Improving antitumor T cell therapy with membrane-tethered engineered cytokine agonists

Chimeric antigen receptor (CAR) T cell therapy has demonstrated marked success in the control of hematological malignancies. However, the hostile milieu and chronic antigen exposure in the tumor microenvironment contribute to the induction of exhaustion and loss of efficacy of CAR T cells in the treatment of solid tumors. Overcoming T cell exhaustion is essential for improving immunotherapeutic efficacy in the treatment of solid tumors. One strategy focuses on engineering CAR T cells that generate a supportive local immune environment through expression of activation and survival-promoting proteins. Specifically, interleukin-2 (IL2) is an attractive candidate as it is a potent stimulator of proliferation and effector function in T cells. However, the therapeutic application of systemic IL2 is associated with life-threatening complications and T cell exhaustion. To address these toxicities, we have developed membrane-tethered engineered cytokine agonists (MECAs), which are cell-surface constrained proteins that transduce a defined subset of cytokine-mediated signals to promote T cell function without toxicity or T cell exhaustion. Here, we evaluate the influence of MECAs on the proliferation and cytotoxicity of CAR T cells in a glioblastoma-targeting model. IL13Ralpha2-targeting CAR T cells co-expressing the MECAs demonstrated improved cytotoxic function and proliferation in recursive challenge in in vitro models. Preliminary results demonstrate that MECA-expressing CAR T cells are not toxic in an in vivo orthotopic glioma model. Additionally, the CAR T cells co-expressing MECA had greater anti-tumor activity compared to CAR only T cells. Exhaustion of antigen-specific T cells is a central challenge across multiple cancer immunotherapy modalities. The proposed MECAs have the potential to revolutionize immunotherapy by providing effective and widely applicable orthogonal signals that improve the proliferation and effector activity of adoptively transferred CAR T cells.