Abstract LB-227: Novel synthetic vesicle for rapid in vivo expansion of CD8 T cells can significantly improve checkpoint inhibitor therapy
Authors: Li Adrienne V. , Eby Jackson K. , DeMuth Peter C. , Irvine Darrell J. 
Published: August 2015

Harnessing the immune system for cancer treatment offers many advantages over traditional methods as the immune system can generate tumor-specific killer cells and long-term memory cells to prevent recurrence. The success of recent clinical trials using T cell therapies has proven the potential of immunotherapy, but the ex vivo generation of T cells in these trials is costly and labor-intensive. Here, we developed wholly synthetic, pathogen-mimicking nanocapsules, Interbilayer-Crosslinked Multilamellar Vesicles (ICMVs), to deliver antigens to the lymphoid system, which prime large tumor-specific CD8 T cell populations in vivo. ICMVs use bilayer-to-bilayer crosslinks in the walls of multi-lamellar lipid vesicles to create an easily manufacturable, highly stable virus-like particle to present antigens and/or adjuvants to immune cells. ICMV carrying HPV16 E6 and E7 full-length proteins were administered alone or co-encapsulated with TLR agonists to mice. CD8 T cell responses were assessed by tetramer staining and intracellular cytokine staining (ICS) was done to assay functionality. Efficacy of ICMV treatment was demonstrated by monitoring tumor size and survival in C57BL/6 mice bearing a lethal dose of TC-1 tumor cells. ICMVs induced unprecedented antigen-specific CD8 T cell frequencies against HPV whole proteins even without added adjuvant. Repeat doses of ICMVs boosted CD8 responses resulting in 30% of the total CD8 T cell population in blood being E7-specific while treatment with free protein elicited &lt;1% E7-specific cells, indicating that ICMVs promote strong cross-presentation of antigens. When ICMVs were combined with anti-PD-1 to treat tumor-bearing mice, 10-15% of CD8 T cells produced IFNγ+ in response to either E6 or E7 antigens, while treatment with anti-PD-1 alone elicited &lt;1% IFNγ+ T cells. Significant tumor regression was seen with ICMV+anti-PD-1 treatment, doubling overall survival time while anti-PD-1 treatment alone delayed tumor growth only slightly. Similar results were seen when ICMV were combined with various immunomodulators including anti-PD-L1, anti-CTLA-4 and anti-CD40. These results indicate that the ICMV-induced expansion of antigen-specific CD8 T cells can significantly improve the therapeutic efficacy of checkpoint inhibitors. A triple therapy of ICMV + checkpoint inhibitor + Treg inhibiting drugs is now being assessed and eradication of &gt;85% of established tumors was detected in preliminary experiments. These findings demonstrate the potential of ICMVs as a novel cancer immunotherapy platform for the in vivo generation of CD8 T cells. ICMV are a cost effective, easily manufactured and versatile strategy to generate T cells for immunotherapy.

Citation Format: Adrienne V. Li, Jackson K. Eby, Peter C. DeMuth, Darrell J. Irvine. Novel synthetic vesicle for rapid in vivo expansion of CD8 T cells can significantly improve checkpoint inhibitor therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-227. doi:10.1158/1538-7445.AM2015-LB-227