Abstract Background: While TCR-engineered T cell therapies show promise in solid tumors, long-term efficacy is limited by insufficient in vivo expansion and persistence. Current strategies also face significant challenges in manufacturing and clinical management. We present a novel strategy combining low-dose TCR-T cells (Seed) with a TCR-targeted cytokine biologic (Boost) to drive selective in vivo expansion, enhance tumor infiltration, and sustain tumor-specific responses. We demonstrate this by targeting WT1-positive solid tumors using WT1-specific TCR-T cells plus CUE-102, a clinically validated ImmunoSTAT™ fusion protein enabling controlled TCR engagement and delivery of IL-2 to WT1-specific T cells. Methods: We generated a highly specific dual HLA (HLA-A:02:01 and HLA-A:02:07) targeting TCR against the WT137-45 antigen. Preclinical characterization of this TCR, engineered into human primary T cells, included potency assessment against various WT1-positive cancer cell lines and testing for antigen cross-reactivity and HLA alloreactivity. WT1-specific TCR-T cells were combined with CUE-102 to assess specific TCR-T cell expansion, anti-tumor efficacy, tumor infiltration, and long-term efficacy both in vitro and in various xenograft models using WT1-expressing ovarian and pancreatic cell lines. Results: WT1-specific TCR-T cells demonstrated potent in vitro cytotoxicity against HLA-A*02:01 and HLA-A*02:07 WT1-positive cancer cell lines. In addition, we observed a favorable safety profile with no antigen cross-reactivity or HLA alloreactivity. In combination with CUE-102, we observed high potency and sustained anti-tumor cell efficacy at very low effector to target cell ratios and a vigorous selective in vivo expansion of WT1-specific TCR-T cells. In xenograft models of WT1-positive ovarian and pancreatic cancers, the combination therapy led to significantly higher numbers of circulating TCR-T cells, enhanced tumor infiltration, and robust tumor control even at very low TCR-T cell doses, compared to TCR-T cell monotherapy. Furthermore, in animals with higher tumor burden, the combined treatment resulted in sustained tumor regression and significantly extended survival. Conclusion: Our data demonstrate that boosting with CUE-102 triggers robust in vivo expansion and activation of engineered TCR-T cells seed, resulting in effective anti-tumor responses, T cell persistence, and prolonged survival without additional cell engineering. This approach offers a potentially transformative solution for long-term benefits in solid tumor patients and can address cell therapy manufacturing and clinical management challenges by enabling the infusion of fewer seed TCR-T cells, eliminating the need for systemic IL-2 administration, and potentially avoiding toxic conditioning regimens. Citation Format: Kar Wai Tan, Kan Xing Wu, Jin Wei Tan, Melissa Wirawan, Yovita Purwanti, Ana Dios, Fan Zhao, Natasha Girgis, Alessandra Nardin, Evan W. Newell, Anish Suri, Steven N. Quayle, Michael Fehlings. A novel 'Seed-and-Boost' immunotherapy drives potent TCR-T cell expansion, tumor infiltration, and durable tumor control abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3812.
Tan et al. (Fri,) studied this question.