To augment anti-PD-1 efficacy safely with IL-2, Ren and Zhang et al. engineered a fusion protein (PD-1–laIL-2) by combining anti-PD-1 with low affinity IL-2, resulting in avidity-enhanced binding of IL-2 to PD-1+CD8+ TILs and low to no binding to peripheral/intratumoral Tregs and other peripheral T cell populations. PD-1–laIL-2 significantly improved tumor control with lower toxicity, induced a CD8+ T cell-dependent memory response, and promoted proliferation, differentiation, and reactivation of dysfunctional, tumor-specific PD-1+TIM3+CD8+ TILs. These results suggest targeting IL-2 binding to tumor-specific PD-1+ TILs can regress tumors safely and overcome resistance.
Contributed by Katherine Turner
ABSTRACT: PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti-PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti-PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti-PD-1-induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. PD-1-laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1-laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1-laIL-2. Collectively, these results highlight that PD-1-laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.
Author Info: (1) Department of Pathology. (2) Department of Pathology. (3) Department of Pathology. Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, and. (4) Departmen
Author Info: (1) Department of Pathology. (2) Department of Pathology. (3) Department of Pathology. Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, and. (4) Department of Pathology. (5) Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA. (6) Department of Pathology. (7) Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA. (8) Department of Pathology. Department of Basic Medical Science, Tsinghua University, Beijing, China.
