Background/Purpose: The clinical application of CAR-T therapy remains limited by its dependence on lymphodepleting chemotherapy. Although cytokine support can enhance CAR T cell persistence and improve survival in lymphoreplete environments, constitutive cytokine exposure may disrupt immune homeostasis. Therefore, strategies that provide beneficial cytokine signaling in a controlled, cell-intrinsic manner are needed.

Methods: We performed an unbiased screen of 19 non-common γ-chain cytokines to identify cytokines capable of enhancing CAR T cell antitumor activity. Based on the screening results, synthetic cytokine receptors were engineered to deliver intracellular signaling without systemic cytokine administration. CAR T cells expressing a constitutively active GP130 receptor were evaluated for STAT signaling, antitumor activity, in vivo expansion, and therapeutic efficacy in non-human primates under no-lymphodepletion and in patients with systemic lupus erythematosus with lupus nephritis under reduced-intensity lymphodepletion.

Results: IL-27, IL-10, and IL-4 were identified as enhancers of CAR T cell antitumor activity. CAR T cells expressing constitutively active GP130 showed enhanced STAT1/3 activation similar to IL-27 stimulation and demonstrated superior antitumor activity. In non-human primates, autologous cGP130-armored CAR T cells expanded robustly and induced sustained B cell aplasia without lymphodepletion, whereas control CAR T cells failed to engraft. In patients with systemic lupus erythematosus with lupus nephritis, cGP130-armored universal CAR T cells expanded markedly in vivo under cyclophosphamide-only reduced-intensity lymphodepletion without fludarabine and induced clinical complete remission, with manageable dose-dependent toxicity.

Conclusion: Synthetic cytokine receptor armoring enables CAR T cell engraftment, persistence, and therapeutic efficacy without conventional lymphodepletion. This strategy offers a promising approach to broaden the clinical application of CAR-T therapy in both oncology and autoimmune diseases.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/induction-of-b-cell-aplasia-with-cgp130-armored-car-t-cells-without-lymphodepletion/