Discussion
tumor, tumor necrosis, melanoma, fever, breast cancer, toxicity, toxicities, hepatotoxicity, Anaphylaxis, CRS, B-cell hematologic malignancies, neurotoxicity, TNBC, Hodgkin lymphoma, mTNBC, leukemia and lymphoma, tumors
TUMOR, INFILTRATION, TUMOR NECROSIS, MELANOMA, INFLAMMATORY RESPONSE, BREAST CANCER, ADVERSE EVENTS, PROLIFERATION, DISEASE, SOLID TUMORS, ANAPHYLAXIS, MALIGNANCIES, HODGKIN LYMPHOMA, TUMORS, METASTATIC MELANOMA
CAR T-cell therapy can confer effective and durable disease control for patients with B-cell hematologic malignancies. To date, however, CAR T efforts have been less successful in solid tumors due to restricted trafficking to, infiltration of, and activation within tumors, in the context of potentially immunosuppressive microenvironments. Additional challenges include on-target, off-tumor effects due to the presence of tumor-associated antigens in physiologically present tissues. Here, we present a pilot clinical trial of RNA-electroporated T cells expressing a CAR directed against the cMET protein in patients with metastatic melanoma and TNBC. To our knowledge, the current study represents the first published clinical trial of systemic CAR T administration in patients with melanoma and breast cancer.The rationale for selecting this construct was based on the following: first, the cMET antigen was felt to have substantial expression on melanoma and TNBC cells with somewhat limited expression on physiologic tissues; second, an RNA vector was felt to have a lower risk of severe and persistent on-target, off-tumor toxicities as compared with a lentiviral vector, and third, limited available data suggested that the mRNA approach could potentially yield antitumor activity. A prior study of intratumoral cMET CAR T injections demonstrated tumor necrosis and an inflammatory response at the site of therapy without substantial toxicity, specifically hepatotoxicity (Seventy-seven subjects with breast cancer and melanoma consented to tumor prescreening for potential involvement in this CAR T study, demonstrating patients’ interest in, and providers’ support for exploring CAR T approaches, a necessary element for feasibility of CAR T trials in solid tumors. In the current study, the eligibility threshold for cMET expression was 30%, and approximately half of subjects screened met this threshold. The median cMET expression for patients with mTNBC was 35% and the median cMET expression for patients with melanoma was 10%. This is lower than target expression of CAR T therapy targets for hematologic indications; for B-cell hematologic malignancies, a minimum CAR T target antigen expression is not specified since substantial expression is nearly universal. It is possible that either cMET is not an optimal target for CAR T approaches in metastatic melanoma and TNBC, or that the target expression threshold for CAR T approaches in solid tumors may be lower than in leukemia and lymphoma.This pilot study involved systemic administration of RNA-electroporated cMET CAR T without lymphodepleting chemotherapy in six planned infusions over an elapsed 2 weeks. Dose escalation, for example with doses greater than 1 × 10e8 cells or including cohorts with lymphodepleting chemotherapy were not planned as part of this study, given the pilot nature of this trial and the original plan for a lentiviral study that might include such features. This schedule was selected in light of the short-lived RNA construct and it proved feasible, with only 1 patient having five of six planned infusions due to the quantity of manufactured cells. Treatment was also safe, with only grade 1 and grade 2 adverse events that were medically manageable, and no serious adverse events or TLTs. One patient experienced grade 1 CRS, manifested only by low-grade fever that resolved without intervention. No neurotoxicity occurred on study. Anaphylaxis felt to be mediated by the development of human anti-CAR IgE antibodies has been noted after repeated, intermittent mRNA CAR T-cell infusions (In this heavily pretreated population, no responses were seen by either RECIST or irRECIST. PFS and OS were low, with a median PFS of 0.9 months (range: 0.6–1.7 months) and median OS of 4.4 months (range: 1.3–24.7 months). Clinical activity was not seen. It is possible that the lack of treatment response was related to limited trafficking to tumor, given that postinfusion tumor tissue from 5 subjects demonstrated no evidence of cMET CAR. In addition, mRNA CAR T cells have a limited quantity of RNA and there is a dilution of CAR expression upon proliferation, potentially limiting clinical activity. The absence of lymphodepletion may have contributed to lack of efficacy. In a study of patients with Hodgkin lymphoma treated with CD19-directed RNA-electroporated CAR T cells, transient responses were seen; lymphodepleting chemotherapy was administered prior to cell infusion (mRNA signals corresponding to CAR T cells were detected in the peripheral blood of 3 unique subjects on the day following the first infusion and in some patients, on the days of infusion, prior to infusion. However, no such signals were seen in day +25 samples or in available postinfusion tumor tissue. In contrast to CAR engineering using viral vector transduction resulting in genomic integration, CAR expression through RNA electroporation allows for a transiently expressed CAR molecule on the surface of delivered T cells (IHC analysis was performed on 3 subjects who had available paired [preinfusion and postinfusion on day 11 or within 3 days of last CAR T infusion (Consideration was given to expansion of the current clinical trial with additional subjects treated with RNA-electroporated cMET CAR T cells or evaluation of lentiviral cMET CAR T-cell therapy in patients with metastatic TNBC and/or metastatic melanoma. Given the therapeutic landscape in both disease subtypes which broadened over the study period to include additional treatments including checkpoint inhibition, the decision was made to no longer pursue the RNA-electroporated cMET CAR T approach in metastatic TNBC or melanoma. Evaluation using a lentiviral construct may yield improved efficacy. A higher cMET expression threshold may also help to maximize efficacy.This pilot study of RNA electroporated cMET CAR T cells evidences safety of RNA-electroporated cMET CAR T cells and feasibility of the CAR T-cell approach in subjects with advanced solid tumors, and given the promise of CAR T approaches in relapsed liquid malignancies, further study of CAR T-cell therapy in patients with advanced solid tumors is warranted. Thoughtfully selected, highly-expressed, tumor-specific antigens and use of a durable construct may maximize efficacy.