Developing a novel agonist of CD137 for cancer immunoprevention - PROJECT SUMMARY The primary objective of this proposal is to assess a novel agonist of 4-1BB costimulatory pathway, SA-4-1BBL, as a single agent for cancer immunoprevention in preclinical models that closely represent high-risk populations susceptible to lung cancer resulting from environmental exposures. Advances in immunology led to the development of immunotherapies with remarkable clinical efficacy against various tumors and put the immune system at the forefront of the battle to prevent, intercept, and treat cancer. The perceived modalities for cancer immunoprevention are vaccines, which are well-suited for virally-derived tumors because of the known nature of target antigens. In marked contrast, the design of preventive vaccines against non-viral tumors for high-risk populations faces a significant challenge due to the unknown nature of target antigens. Thus, a cancer immunoprevention approach that does not require antigens and serves as a platform to prevent a wide range of tumor types will be transformative. The 4-1BB costimulatory pathway has been targeted for cancer immunotherapy because of the critical role signaling through this receptor plays in the expansion of CD8+ T cells, acquisition of effector function, and long-term survival. The natural ligand, 4-1BBL, is a cell surface protein and lacks costimulatory activity as a soluble molecule. As an alternative, agonistic antibodies (Abs) to 4-1BB have been pursued for cancer immunotherapy and shown significant toxicity with limited clinical efficacy. We hypothesized that a natural ligand would lack these attributes of Abs and generated an oligomeric form of mouse ligand, mSA-4-1BBL. This molecule has robust costimulatory activity in soluble form and showed therapeutic efficacy as the immune adjuvant component of tumor-associated antigens-based vaccines in various preclinical cancer models without detectable toxicity. mSA-4-1BBL as a single agent also protects mice against various tumor types, a highly significant and unexpected finding. Cancer immunoprevention efficacy is a bona fide feature of mSA-4-1BBL, as agonistic Abs to 4-1BB receptor are ineffective. mSA-4-1BBL exhibits unexpected efficacy in preventing cancer in mice lacking the 4-1BB receptor, suggesting the involvement of additional immune pathway(s). A series of studies under 4 Specific Aims will be conducted to; i) identify additional pathways targeted by SA-4-1BBL for cancer immunoprevention, ii) assess the efficacy of SA-4-1BBL in a tobacco carcinogen- induced preclinical lung cancer model, iii) generate the human version of SA-4-1BBL and assess its efficacy against lung cancer in a mouse model expressing human 4-1BB receptor, and iv) assess the cancer immunoprevention efficacy of human SA-4-1BBL in a mouse model humanized with hematopoietic stem cells and transplanted with patient-derived lung cancer. Various studies will be conducted to elucidate the mechanistic underlying of success or failure of SA-4-1BBL-based cancer immunoprevention. Validation of SA-4-1BBL as an effective cancer immunoprevention agent will be transformative and substantially change clinical practice for cancer treatment with significant health and financial benefits worldwide.
