CAR Natural Killer Cells Show Promise in Patients With CLL, NHL

In an interview with Oncology Learning Network, Katayoun Rezvani, MD, PhD, Professor of Medicine, University of Texas M.D. Anderson Cancer Center, Houston, spoke about the use of CAR natural killer (NK) cells in patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia (CLL; N Engl J Med. 2020;382[6]:545-553).

Dr Rezvani is Chief of Section of Cellular Therapy in Department of Stem Cell Transplant and Cellular Therapy; Director of Translational Research; and Medical Director of the M.D. Anderson GMP and Cell Therapy Laboratory, University of Texas M.D. Anderson Cancer Center, and was awarded the Sally Cooper Murray Endowed Chair in Cancer Research in 2019.

What existing data led you and your co-investigators to conduct this research?

We were very encouraged by the exciting data on CAR T-cell therapy in lymphoid malignancy published by Carl H. June, MD, at University of Pennsylvania; Michel Sadelain, MD, PhD, at Memorial Sloan Kettering Cancer Center; Steven A. Rosenberg, MD, PhD, at National Institutes of Health, and many other pioneers in the field.

We decided to build on these results to engineer another subset of immune cells, namely NK cells. Unlike commercial CAR T-cells where the product is generated from the patient’s own T-cells and can only be used to treat that patient (an autologous product), CAR NK cells are not patient-specific.

This allows for multiple doses of CAR NK cells to be manufactured from one donor (in our case umbilical cord blood) that can then be used to treat multiple patients. In addition, CAR NK cells appear to have a better toxicity profile, as detailed below.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

We have developed a novel strategy to genetically modify cord blood-derived NK cells to express a CAR, ectopically produce IL-15 to support NK cell proliferation and persistence in vivo, and to express a suicide gene, inducible caspase 9 (iC9), in case of toxicity.

In a phase 1/2 clinical trial, we infused iC9/CAR19/IL15-NK cells after lymphodepleting chemotherapy to 11 patients with relapsed/refractory B-cell lymphoid malignancies. We did not observe any cytokine release syndrome, neurotoxicity or other toxicity associated with the CAR-NK product. Eight of the 11 evaluable patients achieved a response (7 complete remission, 1 partial response). This was associated with in vivo expansion and persistence of CAR-NK cells for up to 12 months post-infusion.

We were highly encouraged by the relative lack of toxicity with CAR NK cells, in particular when compared to other cellular therapies. With other types of CAR therapy, severe toxicities requiring a stay in hospital or even treatment in intensive care have been reported. Our treatment has a great safety profile and can be given as an outpatient.

What are the possible real-world applications of these findings in clinical practice?

While these initial results are encouraging, we need to treat more patient with longer follow up to confirm these data. Our ultimate aim is to add CAR NK cells to the arsenal of therapies against cancer and to give patients more treatment options.

We are working with our commercial partner Takeda Pharmaceutical to develop a large multi-center study with the objective of obtaining FDA approval for our product. We are also working in the lab to develop CAR NK cells for other types of malignancies, such as glioblastoma and breast cancer.