Bypassing NK cell limitations in the tumor microenvironment through novel Poly-Antigen Cytokine Complexes 2287

Abstract Description Immunotherapies are limited by a variety of complex suppressive signals within the tumor microenvironment, including restriction of activating anti-tumor signaling through alteration of the activating receptor repertoire. One such mechanism involves A Disintegrin And Metalloprotease 17 (ADAM17)-mediated shedding of CD16, a potent activating receptor on natural killer (NK) cells that mediates antibody dependent cellular cytotoxicity (ADCC). Our group has been exploiting ADCC for immunotherapy, pre-clinically and clinically, through a Tri-specific Killer Engager (TriKE) platform, which leverages an anti-CD16 arm, an IL-15 moiety, and an anti-tumor antigen arm (B7H3 in this case, expressed in various solid tumors). While the TriKEs display robust pre-clinical activity, in certain tumor settings (like mesothelioma and ovarian cancer) CD16 expression could be limiting, affecting the overall efficacy of the therapy. To bypass this potential issue, we created a Poly-Antigen Cytokine Complex (PACC), consisting of interleukin-15 receptor alpha (IL-15Rα ) linked to an ADAM17-blocking antibody-fragment arm, to noncovalently bind IL-15 in the TriKE molecule, as a backpack, and enhance CD16-mediated NK cell-directed anti-tumor responses against B7H3-expressing solid tumors. Our data shows that the TriKE-PACC molecule complex can prevent CD16 shedding and improve anti-tumor activity in models of mesothelioma and ovarian cancer, indicating the potential translational value of this complex. Funding Sources This work was supported by US Department of Defense HT9425-24-1-0706; NIH/NCI P01 CA111412 and R35 CA283892; and the Randy Shaver Community Fund. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)