Long-term outcomes following CAR T cell therapy: what we know so far

Abstract

Chimeric antigen receptors (CAR) are engineered fusion proteins designed to target T cells to antigens expressed on cancer cells. CAR T cells are now an established treatment for patients with relapsed and/or refractory B cell lymphomas, B cell acute lymphoblastic leukaemia and multiple myeloma. At the time of this writing, over a decade of follow-up data are available from the initial patients who received CD19-targeted CAR T cells for B cell malignancies. Data on the outcomes of patients who received B cell maturation antigen (BCMA)-targeted CAR T cells for multiple myeloma are more limited owing to the more recent development of these constructs. In this Review, we summarize long-term follow-up data on efficacy and toxicities from patients treated with CAR T cells targeting CD19 or BCMA. Overall, the data demonstrate that CD19-targeted CAR T cells can induce prolonged remissions in patients with B cell malignancies, often with minimal long-term toxicities, and are probably curative for a subset of patients. By contrast, remissions induced by BCMA-targeted CAR T cells are typically more short-lived but also generally have only limited long-term toxicities. We discuss factors associated with long-term remissions, including the depth of initial response, malignancy characteristics predictive of response, peak circulating CAR levels and the role of lymphodepleting chemotherapy. We also discuss ongoing investigational strategies designed to improve the length of remission following CAR T cell therapy. Chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of patients with certain relapsed and/or refractory haematological malignancies. Owing to the promising short-term survival outcomes achieved, long-term data on both safety and survival are becoming increasingly relevant. In this Review, the authors describe the available long-term follow-up data from early studies testing the safety and efficacy of receiving CAR T cells targeting CD19 as well as more recent data on BCMA-targeted CAR T cells in patients with relapsed and/or refractory multiple myeloma. Among haematological malignancies, the indications for use of chimeric antigen receptor (CAR) T cells are rapidly expanding. CD19-targeted CAR T cells are now approved for relapsed and/or refractory B cell lymphoma and B cell acute lymphoblastic leukaemia, and B cell maturation antigen-targeted CAR T cells are approved for relapsed and/or refractory multiple myeloma. Long-term follow-up data indicate that CD19-targeted CAR T cells are likely to be curative for a subset of patients with B cell lymphomas. These CAR T cells might need to be combined with consolidative allogeneic haematopoietic stem cell transplantation to enable long-term remissions for patients with B cell acute lymphoblastic leukaemia. B cell maturation antigen-targeted CAR T cells can induce prolonged remissions in patients with relapsed and/or refractory multiple myeloma, although whether any of these responses are curative remains unclear. Factors associated with durable remission after CAR T cell therapy include a deep initial response, lower baseline tumour volume, an absence of extramedullary disease, higher peak circulating CAR T cell levels and receipt of lymphodepleting chemotherapy. The most prominent long-term toxicities after CAR T cell therapy include cytopenias and hypogammaglobulinaemia. The incidence of severe infections >1 month after CAR T cell therapy is low compared to infections seen in the acute period immediately after cell infusion. Ongoing research efforts are attempting to improve the durability of responses after CAR T cell therapy, for example, through improved patient selection, novel CAR designs, including those targeting multiple antigens, and modifications to the manufacturing process.