains, which present ideal drug targets. Mutated domains can be identified that are essential for cancer cell survival and small molecule inhibitors designed that bind to them to kill cancer cells.

The technique has already been used to identify such a domain on the BRD4 protein and inhibitors that bind to this domain had significant antitumor activity in leukemia, Dr. Vakoc reported. A screen targeting 192 chromatin regulatory domains expressed in mouse acute myeloid leukemia cells was subsequently performed and identified 25 domains that impacted survival, 6 that are already being therapeutically targeted, and 19 novel potential targets.

Another development in CRISPR-Cas9 technology creates an inactive version of the Cas9 enzyme, one that has lost the ability to cut DNA. Though it seems counterintuitive, this has opened up a wealth of new possible uses. Jonathan S. Weissman, Ph.D., professor of cellular and molecular pharmacology, University of California, San Francisco, part of the group to develop this ‘dead’ Cas9 (dCas9), published a description of the use of two new tools dubbed CRISPR interference and CRISPR activation (Cell 2013;152[5]:1173-83).

Essentially, by fusing dCas9 with different proteins, such as epigenetic modifiers or transcriptional activators or repressors, it can be used as a delivery system to fine-tune gene expression, instead of editing the gene sequence.

Treating cancer?

Ultimately, CRISPR-Cas9 could be used to treat cancers by cutting out defective genes and replacing them with a wild-type version, or by repairing mutations, though for the time being this is theoretical. Studies have suggested it is possible with other types of diseases, however.

“It is not clear exactly how the CRISPR system would be used to directly treat cancer, but the discoveries that come from its use will likely lead to new ways to treat cancer,” said Dr Armstrong.

Dr Jacks highlighted the technical challenges that will need to be overcome first. “In principle, CRISPR-based genome editing could be used to correct cancer-causing mutations in tumors in vivo or to inactivate activated cancer genes,” he said. “At this point, however, we lack the technology necessary to deliver the CRISPR system to all cancer cells in the body. Improvements in this so-called ‘delivery problem’ may allow CRISPR to become a powerful anticancer therapy strategy.”

CRISPR technology, a simple, yet incredibly powerful tool for genetic engineering, is not only allowing cancer researchers to screen for drug targets more efficiently, but is also opening the door for direct cancer treatment through gene interference or activation.

“The pace at which this technology is developing is astounding and almost every cancer research lab is now using some version of it in their studies,” Dr. Scott A. Armstrong, director of Memorial Sloan Kettering Leukemia Center, New York, said in an interview.

Ancient defense mechanism

While the term CRISPR is now synonymous with the editing of human genes, it actually refers to a sort of primitive immune system used by bacteria for billions of years. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, but the complex terminology belies an elegantly simple mechanism by which bacterial cells destroy invading pathogens.

The bacterial genome contains regions with short repetitive stretches of DNA that are separated by spacers. Researchers made the startling discovery that the spacers are often composed of bits of foreign DNA and it transpired that bacteria use it as a molecular memory of prior infection.

When the same pathogen is encountered again, the stretches of repeats and spacers are transcribed to form CRISPR RNAs (crRNA). Together with a transactivating RNA (tracrRNA), it forms a kind of GPS system for a series of CRISPR-associated (Cas) proteins that function like molecular scissors, destroying the target DNA sequence in the invader’s genome.

There are three CRISPR systems – type I, II, and III – that are associated with different sets of Cas proteins and each employ unique methods for achieving the same ultimate function. The type II system that pairs with Cas9 has received the most attention.

Cut and paste gene editing

The discovery that CRISPR could be exploited as a tool for genetic manipulation in mammalian cells sparked a revolution in the genome editing field. “The CRISPR-Cas9 system has been adapted to specifically edit the genomes of mammalian cells, allowing one to make targeted changes to almost any gene,” Dr. Armstrong said.

