Abstract 2792: Engineering T lymphocytes with protein nanogels for cancer immunotherapy

Abstract

Abstract Adoptive cell transfer (ACT) with autologous tumor-reactive T-lymphocytes is a promising strategy in cancer immunotherapy, but treatment of solid tumors is limited by the rapid decline in function of the transplanted T cells. In order to maintain high numbers of viable tumor-specific cytotoxic T cells in tumors, co-administration of supporting immunostimulant agents together with transferred cells is typically necessary in clinical practice. When given systemically at high doses, these agents could enhance the in vivo viability of donor cells, improve their therapeutic function and lead to overall improved efficacy against cancer. However, high doses of such agents can also result in serious side effects. For example, the use of Interleukin-2 (IL-2) as an adjuvant drug significantly enhances the efficacy of ACT in melanoma, where IL-2 provides key adjuvant signals to donor T cells but also elicits severe dose-limiting inflammatory toxicity and expands regulatory T cells (Tregs). One approach to focus adjuvant drug action on the transferred cells and lower systemic toxicity is to genetically engineer donor cells to secrete their own supporting factors. However, the technical difficulty of engineering safe autocrine production of potent adjuvant molecules such as cytokines is a challenge. Thus, an inexpensive technology platform that would allow simple, safe and efficient delivery of adjuvant drugs specifically to therapeutic cells over a defined window of time could be broadly useful in ACT and other cell therapies for cancer. Here, we developed a novel strategy to deliver therapeutic proteins in T cell therapies, via the chemical conjugation of protein-polyethylene glycol (PEG) nanogels (NGs) directly onto the plasma membrane of donor cells, enabling continuous pseudoautocrine release of cargo proteins for stimulation of transferred T-cells. These PEG NGs loaded with IL-2 contained very high level of drug (∼80 wt% of NG was the protein cargo) and released native IL-2 in physiological conditions in a sustained manner through breakdown of a degradable linker between the IL-2 cargo and PEG chains of the NG. T-cells with optimized number of NGs conjugated per cell maintained their cellular functions and cancer targeting and killing capability. We demonstrated that this IL2-PEG NG-T cell conjugation strategy could augment T-cell expansion in vivo and result in markedly improved efficacy against metastatic B16F10 melanoma in mice. This approach provides a readily generalizable strategy to provide autocrine protein drug support to donor cells to enhance the safety and efficacy of ACT. Citation Format: Li Tang, Yiran Zheng, Darrell J. Irvine. Engineering T lymphocytes with protein nanogels for cancer immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2792. doi:10.1158/1538-7445.AM2014-2792