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.
Highlights
Adoptive transfer of chimeric antigen receptor (CAR) T cells is an exciting form of immunotherapy that has garnered interest for the treatment of solid tumor malignancies in recent years
We have described the efficacy of second generation[36] and IL-12 secreting armored[37] CAR T cells directed against the retained portion of Muc-16 (Muc16ecto) on human ovarian cancer cells
We found decreased IL-2 production by 4H1128ζ-IL12 T cells compared to 4H1128ζ (*p = 0.012), consistent with prior reports showing sensitization of T cells to IL-2 in the presence of IL-1238, 39
Summary
Adoptive transfer of chimeric antigen receptor (CAR) T cells is an exciting form of immunotherapy that has garnered interest for the treatment of solid tumor malignancies in recent years. These enhancements include engineering of 1 or 2 additional costimulatory molecules in addition to the CD3ζ signaling domain These “second generation” and “third generation” CARs respectively, have yielded incremental improvements in activation, proliferation and cytotoxicity in various preclinical tumor models[22,23,24], but none of them have translated to gains in clinical trials for solid tumor malignancies. One promising candidate is interleukin-12 (IL-12), a pro-inflammatory cytokine recognized for its ability to enhance the cytotoxic capability of CD8+ cells[26], mitigate antigen-loss tumor escape via recruitment and engagement of macrophages[27], enhance antigen cross presentation and reprogram MDSC’s28, 29 For this reason, exogenous IL-12 therapy has been explored for the treatment of several solid tumor malignancies[30,31,32,33]. Serious toxicities have been described in both preclinical models and clinical applications of IL-1233–35
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