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 longterm 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. Sections• 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.

Biomaterials for in situ cell therapy

“…T cell‐based therapy has been approved by the FDA to treat acute lymphoblastic leukemia, lymphoma, and multiple myeloma [24,25] . T cell engineering has opened up new possibilities for personalized medicine, where a patient's T cell can be genetically modified to treat specific diseases [26] .…”

Theranostics on the immunoactivity of T cells

“…Unfortunately, the broad effectiveness of T cell‐based cancer therapy in the clinic is still elusive. Most representative adoptive T‐cell products for solid tumour types exhibit low durable response rates 8,9 . The regulation of T‐cell activity in the tumour microenvironment remains a challenge to improve T cell‐mediated immunotherapy.…”

Engineered yeast cells simulating CD19+ cancers to control CAR T cell activation

“…CD28 or 4-1BB) and ultimately T cell activation (CD3ζ) 3–6 . Since 2017, six FDA approvals on the use of CARs for hematological cancers have been registered 5 . These include anti-CD19 CAR T cells for relapsed or refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) with clinical trials and real-world studies showing complete remission (CR) in 70-96% of patients 7–16 .…”

“…However, while remission rates are encouraging, 14-57% of r/r B-ALL patients obtaining CR from anti-CD19 CAR T cell immunotherapy eventually experience relapse 7–16 . Indeed, the field of CAR T is still emerging, and major challenges need to be mitigated to further improve their safety and efficacy, including mitigation of inhibitory immunosuppression, severe toxicity, CAR T cell trafficking, and target antigen escape 5,6,17 . While some relapses are caused by immunosuppression, exhaustion, or poorly persistent and ineffectual CAR T cells 16,18–20 , others are attributed directly to escape by cancer cell antigen modulation, where CAR T cells may remain functional, but simply lack a targetable antigen 21 .…”

“…While some relapses are caused by immunosuppression, exhaustion, or poorly persistent and ineffectual CAR T cells 16,18–20 , others are attributed directly to escape by cancer cell antigen modulation, where CAR T cells may remain functional, but simply lack a targetable antigen 21 . Such antigen modulation is hypothesized to be a major factor in determining response durability and the dominant mechanism of tumor escape in r/r B-ALL 5,6 , occurring in 7-28% of r/r B- ALL CRs and being associated with poor prognosis 7–12,15,16,22–24 .…”