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.

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

“…Savoldo et al 28 simultaneously administered autologous anti-CD19 CAR T cells both without (first-generation) and with (second-generation) an intracellular CD28 costimulatory domain to six patients with relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (B-NHL) without prior lymphodepleting chemotherapy. 11,29,30 4-1BB (CD137) 4-1BB (TNFRSF9, CD137) is an activation-induced T cell costimulatory molecule, first described in 1989. 28 Autologous T cells expressing an anti-CD19 CAR incorporating the intracellular CD28 costimulatory domain (axicabtagene ciloleucel) have been licensed for the treatment of r/r aggressive B-NHL, are associated with very high response rates in the treatment of r/r B-cell acute lymphoblastic leukaemia (B-ALL) and have led to promising results in the treatment of chronic lymphocytic leukaemia and multiple myeloma.…”

CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B-cell lymphomas

“…The first published report of a CD19 CAR-T cell for treatment of lymphoma was in a single heavily pretreated FL patient, who after a conditioning chemotherapy regimen was infused with autologous CD19 CAR-T cells (1 × 10 8 CAR-T cells, followed by 3 × 10 8 CAR-T cells the following day) [44]. This patient achieved a 7 month PR, was retreated with the same therapy and remains progression free 7 years later with no subsequent therapy [45]. Since that time, a …”

Chimeric Antigen Receptor T-cell Therapy for Cancer: A Basic Research-Oriented Perspective

“…For example, CD19 CAR, the most intensively studied scFv-based CAR, targets CD19, which is expressed in normal cells derived from B-cell lineages. Because of this characteristic, CD19 CAR T cells frequently induce on-target off-tumor side effects such as B-cell aplasia, although they also show great potential in suppressing CD19-positive hematologic malignancies [63,64]. Because the simple swapping of scFv can readily redirect T-cell specificity against a new antigen expressed on a target cell surface, numerous scFv-based CARs have been developed for various cancer types.…”