746 Vectorized Treg-depleting anti-CTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject “cold” tumors

Background Immune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, majority of cancer patients including those with poorly immune infiltrated “cold” tumors are resistant currently available ICB therapies. CTLA-4 one few validated targets for ICB, but toxicities linked efficacy in approved anti-CTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At mechanistic level, accumulating preclinical clinical data indicate dual mechanisms anti-CTLA-4; Treg depletion both thought contribute toxicity available, systemic, regimens. Accordingly, strategies deliver highly effective, yet safe, therapies been lacking. Here, BioInvent Transgene present preclinically characterize efficacious potentially safe strategy target the context oncolytic virotherapy. Methods A novel human IgG1 antibody (4-E03) was identified using function-first screening mAbs associated superior depleting activity. tumor-selective Vaccinia vector then engineered encode this novel, strongly Treg-depleting, checkpoint-blocking, GM-CSF (VV GM -ahCTLA4, BT-001). Viruses encoding matching Treg-depleting mouse surrogate were additionally generated, enabling proof-of-concept studies syngeneic competent tumor models. Results Our demonstrate that intratumoral (i.t.) administration VV -aCTLA4 achieved tumor-restricted receptor saturation Treg-depletion, which elicited antigen cross-presentation stronger systemic expansion tumor-specific CD8+ T cells antitumor immunity compared therapy. Efficacy correlated FcgR-mediated Treg-depletion reduction exhausted cells. Remarkably, relevant model blockade, i.t. synergized anti-PD-1 reject tumors. Conclusions findings vivo spatial restriction blocking, vectorized as effective able overcome current limitations trial evaluating -ahCTLA4 (BT-001) alone combination metastatic or advanced solid has commenced. Ethics Approval All experiments by local ethical committee experimental animals (Malmö/Lunds djurförsöksetiska nämnd); at under permit numbers 17196/2018 2934/2020; APAFIS Nr21622 project 2019072414343465 performed accordance guidelines.