Chimeric antigen receptor T-cell therapies for lymphoma

Abstract

New therapies are needed for patients with Hodgkin or non-Hodgkin lymphomas that are resistant to standard therapies. Indeed, unresponsiveness to standard chemotherapy and relapse after autologous stem-cell transplantation are indicators of an especially poor prognosis. Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment modality for these patients. Clinical trial data have demonstrated the potent activity of anti-CD19 CAR T cells against multiple subtypes of B-cell lymphoma, including diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, and marginal-zone lymphoma. Importantly, anti-CD19 CAR T cells have impressive activity against chemotherapy-refractory lymphoma, inducing durable complete remissions lasting >2 years in some patients with refractory DLBCL. CAR-T-cell therapies are, however, associated with potentially fatal toxicities, including cytokine-release syndrome and neurological toxicities. CAR T cells with novel target antigens, including CD20, CD22, and κ-light chain for B-cell lymphomas, and CD30 for Hodgkin and T-cell lymphomas, are currently being investigated in clinical trials. Centrally manufactured CAR T cells are also being tested in industry-sponsored multicentre clinical trials, and will probably soon become a standard therapy. Herein, we review the clinical efficacy and toxicity of CAR-T-cell therapies for lymphoma, and discuss their limitations and future directions with regard to toxicity management, CAR designs and CAR-T-cell phenotypes, conditioning regimens, and combination therapies.

Figure 1:. Chimeric antigen receptor structure

1a. A diagram is shown of a second-generation CAR, including a single chain variable region (scFv), hinge and transmembrane regions, a costimulatory domain, and a T-cell activation domain. 1b. First generation CARs incorporate a T-cell activation domain but lack a costimulatory domain. Second generation CARs include both a T-cell activation domain and a single costimulatory domain. In this example the costimulatory domain is either CD28 or 4–1BB. Third generation CARs incorporate two costimulatory domains, as well as a T-cell activation domain.

Figure 2:. Improvements to CAR T-cell therapy.

CAR T-cell therapy is being improved at multiple steps in the overall CAR T-cell therapy process. Areas of improvement include modifications in all aspects of CAR design, incorporation of different genes to enhance CAR T-cell activity or control toxicity into CAR gene therapy vectors, use of gene-editing technologies such as CRISPR/Cas9, changes to cell culture methods, optimization of conditioning regimens, and the addition of post-infusion pharmacologic agents.