Abstract 4058: Nanoparticle delivery of interleukin-2 induces anti-tumor immune response and therapeutic efficacy in mouse tumor models

Abstract Immune checkpoint inhibitors (ICIs) have demonstrated robust responses in some solid tumor types. However, the low response rate, which is associated with lack of pre-existing tumor-infiltrating lymphocytes (TILs), remains a significant challenge. Interleukin-2 (IL-2) can effectively expand TILs and has been FDA-approved for metastatic renal cancer and melanoma. However, IL-2 has several drawbacks—including short circulation half-life, dose-limiting toxicities, and counterproductive activation of regulatory T cells (Tregs) —resulting in less than 10% complete response rate. Numerous efforts have been made to enhance IL-2 formulations, but none have yet received FDA approval. In this study, we utilized our proprietary nanoparticle platform (Pdx-NP™) to improve IL-2 formulation. Pdx-NP™ can load IL-2 with near-complete binding, resulting in a 160-nm nanoconstruct (IL2-NP), suitable for both local and intravenous administrations. To evaluate the efficacy, we utilized bilateral melanoma (B16F10) and colon (MC38) tumor models, in which the local tumor was treated intratumorally for 3 doses and the distal tumor was left untreated to assess the systemic anti-tumor immune response. In the B16F10 model, IL2-NP treatment demonstrated favorable immune profiles in local and distal tumors and the draining lymph nodes, such as increased CD8+ T cell proliferation, CD8+ T cells/Treg ratio, and recruitment of dendritic cells and macrophages, compared to saline or free IL-2 counterparts. These positive immune responses translated into significant growth reduction of IL2-NP treated tumors and improvement in survival of the mice compared to free IL-2. In the MC38 tumor model, the IL2-NP treatment resulted in complete regression of both local and distal tumors in 43% of the mice. When combined with ICIs (αPD-1 and αCTLA-4), the treatment achieved a cure rate of 100%, whereas ICIs alone yielded only a 29% cure rate. In conclusion, IL2-NP induces robust proliferation and activation of TILs and is efficacious both as a monotherapy and in combination with ICIs. This is due to the ability of Pdx-NP™ to protect and retain therapeutics within tumors, with an 8-fold increase in tumor accumulation over the free drug counterpart. Our ongoing efforts are focused on the targeted delivery of IL-2 to tumors upon systemic administration, using αPD-L1 antibody-conjugated Pdx-NP™. This antibody-conjugated nanoparticle has an elimination half-life (t1/2) of about 25 hrs in non-human primates. Paired with αPD-L1 for tumor homing, this nanoconstruct is hypothesized to enhance IL-2 accumulation in tumors compared to free IL-2, which has t1/2 of only 1. 5 hrs in human. The current clinical landscape of cancer immunotherapy focuses on combinational approaches, and our versatile Pdx-NP™ platform, which is capable of co-delivering different classes of therapeutics, is well suited for this endeavor. Citation Format: Ruijie Wang, Alyssa Wallstrum, Natalie White, Pramod Kumar, Tongchatra Watcharawittayakul, Noah A. Crumrine, Cole Baker, Jeremy Saito, Moataz Reda, Worapol Ngamcherdtrakul, Wassana Yantasee. Nanoparticle delivery of interleukin-2 induces anti-tumor immune response and therapeutic efficacy in mouse tumor models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4058.