310 Engineering optimal CAR T cells to overcome pancreatic tumors with secreted antagonistic peptides

• DOI: 10.1136/jitc-2022-sitc2022.0310
• Publication Date: 2022-11-08T00:53:21Z
• Authors: Heather Lin; Ruby Freeman; Alysa Evans; Tenzin Passang Fnu; Tongrui Liu; Elyse Christensen; Raymond Fei; Tanisha Sinha; Sruthi Ravindrana...; Lily Yang; Edmund Waller; Sarwish Rafiq
• Keywords: Ectodomain; Pancreatic tumor

<h3>Background</h3> Chimeric antigen receptor (CAR) T cell therapies have shown remarkable clinical efficacy in hematological cancers, but still face significant obstacles the treatment of solid tumors such as pancreatic ductal adenocarcinoma (PDAC). Two hurdles developing effective CAR for PDAC are identification ideal tumor-associated antigens (TAA) to target and overcoming a complex tumor microenvironment (TME). We hypothesize that optimal treat both recognizes an TAA is protected from immune suppression TME. Here, we propose ectodomain Muc16 (Muc16CD) viable expressed (figure 1) antagonizing vasoactive intestinal peptide (VIP), immunosuppressive neuropeptide,^1,2 overcome <h3>Methods</h3> cells were generated specifically Muc16CD express novel, potent VIP (VIPR) antagonist (antVIPR) peptide.³ assayed vitro vivo against human VIP-expressing lines (Panc1) PDX lines. <h3>Results</h3> first patient-derived xenograft (PDX) expression establish relevance these targets 1). Interestingly, despite modest on lines, anti-Muc16CD had cytotoxic function <i>in vitro</i> reduced burden mice engrafted with orthotopic tumors. Next, investigated whether function. limits proliferative capacity cells, which can be reversed by VIPR peptides. therefore engineered novel antVIPR-secreting provide continuous localized delivery antVIPR peptides within AntVIPR impacts their phenotype improved viability less VIPRs at baseline. Functionally, advantage after antigen-stimulation enhanced activation compared parental cells. Finally, reduces improve overall survival bearing 2). <h3>Conclusions</h3> Collectively, this data demonstrates combination targeting anti-tumor PDAC. Ongoing experiments determining mechanisms locally secreted antagonists modulate TME using syngeneic mouse model long-term goal translating <h3>Acknowledgements</h3> The authors thank healthy volunteers patients blood samples. also shared resources Emory University, namely Pediatrics/Winship Flow Cytometry Core (ECFCC) provided services or instruments subsidized cost conduct some reported experiments. <h3>References</h3> Delgado M, Ganea D. Vasoactive peptide: neuropeptide pleiotropic functions. <i>Amino Acids</i>. 2013; <b>45</b>: 25-39. Ravindranathan S, <i>et al</i>. 819 Targeting signaling: approach enhance response adenocarcinoma. <i>J Immunother Cancer</i>. 2020; <b>8</b>: A489. Fnu TP, Li J, Waller EK. Inhibition signaling more inhibitors augments T-cell prolongs leukemic mice. <i>Blood</i>. 2021; <b>138</b>: 1868.