Abstract CT007: Safety and immunogenicity of a personalized neoantigen-Listeria vaccine in cancer patients
Authors: Hecht J. Randolph , Goldman Jonathan W. , Hayes Sandy , Balli David , Princiotta Michael F. , Dennie Justin G. , Heyburn John , Sands Tammy , Sheeri Sumitra , Petit Robert , Gutierrez Andres A. , Tsai Frank 
Published: August 2019

Abstract
Background. Meaningful anti-tumor immunity in cancer patients (pts) has been associated with the presence of specific T cells directed at neoantigens, a class of unique peptides that arise from tumor-specific mutations. ADXS-NEO, a personalized Listeria monocytogenes (Lm)-based immunotherapy, is a bioengineered Lmthat secretes an antigen-adjuvant fusion protein consisting of ≥ 20 unique (personal) neoantigens and a truncated fragment of listeriolysin O (tLLO), which has adjuvant properties. Preliminary safety and immunogenicity results from an ongoing Phase I trial with ADXS-NEO are herein reported.
Methods. ADXS-NEO-02 is a Phase I dose-escalation study of ADXS-NEO in subjects with metastatic microsatellite stable colon cancer (CRC), metastatic squamous histology head and neck cancer, and metastatic non-small cell lung cancer (NSCLC). Manufacturing of ADXS-NEO starts with whole exome sequencing of each pt-matched normal and tumor samples to detect genetic alterations in the coding regions of the genome followed by its production under GMP specifications. ADXS-NEO is infused intravenously every 3 weeks until disease progression or limiting toxicity. Main endpoints include safety, tolerability and immune-correlative data.
Results. The turnaround time for manufacturing ADXS-NEO has consistently been ≤ 8 weeks from biopsy to first dose. Two pts treated at 1X109 CFU (dose level 1) experienced dose limiting toxicities (i.e., Gr 3 hypoxia ± Gr 3 hypotension) within 4 hours of completing the infusion of the second dose. These acute adverse events correlated with elevation of serum IL-6 and other cytokines, and both cases were manageable and reversible with tocilizumab and/or steroids. A dose de-escalation cohort was initiated at 1X108 CFU, which has been found to be safe and tolerated by one pt. In these pts, ADXS-NEO induced: 1) activation and proliferation of CD4+ / CD8+ T cells; 2) neoantigen-specific T cell responses after 1 week of the initial priming dose and 3) antigen spreading and T cell responses to neoantigens not selected by algorithm.
Conclusions. ADXS-NEO at 1X109 CFU was beyond the maximum tolerated dose but it was effective in eliciting a fast and broad anti-tumor immunity, including T cell responses to neoantigens and antigen spreading. Enrollment continues both in monotherapy and combination therapy arms with anti-PD-1/PD-L1 therapy, to define the recommended Phase II dose.
Citation Format: J. Randolph Hecht, Jonathan W. Goldman, Sandy Hayes, David Balli, Michael F. Princiotta, Justin G. Dennie, John Heyburn, Tammy Sands, Sumitra Sheeri, Robert Petit, Andres A. Gutierrez, Frank Tsai. Safety and immunogenicity of a personalized neoantigen-Listeria vaccine in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT007.