Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites. In vivo, we show enhanced expansion and CAR T cell antitumor efficacy, culminating in improvement in survival in a syngeneic model of ovarian peritoneal carcinomatosis. Armored CAR T cells mediated depletion of tumor associated macrophages and resisted endogenous PD-L1-induced inhibition. These findings highlight the role of the inhibitory microenvironment and how CAR T cells can be further engineered to maintain efficacy.

Macrophage targeting: opening new possibilities for cancer immunotherapy

“…As macrophage depletion by clodronate treatment significantly prolongs overall survival of tumour‐bearing mice treated with the IL‐12‐expressing CAR‐T cells, these results suggest that co‐expression of IL‐12 intensifies the therapeutic potential of CAR‐T cells by depletion of TAM in addition to the augmentation of CAR‐T‐cell cytotoxic capacity (Fig. c) . Although IL‐12 armoured CAR‐T cells deplete TAM via an indirect mechanism, it is suggested that genetic manipulation of T cells to express TAM‐specific CAR can directly eliminate TAM in the tumours.…”

“…c) . Although IL‐12 armoured CAR‐T cells deplete TAM via an indirect mechanism, it is suggested that genetic manipulation of T cells to express TAM‐specific CAR can directly eliminate TAM in the tumours. In the ID8 ovarian cancer model, TAM in peritoneal tumour ascites expresses a high level of folate receptor β (FR β ) and adoptive transfer of FR β ‐specific CAR‐T cells into the tumour‐bearing mice results in destruction of TAMs and delayed tumour growth (Fig.…”

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 .…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[105][106][107][108][109][110] Accordingly, RCD can no longer be perceived as immunogenic when: (1) the intracellular stress responses regulating the emission of ICD-associated DAMPs are pharmacologically or genetically ablated in cancer cells; or (2) when the molecular machinery dedicated to DAMP detection is inhibited or ablated. 13,44,84,91,93,97 Moreover, ICD-driven immunity can no longer operate in the presence of general immunological defects, 111 such as (1) an intrinsically low antigenicity of cancer cells, owing to low levels of TAAs or downregulation of MHC Class I molecules [112][113][114][115][116][117][118][119] ; (2) an increased immunological tolerance of the host, secondary to increased amounts of immunosuppressive cytokines, [120][121][122][123][124][125][126][127][128] or inhibitors of chemotaxis, [129][130][131][132][133][134] increased tumor infiltration by immunosuppressive cell populations, [135][136][137][138][139][140]…”