Abstract 1818: Developing an autologous humanized mouse model to assess responses to novel immunotherapeutics

Abstract Introduction: The development and FDA approval of drugs targeting the PD-1/PD-L1 axis has greatly shifted the paradigm of immunotherapy and has improved the clinical outcome for patients diagnosed with advanced melanoma. Despite the recent advancement of immune checkpoint inhibitors, more than 50% of patients still fail to show a sustained response to therapy. Therefore, there is a critical need to develop therapies specific to novel immune targets as well as combination drug regimens. Current immunocompetent preclinical models do not adequately model the responses to immunotherapy, reflecting the urgent need to develop models with greater translational utility. To address this need, we developed a humanized xenograft melanoma model engrafted with autologous peripheral blood lymphocytes (PBLs) to evaluate the utility of nemvaleukin alfa, an engineered IL-2 cytokine which preferentially activates and expands cytotoxic NK cells and antigen-experienced CD8 T cells. Methods: Melanoma-bearing mice were injected intravenously with matched melanoma patient PBLs and treated for four cycles (1 cycle/week) with anti-PD-1, nemvaleukin, or rhIL-2. Tumor growth was monitored, and correlative analyses were done on blood, spleen, and tumors by flow cytometry after 4 cycles of treatment. Results: This humanized melanoma mouse model exhibited good T cell engraftment and was characterized by expression of the proliferative marker Ki-67 in 50-60% of CD8+ and CD4+ T cell populations. Treatment with nemvaleukin resulted in significant tumor growth inhibition rates (TGIs) of an average of 48% compared to vehicle-treated mice. In addition, nemvaleukin promoted expansion of CD8+ and CD4+ T cells, without expansion of CD4+ regulatory T cells, which are known to suppress immunological responses. Compared to rhIL-2 and vehicle, nemvaleukin treatment delayed tumor growth and enhanced survival with a median survival time of 56 days compared to 21 and 50 days, respectively. Nemvaleukin-treated mice had higher CD45+ cell engraftment in spleens and tumors compared to anti-PD-1 treatment, indicating that nemvaleukin boosts T cell proliferation and expansion. Of note, we observed better antitumor efficacy in response to nemvaleukin or anti-PD-1 when mice were engrafted with tumors from patients who responded to checkpoint immunotherapy with TGIs of 36% and 51%, respectively, compared to those who did not with TGIs of 16% and 12%, respectively. These data indicate that treatment responses in our humanized model correlates with clinical outcomes. Conclusion: In this all autologous humanized melanoma mouse model, nemvaleukin treatment not only enhances T cell engraftment, it significantly augments anti-tumor efficacy. These data support the use of this personalized melanoma xenograft model to analyze the underlying immune responses in responders and non-responders to novel immunotherapies. Citation Format: Yee Peng Phoon, Jared E. Lopes, Lukas W. Pfannenstiel, C. Marcela Diaz-Montero, Ye F. Tian, Marc S. Ernstoff, Pauline Funchain, XiaoXia Li, Heather C. Losey, Raymond J. Winquist, Brian R. Gastman. Developing an autologous humanized mouse model to assess responses to novel immunotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1818.