Sa-4-1bbl As A Novel Agonist Of Cd137 Has Immunoprevention Efficacy Against Various Tumor Types

Introduction: CD137 costimulation plays a paramount role in the generation of CD8+ T cell effector and long-term memory responses. Given the importance of CD8+ T cells for tumor destruction, we generated an oligomeric form of 4-1BB ligand, SA-4-1BBL, and demonstrated that it has better costimulatory activity and safety profile than an agonistic CD137 Ab. Importantly, prophylactic treatment of naive mice with SA-4-1BBL as a single agent trains the immune system for long-term protection against cervical cancer. In this study, we expand on this initial observation and further demonstrate that the cancer immunoprevention efficacy of SA-4-1BBL extends to various tumor types and in different mouse strains, and that agonists Ab does not have such an attribute. Study design: Mice were treated subcutaneously with SA-4-1BBL protein or an agonistic Ab to CD137 receptor. Two weeks later, C57BL/6 mice were challenged subcutaneously in the left-back flank with syngeneic B16-F10 melanoma or 3LL lung cancer, whereas BALB/c mice were challenged with A20 lymphoma or 4T1 triple-negative breast cancer cell lines. Animals were monitor for tumor growth. For post-surgical tumor recurrences study, C57BL/6 mice with established B16-F10 tumors (~ 4mm in diameter) were subjected to surgery to debulk the tumor under sterile conditions. After 48 hours of the recovery period, animals were treated subcutaneously with SA-4-1BBL protein twice, two weeks apart. Animals without any treatment served as controls and mice were monitored for tumor relapse. Results: Pretreatment with SA-4-1BBL provided complete protection against both B16-F10 melanoma and 3LL lung cancer, ~80% protection against A20 lymphoma, and ~ 60% protection against triple negative 4T1 breast cancer. Importantly, the immunoprevention was a bona fide feature of SA-4-1BBL as the agonistic Ab to CD137 receptor had no impact on the tumor growth in the A20 lymphoma model tested. The immunoprotective effect was long lasting as challenge with the 3LL lung cancer cells 14 weeks post SA-4-1BBL treatment was still effective in controlling tumor growth in \u003e80% of mice. SA-4-1BBL was also effective in controlling post-surgical recurrence against melanoma with ~75% efficacy. Ongoing RNA sequencing studies are aimed to dissect mechanistic basis of SA-4-1BBL-mediated cancer immunoprevention. Conclusions: These results demonstrate that SA-4-1BBL generates a blanket and long-lasting protective immune response against various tumor types. The ability of an immune checkpoint stimulator as a single agent to train the immune system for long-lasting protection independent of tumor type is exciting and sets the stage for a cancer immunoprevention modality that does not require tumor antigens. Funded in parts by NIH R41CA199956, T32HL134644, NCI R25CA134283 and Kentucky KSTC-184-512-16-237 awards. Citation Format: Haval Shirwan, Lalit Batra, Mohammad Tariq Malik, Pradeep Shrestha, Jenci L. Hawthorne, Esma S. Yolcu. SA-4-1BBL as a novel agonist of CD137 has immunoprevention efficacy against various tumor types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4516.