Improved natural killer cell targeting of prostate carcinoma with ATR inhibitor tuvusertib in combination with IL-15 receptor superagonist N-803 2299576

Abstract

Abstract Introduction Given its role in DNA damage repair, ataxia telangiectasia and Rad3-related (ATR) represents a viable target for cancer therapy with ATR inhibitors (ATRi) demonstrating anticancer activity and synergy with other therapies. We hypothesize that the ATRi tuvusertib could induce immunogenic modulation, thereby sensitizing prostate cancer (PCa) cells to natural killer (NK) cell-mediated lysis. Methods DU145 human PCa cells were treated with tuvusertib (provided by Merck KGaA, Darmstadt, Germany; CrossRef Funder ID: 10.13039/100009945) for 48 hours. Resulting immunogenic changes were evaluated via flow cytometry. PBMC-derived NK cells were exposed to interleukin-15 (IL-15) receptor superagonist N-803 (nogapendekin alfa inbakicept; provided by ImmunityBio, Culver City, CA, USA) overnight. Tuvusertib-treated DU145 were co-cultured with NK cells (untreated or N-803-treated), PD-L1 targeting high-affinity NK (t-haNK) cells (provided by ImmunityBio), or KillerTRAIL. Anti-PD-L1 avelumab or anti-TRAIL antibody was included in select assays. Cell lysis was quantified using impedance-based real-time cell analysis. The efficacy of tuvusertib + N-803 combination therapy was assessed in DU145 tumor-bearing NU/NU mice. Results Increased expression of TRAIL-R2, ULBP-1, and PD-L1 was observed in tuvusertib-exposed DU145. Tuvusertib rendered PCa cells more susceptible to NK-mediated lysis and PD-L1-targeting by avelumab-mediated antibody-dependent cellular cytotoxicity (ADCC) and PD-L1 t-haNK cells. N-803 pretreatment of NK cells further enhanced killing of tuvusertib-treated DU145, while NK-mediated lysis was partially blocked by TRAIL signaling blockade. In the DU145 xenograft model, concurrent tuvusertib and N-803 treatment improved tumor growth inhibition and animal survival. Conclusion Immune-mediated targeting of prostate carcinoma is improved by tuvusertib ATRi which can be combined with avelumab and/or N-803. Funding Source This work was funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health, as well as via Cooperative Research and Development Agreements (CRADAs) between the NCI and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and the NCI and ImmunityBio, Culver City, CA, USA. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)