Abstract 692: Optimized antagonist anti-PD-1/IL-7 bispecific antibody to sustain exhausted T cell function and to disarm Treg suppressive activity

Although anti PD(L)-1 therapy lead to impressive responses, the majority of patient are unresponsive or fail to develop a durable response after treatment. Immunocytokines have the potential to strengthen PD-(L)1 therapy by promoting T cell survival, however, their clinical developments are limited by a shortened half-life and systemic toxicity. To redirect immunotherapy to tumor specific T cells, we propose to selectively deliver IL-7 to PD1+ T cells using a bispecific anti-PD1 fused to IL-7 (BiCKI®IL-7). Intratumoral progenitor exhausted CD8+ T cells (Tpex) coexpressing PD1/IL-7R+ were described as the key subset responsive to anti PD-(L)1; but their efficacies are transient as Tpex rapidly undergo apoptosis limiting the full efficacy of anti-PD-(L)1. BICKI®IL7 was specifically designed to preferentially reinvigorate effector functions of PD1+IL-7R+ tumor-specific T cells, to sustain long-term anti-tumor response and counteract immune resistance in refractory patients. BICKI®IL7 was created by the fusion of a flexible linker and human IL-7 to the Fc portion of a high affinity antagonist anti-PD1 antibody. BICKI®IL7 constructed with wild-type IL-7 exhibited a high binding and potency (pSTAT5 IL-7 signaling) irrespective of PD1 expression. As our goal is to selectively activate the IL-7 signaling into PD1+ T cells but not PD1 negative cells, we fused different IL-7 muteins having 2 to 30,000-fold lower affinity for CD127/CD132 complex. One BICKI®IL7 mutein construction was selected for its loss of potency on PD1- cells and its optimal cis-binding/redirection and cis-activity on PD1+ cells. Furthermore, BICKI®IL7 mutein fully antagonized the PD-L1/2 interactions and inhibitory signaling to a similar extent to the naked anti PD1. Interestingly, BICKI®IL7 mutein synergistically activates TCR signaling while IL-7+anti-PD1 combo has no additive effect. Using a chronic antigen stimulation model, we demonstrated that BICKI®IL-7 efficiently activates and sustains the proliferation of early and fully exhausted T cells, and also confirmed the synergy. In parallel, we also explored the effect of the BICKI®IL7 mutein on Tregs in coculture assay. BICKI®IL7 mutein preferentially stimulated CD8 Teff over Treg as opposed to IL-2 & IL-15 and, also abrogated Treg suppression by restoring Teff IFN-γ secretion and proliferation. In vivo, BICKI®IL-7 mutein enhanced anti-tumor responses in mesothelioma model and promoted the proliferation and generation of memory CD8 T cells to higher extent to anti-PD1 treatment. Taken together, our data validate the therapeutic potential of providing IL-7 signal to strengthen PD1 therapy and prevent immunoresistance by sustaining T cell response and overcoming Treg suppression. The bispecific BiCKI®IL-7 mutein can preferentially deliver and activate IL-7 into PD1+ tumor-specific T cells limiting the risk of I-O/I-O immunotoxicity. Citation Format: Aurore Morello, Justine Durand, Margaux Seite, Virginie Thepenier, Geraldine Teppaz, Emmanuelle Wilhelm, Arianne Desselle, Caroline Mary, Nicolas Poirier. Optimized antagonist anti-PD-1/IL-7 bispecific antibody to sustain exhausted T cell function and to disarm Treg suppressive activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 692.