CLL patients achieve remission with CAR-modified T-cells

Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved a response in 8 of 14 patients (57%) with advanced chronic lymphocytic leukemia (CLL), of whom 4 experienced a complete remission without relapse, based on the mature results of a small pilot study.

Of these four patients, two have remained free of their disease for up to 4 years after they received treatment. An analysis of blood samples also showed that these modified T cells can multiply and persist in the body for a period of years, the researchers report in a study published Sept. 2 in Science Translational Medicine

“Both patients remain alive and cancer free and just passed the 5-year anniversary of their treatment this summer,” said Dr. David L. Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of blood and marrow transplantation at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “A third patient in remission just passed the 3-year anniversary with no signs of leukemia” (Sci Transl Med. 2015;7:303ra139).

The current study indicates the mature results from this trial, which began in the summer of 2010. In 2011, preliminary findings from the first three patients to enroll in the study were published and showed that two of them had experienced a complete response. Their disease currently remains in remission more than 4 years after beginning treatment. The first patient to receive the therapy has been cancer free for 5 years.

© Ed Uthman/Flickr

In the current trial, 14 patients with relapsed or refractory CLL received at least one infusion of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector. All of the patients had active disease at the time they received the experimental treatment, and had received a median of 5 previous therapies (range, 1-11). One participant had undergone two previous autologous stem cell transplants and one had progressed on ibrutinib therapy.

In addition to those who achieved a complete remission, four other patients (29%) had partial responses to the therapy with responses that persisted for a median of 7 months. Two died of disease progression at 10 and 27 months after receiving CTL019, and one died from a pulmonary embolism; the remaining patient remains alive after CLL progressed at 13 months, and is receiving other therapies.

Overall, the CTL019 infusions were well tolerated, with grade less than 2 toxicities that included primarily low-grade fevers and chills. The most frequent related events were associated with complications of neutropenia and delayed cytokine release syndrome, which correlated with in vivo CTL019 expansion. There were two cases of tumor lysis syndrome, and one patient died in remission 21 months after T cell infusion, after developing ecthyma gangrenosum after pseudomonas infection at a skin biopsy site.

Six subjects (43%) had no response and all six progressed within 1-9 months (median, 4 months) of CTL019 therapy. “We are working hard to determine why this therapy may be appropriate for some patients and not others, and trying to optimize either treatment conditions or patient-specific factors so that this might be more effective for more patients,” Dr. Porter wrote.

Minimal residual disease was not detectable in patients who achieved a complete response, suggesting that disease eradication may be possible in some patients with advanced CLL. The activity of CTLO19 seemed to be on par with results achieved with allogeneic stem cell transplantation, suggesting that this therapy could possibly cure CLL. But Dr. Porter pointed out that this study was conducted with a small number of patients and for CLL, a relatively short follow-up.

“However, these patients all had heavily pretreated resistant disease,” he said. “Though we do not know if patients are indeed cured, it is certainly our goal to find a cure for CLL and without the toxicities and limitations of allogeneic stem cell transplantation. Indeed, longer follow-up will be needed but we are quite excited about the results to date.”

Dr. Porter said he and his team have ongoing trials in CLL in progress, where they are working on trying to identify the optimal dose of T cells for this approach. Also, “this research has led to expansion of this approach to other B cell malignancies such as acute lymphocytic leukemia.”

Novartis, the Leukemia and Lymphoma Society (Specialized Center of Research Award), and the National Institutes of Health funded the study. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some scientists involved in these trials, including Dr. Porter, are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially and/or may benefit financially in the future.

Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved a response in 8 of 14 patients (57%) with advanced chronic lymphocytic leukemia (CLL), of whom 4 experienced a complete remission without relapse, based on the mature results of a small pilot study.

Of these four patients, two have remained free of their disease for up to 4 years after they received treatment. An analysis of blood samples also showed that these modified T cells can multiply and persist in the body for a period of years, the researchers report in a study published Sept. 2 in Science Translational Medicine

“Both patients remain alive and cancer free and just passed the 5-year anniversary of their treatment this summer,” said Dr. David L. Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of blood and marrow transplantation at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “A third patient in remission just passed the 3-year anniversary with no signs of leukemia” (Sci Transl Med. 2015;7:303ra139).

The current study indicates the mature results from this trial, which began in the summer of 2010. In 2011, preliminary findings from the first three patients to enroll in the study were published and showed that two of them had experienced a complete response. Their disease currently remains in remission more than 4 years after beginning treatment. The first patient to receive the therapy has been cancer free for 5 years.

© Ed Uthman/Flickr

In the current trial, 14 patients with relapsed or refractory CLL received at least one infusion of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector. All of the patients had active disease at the time they received the experimental treatment, and had received a median of 5 previous therapies (range, 1-11). One participant had undergone two previous autologous stem cell transplants and one had progressed on ibrutinib therapy.

In addition to those who achieved a complete remission, four other patients (29%) had partial responses to the therapy with responses that persisted for a median of 7 months. Two died of disease progression at 10 and 27 months after receiving CTL019, and one died from a pulmonary embolism; the remaining patient remains alive after CLL progressed at 13 months, and is receiving other therapies.

