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Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.
Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.
The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.
“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”
Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.
Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.
Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.
When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.
Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).
To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.
The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.
Next steps
A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.
Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.
She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.
The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.
MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.
Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society. 
Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.
Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.
The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.
“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”
Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.
Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.
Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.
When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.
Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).
To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.
The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.
Next steps
A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.
Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.
She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.
The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.
MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.
Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.
Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.
Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.
The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.
“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”
Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.
Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.
Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.
When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.
Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).
To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.
The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.
Next steps
A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.
Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.
She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.
The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.
MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.
Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.