Immunogenicity of CAR T cells in cancer therapy

Abstract

Patient-derived T cells genetically reprogrammed to express CD19-specific chimeric antigen receptors (CARs) have shown remarkable clinical responses and are commercially available for the treatment of patients with certain advanced-stage B cell malignancies. Nonetheless, several trials have revealed pre-existing and/or treatment-induced immune responses to the mouse-derived single-chain variable fragments included in these constructs. These responses might have contributed to both treatment failure and the limited success of redosing strategies observed in some patients. Data from early phase clinical trials suggest that CAR T cells are also associated with immunogenicity-related events in patients with solid tumours. Generally, the clinical implications of anti-CAR immune responses are poorly understood and highly variable between different CAR constructs and malignancies. These observations highlight an urgent need to uncover the mechanisms of immunogenicity in patients receiving CAR T cells and develop validated assays to enable clinical detection. In this Review, we describe the current clinical evidence of anti-CAR immune responses and discuss how new CAR T cell technologies might impact the risk of immunogenicity. We then suggest ways to reduce the risks of anti-CAR immune responses to CAR T cell products that are advancing towards the clinic. Finally, we summarize measures that investigators could consider in order to systematically monitor and better comprehend the possible effects of immunogenicity during trials involving CAR T cells as well as in routine clinical practice. CD19-specific chimeric antigen (CAR)-modified T cells are approved for patients with advanced-stage forms of certain B cell malignancies. However, a subset of patients will have anti-CAR immune responses, leading to a lack of CAR T cell persistence and a rapid loss of any antitumour efficacy. In this Review, the authors describe the extent of anti-CAR immune responses in patients and suggest measures that could be used to better monitor for these events. Additionally, they describe novel approaches to CAR T cell therapy that might reduce the risk of such responses in the future. Pre-existing and/or treatment-induced immunity to chimeric antigen receptor (CAR) constructs containing mouse-derived single-chain variable fragments are associated with treatment failure in certain patients and might limit the success of redosing strategies. The possible effects of immunogenicity on CAR T cell persistence and function are currently poorly understood. Novel technologies designed to enhance CAR T cell performance and/or the application of allogeneic CAR T cells might further amplify the likelihood of anti-CAR immune responses, thus necessitating strategies to overcome such risks. Various monitoring, mitigation and management approaches can be used to reduce the risk of anti-CAR immunity, although validated assays enabling adequate assessments of anti-CAR immune responses remain an unmet need. We advocate for the inclusion of CAR-associated immunogenicity analysis in both preclinical and clinical investigations of CAR T cell therapy.