Effect of camelid B7-H3 tri-specific killer engagers on natural killer cells in patients with prostate cancer.

• DOI: 10.1200/jco.2024.42.4_suppl.155
• Publication Date: 2024-01-29T21:06:41Z
• Authors: Nicholas Zorko; Madison Shackelford; Asha Bozicevich; Joshua Walker; Peter Hinderlie; Gwen Phung; Melissa Khaw; Jacobi Rugloski; Amanda Russell; Yvette Soignier; Laura Kotz; Laura Bendzick; Justin Hwang; Emmanuel S. Anton...; Martin Felices; Jeffrey S. Miller
• Keywords: 03 medical and health sciences; 0302 clinical medicine

155 Background: Recombinant human (rh) IL-15, the homeostatic factor for natural killer (NK) cells, is being clinically developed, but it has little antitumor activity alone. B7H3 (CD276) an immune checkpoint inhibitor that associated with poorer prognosis and highly-expressed on prostate cancer. NK cells can be given as allogeneic products and, unlike T do not induce cytokine-release syndrome or neurotoxicity. Here we developed a targeting Tri-Specific Killer Engager (TriKE) novel dual camelid (cam) TriKE containing WT IL-15 two cam engagers CD16 tumor targets, making antigen specific. We have previously demonstrated infiltrate cancer tumors. As proof of concept, clinical trial CD33-targeted AML (NCT03214666) induced endogenous cell expansion activation in refractory patients. Methods: Prostate lines patient-derived xenografts (PDX) were incubated healthy donor patient without TriKE. PDX propagated NSG mice then homogenized vitro assays. function was measured by flow cytometry IncuCyte live imaging Castration-sensitive -resistant (CSPC CRPC, respectively) normal peripheral blood mononuclear (PBMC) immunophenotyped using 42-marker specific broad time-of-flight (CyToF) panels. Results: resulted dose-dependent proliferation cells. This marked contrast to rhIL-15, which stimulated both types. camB7H3 broadly expressed prostate, head neck, ovarian glioblastoma cancers well multiple myeloma. observed increase CD107a degranulation inflammatory cytokines all positive targets highly specific, no response seen negative hematologic CRISPR KO controls. Compared at molar equivalent dosing B7H3+ target killing manner above rhIL-15 cytotoxicity. Using CSPC CRPC PBMC (n=11-15), there significant loss degranulation/interferon gamma production cytotoxicity compared age- sex-matched donors when treated CyToF analysis ongoing. In vivo xenogeneic models underway. Conclusions: delivers specific signal expand against PDX. Clinical-grade undergoing validation Phase 1/2 planned open 3rd Quarter 2024 patients progressing one more therapies setting.