Overall, the CTL019 infusions were well tolerated, with grade less than 2 toxicities that included primarily low-grade fevers and chills. The most frequent related events were associated with complications of neutropenia and delayed cytokine release syndrome, which correlated with in vivo CTL019 expansion. There were two cases of tumor lysis syndrome, and one patient died in remission 21 months after T cell infusion, after developing ecthyma gangrenosum after pseudomonas infection at a skin biopsy site.

Six subjects (43%) had no response and all six progressed within 1-9 months (median, 4 months) of CTL019 therapy. “We are working hard to determine why this therapy may be appropriate for some patients and not others, and trying to optimize either treatment conditions or patient-specific factors so that this might be more effective for more patients,” Dr. Porter wrote.

Minimal residual disease was not detectable in patients who achieved a complete response, suggesting that disease eradication may be possible in some patients with advanced CLL. The activity of CTLO19 seemed to be on par with results achieved with allogeneic stem cell transplantation, suggesting that this therapy could possibly cure CLL. But Dr. Porter pointed out that this study was conducted with a small number of patients and for CLL, a relatively short follow-up.

“However, these patients all had heavily pretreated resistant disease,” he said. “Though we do not know if patients are indeed cured, it is certainly our goal to find a cure for CLL and without the toxicities and limitations of allogeneic stem cell transplantation. Indeed, longer follow-up will be needed but we are quite excited about the results to date.”

Dr. Porter said he and his team have ongoing trials in CLL in progress, where they are working on trying to identify the optimal dose of T cells for this approach. Also, “this research has led to expansion of this approach to other B cell malignancies such as acute lymphocytic leukemia.”

Novartis, the Leukemia and Lymphoma Society (Specialized Center of Research Award), and the National Institutes of Health funded the study. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some scientists involved in these trials, including Dr. Porter, are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially and/or may benefit financially in the future.

Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved a response in 8 of 14 patients (57%) with advanced chronic lymphocytic leukemia (CLL), of whom 4 experienced a complete remission without relapse, based on the mature results of a small pilot study.

Of these four patients, two have remained free of their disease for up to 4 years after they received treatment. An analysis of blood samples also showed that these modified T cells can multiply and persist in the body for a period of years, the researchers report in a study published Sept. 2 in Science Translational Medicine

“Both patients remain alive and cancer free and just passed the 5-year anniversary of their treatment this summer,” said Dr. David L. Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of blood and marrow transplantation at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “A third patient in remission just passed the 3-year anniversary with no signs of leukemia” (Sci Transl Med. 2015;7:303ra139).

The current study indicates the mature results from this trial, which began in the summer of 2010. In 2011, preliminary findings from the first three patients to enroll in the study were published and showed that two of them had experienced a complete response. Their disease currently remains in remission more than 4 years after beginning treatment. The first patient to receive the therapy has been cancer free for 5 years.

© Ed Uthman/Flickr

In the current trial, 14 patients with relapsed or refractory CLL received at least one infusion of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector. All of the patients had active disease at the time they received the experimental treatment, and had received a median of 5 previous therapies (range, 1-11). One participant had undergone two previous autologous stem cell transplants and one had progressed on ibrutinib therapy.

In addition to those who achieved a complete remission, four other patients (29%) had partial responses to the therapy with responses that persisted for a median of 7 months. Two died of disease progression at 10 and 27 months after receiving CTL019, and one died from a pulmonary embolism; the remaining patient remains alive after CLL progressed at 13 months, and is receiving other therapies.

Overall, the CTL019 infusions were well tolerated, with grade less than 2 toxicities that included primarily low-grade fevers and chills. The most frequent related events were associated with complications of neutropenia and delayed cytokine release syndrome, which correlated with in vivo CTL019 expansion. There were two cases of tumor lysis syndrome, and one patient died in remission 21 months after T cell infusion, after developing ecthyma gangrenosum after pseudomonas infection at a skin biopsy site.

Six subjects (43%) had no response and all six progressed within 1-9 months (median, 4 months) of CTL019 therapy. “We are working hard to determine why this therapy may be appropriate for some patients and not others, and trying to optimize either treatment conditions or patient-specific factors so that this might be more effective for more patients,” Dr. Porter wrote.

Minimal residual disease was not detectable in patients who achieved a complete response, suggesting that disease eradication may be possible in some patients with advanced CLL. The activity of CTLO19 seemed to be on par with results achieved with allogeneic stem cell transplantation, suggesting that this therapy could possibly cure CLL. But Dr. Porter pointed out that this study was conducted with a small number of patients and for CLL, a relatively short follow-up.

“However, these patients all had heavily pretreated resistant disease,” he said. “Though we do not know if patients are indeed cured, it is certainly our goal to find a cure for CLL and without the toxicities and limitations of allogeneic stem cell transplantation. Indeed, longer follow-up will be needed but we are quite excited about the results to date.”

Dr. Porter said he and his team have ongoing trials in CLL in progress, where they are working on trying to identify the optimal dose of T cells for this approach. Also, “this research has led to expansion of this approach to other B cell malignancies such as acute lymphocytic leukemia.”

Novartis, the Leukemia and Lymphoma Society (Specialized Center of Research Award), and the National Institutes of Health funded the study. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some scientists involved in these trials, including Dr. Porter, are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially and/or may benefit financially in the future.