Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System

Abstract

SUMMARY Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CART cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy.

Mechanisms of resistance to CAR T cell therapy

“…Armoured CAR T cells that constitutively secrete pro-inflammatory cytokines as a mechanism to overcome local immunosuppression are a novel concept. Similarly, incorporation of immune-checkpoint inhibition into CAR T cell-based strategies, by various combinatorial or built-in approaches, might improve responses 98 ; the findings of several preclinical studies support the effectiveness of this approach, warranting further clinical translation 98,152,159,160 .…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Conversely, other investigators are testing dual constructs requiring both targets to be expressed on tumor cells in order to exert their cytotoxic activity (114) and inhibitory CARs able to redirect T cells activity from healthy tissues (115), with the aim of increasing CAR specificity and of preventing off-tumor side effects. Furthermore, many efforts are being made to optimize co-stimulatory molecules and to improve the structure of CARs (116), and new constructs able to locally deliver immune-modulating cytokines (117)(118)(119)(120), bearing modified cytokine receptors (121) or targeting tumor matrix components (122,123) are being developed to overcome environmental barriers. Some groups are also exploring the possibility of combing CAR T cells with oncolytic viruses (124) or with checkpoint inhibitors (125)(126)(127).…”

Advances in Chimeric Antigen Receptor T‐Cell Therapies for Solid Tumors

“…These armored CAR T cells promoted the expansion of NK cells, NK T cells, DCs, and endogenous CD8 + T cells. There were also more proinflammatory M1 macrophages present . IL‐18 functions in tandem with TCR signaling, so it was important to determine if IL‐18–mediated antitumor efficacy was the result of nonspecific, endogenous TCR activation of the CAR T cells or if the CAR was sufficient to produce the observed IL‐18 response.…”

“…There were also more proinflammatory M1 macrophages present. 34 IL-18 functions in tandem with TCR signaling, so it was important to determine if IL-18-mediated antitumor efficacy was the result of nonspecific, endogenous TCR activation of the CAR T cells or if the CAR was sufficient to produce the observed IL-18 response. Hu et al 35 used TCR knockout CAR T cells to demonstrate that the IL-18-mediated effects were maintained by the signaling through the CAR.…”