Listeria monocytogenes personalized cancer vaccines drive therapeutic immune responses to cancer derived neoantigens
Year: 2020
Type: preprint
Abstract: Background Recent advances in the field of cancer immunotherapy have identified CD8 + T cell responses against tumor-specific mutations as a key driver of tumor regression and overall survival. ADXS-NEO is a personalized Listeria monocytogenes ( Lm )-based immunotherapy designed to target a patient’s mutation-derived tumor-specific neoantigens. The objective of this study is to demonstrate the feasibility of using the ADXS-NEO platform to target tumor-specific point mutations and control tumor growth by generating neoantigen-specific T cell responses using a pre-clinical mouse tumor model. Methods Whole-exome sequencing of the MC38 mouse tumor cell line identified 2870 unique non-synonymous mutations. The netMHCcons algorithm was used to predict 137 potential neoantigens. We validated 20 immunogenic neoantigens either by peptide immunization followed by ELISPOT or by the presence of CD8 + T cells recognizing the neoantigen peptide following checkpoint inhibitor treatment. Two ADXS-NEO vectors were constructed; Lm20, targeting 20 validated immunogenic neoantigens, and Lm19, targeting most of the non-validated NSMs. Results Both Lm19 & Lm20 significantly slowed tumor growth in C57BL/6 mice compared to control. An accumulation of ADXS-NEO-specific TILs was observed in tumor bearing mice treated with either Lm19 or Lm20. Examination of the tumor microenvironment in Lm19 or Lm20 treated mice revealed a decrease in the frequency and absolute number of Tregs, TAMs, MDSCs, and PD1 high exhausted CD8 + T cells as well as an increase in the frequency and absolute number of effector CD8 + T cells, relative to control. Conclusion ADXS-NEO is a potent immunotherapy capable of driving immune responses against tumor-specific mutations and leading to tumor control in mice.
Authors: Brandon Coder, Olga Pryshchep, Dipti Kelkar, Elena Filippova, Xiaoming Ju, David Balli, Cristina Mottershead, Kim Ramos, Nithya Thambi, Zhiyong Cheng, Bryan Vander Lugt, Justin Lesch, Xian Liu, Jason DeVoss, Keegan Cooke, Siyuan Liu, Jinghui Zhan, Petia Mitchell, Daniel O Villarreal, Sandra M. Hayes, James A Johnston, Robert Petit, Hyewon Phee, Michael F. Princiotta
Institutions: Advaxis (United States), Amgen (United States)
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3025802149