The use of CRISPR-Cas9 as a genome editing tool is simplified by joining the crRNA and tracrRNA together so they are transcribed in a single guide RNA (gRNA). The GPS coordinates of the gRNA can be preprogrammed to target a gene of interest, specifically directing the co-transcribed Cas9 protein to cut at that location, and introducing a double-strand break (DSB) in the DNA. Cells employ a number of different mechanisms to repair DSBs and these can then be exploited for genome editing purposes, allowing researchers to introduce changes to the DNA as it is repaired.

The CRISPR-Cas9 system excels in its simplicity – allowing alterations to be made to the genome much more easily, quickly, and cheaply than ever before, plagued by far fewer off-target effects. It also allows researchers to examine the function of multiple genes at once, where before they were mostly limited to a single gene.

Alisha Siegel

“Cancer genomics has identified a large number of genes that are mutated in human cancer,” Tyler Jacks, Ph.D., director of the Koch Institute for Integrative Cancer Research at MIT, Boston, said in an interview. “CRISPR allows us to study these genes in cancer cells and in whole animals much more efficiently than the methods that were in use just a few years ago.”

But the potential of the CRISPR-Cas9 system doesn’t stop there. “At the moment, a particularly exciting application is the use of this approach to inactive genes in very specific fashion to assess the function of a given protein in a cancer cell, which should speed the identification of proteins that are important for cancer cells and thus potentially aid drug discovery efforts,” Dr. Armstrong said.

CRISPR at AACR

The latest developments in the use of the CRISPR-Cas9 system were highlighted at the annual meeting of the American Association of Cancer Research. Dr. David Sabatini, professor of biology at MIT, Boston, described his own lab’s method for using CRISPR-Cas9 to seek out the essential genes involved in different types of cancers. In a study recently published in Science, he and his colleagues employed this method in chronic myelogenous leukemia and Burkitt’s lymphoma cell lines. The gRNA library targeted just over 18,000 genes and roughly 10% of these proved to be essential. Mostly, these genes were linked to key cellular processes (Science 2015;350[6264]:1096-1101).

Dr. Christopher Vakoc of Cold Spring Harbor (N.Y.) Laboratory, presented a slightly different kind of CRISPR screen for drug targets. Most commonly, CRISPR introduces edits at the start of the gene, which may or may not change the DNA enough to produce a nonfunctional protein. Dr. Vakoc’s lab has developed a system that instead edits functional protein domains, which present ideal drug targets. Mutated domains can be identified that are essential for cancer cell survival and small molecule inhibitors designed that bind to them to kill cancer cells.

The technique has already been used to identify such a domain on the BRD4 protein and inhibitors that bind to this domain had significant antitumor activity in leukemia, Dr. Vakoc reported. A screen targeting 192 chromatin regulatory domains expressed in mouse acute myeloid leukemia cells was subsequently performed and identified 25 domains that impacted survival, 6 that are already being therapeutically targeted, and 19 novel potential targets.

Another development in CRISPR-Cas9 technology creates an inactive version of the Cas9 enzyme, one that has lost the ability to cut DNA. Though it seems counterintuitive, this has opened up a wealth of new possible uses. Jonathan S. Weissman, Ph.D., professor of cellular and molecular pharmacology, University of California, San Francisco, part of the group to develop this ‘dead’ Cas9 (dCas9), published a description of the use of two new tools dubbed CRISPR interference and CRISPR activation (Cell 2013;152[5]:1173-83).

Essentially, by fusing dCas9 with different proteins, such as epigenetic modifiers or transcriptional activators or repressors, it can be used as a delivery system to fine-tune gene expression, instead of editing the gene sequence.

Treating cancer?

Ultimately, CRISPR-Cas9 could be used to treat cancers by cutting out defective genes and replacing them with a wild-type version, or by repairing mutations, though for the time being this is theoretical. Studies have suggested it is possible with other types of diseases, however.

“It is not clear exactly how the CRISPR system would be used to directly treat cancer, but the discoveries that come from its use will likely lead to new ways to treat cancer,” said Dr Armstrong.

