A special session on CAR-T future perspectives and beyond took place on 21 March 2018 at the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT). A talk was presented by Professor Katy Rezvani, department of stem cell transplantation and cellular therapy, University of Texas MD Anderson Cancer Center, Houston, about engineered blood-derived chimeric antigen receptor (CAR) natural killer (NK) cells and its application to cancer immunotherapy.
Professor Rezvani began her talk by describing previous studies that have used NK cell immunotherapy in cancers such as leukemia and solid tumors but noted that the results have been quite varied. She added, “the main problem was limited persistence of NK cells, which is to do with the biology of NK cells,” and that “NK cells have a limited life span.” It has therefore become important to understand the limiting factors of using NK cell immunotherapy. Autologous cells tend to be less effective as the NK cells are “dysfunctional” due to their biology however, the logistics of obtaining a donor is more difficult. Finding a donor who is healthy and willing to donate might be a challenge. Additionally, infused NK cells lack antigen-specificity.
Professor Rezvani suggested that a solution for these limitations would be to use off-the-shelf cord blood (CB) as it is “immediately available” from CB banks. CB NK cells can be used as a platform for engineering the cells to make them more functional. For example, the research team at MD Anderson found that the NK cells can be engineered to express a CAR to increase specificity and adding a cytokine would enhance their persistence.
Professor Rezvani described a dose-escalation phase I/II study that assessed CAR-CB NK cells in relapsed / refractory B-lymphoid malignancies such as diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). A total of six patients who were very refractory, including multiple failed lines of previous treatment and complex cytogenetics were included in the study. Two patients had DLBCL, one with double-hit and failed treatment with autologous stem cell transplantation, and four were diagnosed with CLL and had prior ibrutinib treatment failure.
Patients received lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2. Three dose levels (DL) were used ; 1x10e5/kg (DL1), 1x10e6/kg (DL2) and 1x10e7/kg (DL3).
Responses were seen in four out of the six patients. Two had complete responses (CR). One had CR but had persistent marrow disease and so a second CAR-NK infusion was planned. Finally, one patient had near CR. Professor Rezvani noted that, “of the six patients treated, none of the patients developed toxicity including cytokine release syndrome and neurotoxicity”. Higher frequencies of CAR-NK cells and in vivo expansion was seen with DL2 that professor Rezvani said “suggested an antigen-driven expansion”. She added, “we do find some cytokines (at DL1) but they seem to come up late in the patients around 5 weeks which is why they are not getting CRS, which is related to the biology of the NK cells.”
She concluded that “though CAR-T will revolutionize treatment, autologous T-cell products are expensive and restrictive”. Benefits of CB CAR-NK cells would be that there is no risk of graft-versus-host-disease (GvHD) and more than 100 doses of CAR-NK can be generated from one cord unit thus increasing accessibility and reducing cost. She added that CB is a viable source of off-the-shelf NK cells. According to Professor Rezvani, this therapy may be used in the future as an alternative to T-cells and so far the data has been promising.