Dr Jacks highlighted the technical challenges that will need to be overcome first. “In principle, CRISPR-based genome editing could be used to correct cancer-causing mutations in tumors in vivo or to inactivate activated cancer genes,” he said. “At this point, however, we lack the technology necessary to deliver the CRISPR system to all cancer cells in the body. Improvements in this so-called ‘delivery problem’ may allow CRISPR to become a powerful anticancer therapy strategy.”

CRISPR technology, a simple, yet incredibly powerful tool for genetic engineering, is not only allowing cancer researchers to screen for drug targets more efficiently, but is also opening the door for direct cancer treatment through gene interference or activation.

“The pace at which this technology is developing is astounding and almost every cancer research lab is now using some version of it in their studies,” Dr. Scott A. Armstrong, director of Memorial Sloan Kettering Leukemia Center, New York, said in an interview.

Ancient defense mechanism

While the term CRISPR is now synonymous with the editing of human genes, it actually refers to a sort of primitive immune system used by bacteria for billions of years. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, but the complex terminology belies an elegantly simple mechanism by which bacterial cells destroy invading pathogens.

The bacterial genome contains regions with short repetitive stretches of DNA that are separated by spacers. Researchers made the startling discovery that the spacers are often composed of bits of foreign DNA and it transpired that bacteria use it as a molecular memory of prior infection.

When the same pathogen is encountered again, the stretches of repeats and spacers are transcribed to form CRISPR RNAs (crRNA). Together with a transactivating RNA (tracrRNA), it forms a kind of GPS system for a series of CRISPR-associated (Cas) proteins that function like molecular scissors, destroying the target DNA sequence in the invader’s genome.

There are three CRISPR systems – type I, II, and III – that are associated with different sets of Cas proteins and each employ unique methods for achieving the same ultimate function. The type II system that pairs with Cas9 has received the most attention.

Cut and paste gene editing

The discovery that CRISPR could be exploited as a tool for genetic manipulation in mammalian cells sparked a revolution in the genome editing field. “The CRISPR-Cas9 system has been adapted to specifically edit the genomes of mammalian cells, allowing one to make targeted changes to almost any gene,” Dr. Armstrong said.

The use of CRISPR-Cas9 as a genome editing tool is simplified by joining the crRNA and tracrRNA together so they are transcribed in a single guide RNA (gRNA). The GPS coordinates of the gRNA can be preprogrammed to target a gene of interest, specifically directing the co-transcribed Cas9 protein to cut at that location, and introducing a double-strand break (DSB) in the DNA. Cells employ a number of different mechanisms to repair DSBs and these can then be exploited for genome editing purposes, allowing researchers to introduce changes to the DNA as it is repaired.

The CRISPR-Cas9 system excels in its simplicity – allowing alterations to be made to the genome much more easily, quickly, and cheaply than ever before, plagued by far fewer off-target effects. It also allows researchers to examine the function of multiple genes at once, where before they were mostly limited to a single gene.

Alisha Siegel

“Cancer genomics has identified a large number of genes that are mutated in human cancer,” Tyler Jacks, Ph.D., director of the Koch Institute for Integrative Cancer Research at MIT, Boston, said in an interview. “CRISPR allows us to study these genes in cancer cells and in whole animals much more efficiently than the methods that were in use just a few years ago.”

But the potential of the CRISPR-Cas9 system doesn’t stop there. “At the moment, a particularly exciting application is the use of this approach to inactive genes in very specific fashion to assess the function of a given protein in a cancer cell, which should speed the identification of proteins that are important for cancer cells and thus potentially aid drug discovery efforts,” Dr. Armstrong said.

CRISPR at AACR

The latest developments in the use of the CRISPR-Cas9 system were highlighted at the annual meeting of the American Association of Cancer Research. Dr. David Sabatini, professor of biology at MIT, Boston, described his own lab’s method for using CRISPR-Cas9 to seek out the essential genes involved in different types of cancers. In a study recently published in Science, he and his colleagues employed this method in chronic myelogenous leukemia and Burkitt’s lymphoma cell lines. The gRNA library targeted just over 18,000 genes and roughly 10% of these proved to be essential. Mostly, these genes were linked to key cellular processes (Science 2015;350[6264]:1096-1101).

Dr. Christopher Vakoc of Cold Spring Harbor (N.Y.) Laboratory, presented a slightly different kind of CRISPR screen for drug targets. Most commonly, CRISPR introduces edits at the start of the gene, which may or may not change the DNA enough to produce a nonfunctional protein. Dr. Vakoc’s lab has developed a system that instead edits functional protein domains, which present ideal drug targets. Mutated domains can be identified that are essential for cancer cell survival and small molecule inhibitors designed that bind to them to kill cancer cells.

The technique has already been used to identify such a domain on the BRD4 protein and inhibitors that bind to this domain had significant antitumor activity in leukemia, Dr. Vakoc reported. A screen targeting 192 chromatin regulatory domains expressed in mouse acute myeloid leukemia cells was subsequently performed and identified 25 domains that impacted survival, 6 that are already being therapeutically targeted, and 19 novel potential targets.

Another development in CRISPR-Cas9 technology creates an inactive version of the Cas9 enzyme, one that has lost the ability to cut DNA. Though it seems counterintuitive, this has opened up a wealth of new possible uses. Jonathan S. Weissman, Ph.D., professor of cellular and molecular pharmacology, University of California, San Francisco, part of the group to develop this ‘dead’ Cas9 (dCas9), published a description of the use of two new tools dubbed CRISPR interference and CRISPR activation (Cell 2013;152[5]:1173-83).

Essentially, by fusing dCas9 with different proteins, such as epigenetic modifiers or transcriptional activators or repressors, it can be used as a delivery system to fine-tune gene expression, instead of editing the gene sequence.

Treating cancer?

Ultimately, CRISPR-Cas9 could be used to treat cancers by cutting out defective genes and replacing them with a wild-type version, or by repairing mutations, though for the time being this is theoretical. Studies have suggested it is possible with other types of diseases, however.

“It is not clear exactly how the CRISPR system would be used to directly treat cancer, but the discoveries that come from its use will likely lead to new ways to treat cancer,” said Dr Armstrong.

Dr Jacks highlighted the technical challenges that will need to be overcome first. “In principle, CRISPR-based genome editing could be used to correct cancer-causing mutations in tumors in vivo or to inactivate activated cancer genes,” he said. “At this point, however, we lack the technology necessary to deliver the CRISPR system to all cancer cells in the body. Improvements in this so-called ‘delivery problem’ may allow CRISPR to become a powerful anticancer therapy strategy.”

The pace of drug development for multiple myeloma was dizzying in 2015, with 5 regulatory approvals for the treatment of relapsed/refractory disease, 3 in a single month. As we stand on the brink of another paradigm shift in the management of this disease, we discuss the new classes of drugs and how they are shaping standard of care with the potential to make multiple myeloma a chronic disease.

Click on the PDF icon at the top of this introduction to read the full article.

The pace of drug development for multiple myeloma was dizzying in 2015, with 5 regulatory approvals for the treatment of relapsed/refractory disease, 3 in a single month. As we stand on the brink of another paradigm shift in the management of this disease, we discuss the new classes of drugs and how they are shaping standard of care with the potential to make multiple myeloma a chronic disease.

Click on the PDF icon at the top of this introduction to read the full article.

The pace of drug development for multiple myeloma was dizzying in 2015, with 5 regulatory approvals for the treatment of relapsed/refractory disease, 3 in a single month. As we stand on the brink of another paradigm shift in the management of this disease, we discuss the new classes of drugs and how they are shaping standard of care with the potential to make multiple myeloma a chronic disease.

Click on the PDF icon at the top of this introduction to read the full article.