Abstract LB196: NOUS-PEV, a personalized cancer immunotherapy targeting neoantigens, induces long lasting, tumor infiltrating memory T cells

Abstract

Personalized vaccines hold great promise to exert meaningful clinical efficacy, with durable tumor control maintained by a vaccine–induced memory response. NOUS–PEV is a personalized viral prime–boost cancer vaccine that expresses 60 patient–specific neoantigens identified by next generation sequencing (NGS) and selected with a proprietary algorithm VENUS (Leoni & D’Alise et al, Vaccines, 9, 2021). Administration is intramuscular, with a priming Great Ape Adenovirus (GAd) vaccination, followed by Modified Vaccinia Ankara (MVA) “boosts”, administered in combination with the PD–1 blocking antibody pembrolizumab in patients with metastatic malignant melanoma and non–small cell lung cancer. Data from the Part 1 dose–confirmation cohort of 3 patients demonstrated the combination of NOUS–PEV and pembrolizumab to be safe and well–tolerated, with early indications of efficacy and immunogenicity (Bechter, et al SITC 2022 Poster number: 706). Now in Part 2 extension–expansion cohorts, we present extended safety, immunogenicity and clinical data at 11 months median follow–up for 6 vaccinated melanoma patients. Tolerability remains good with no grade 3 or 4 vaccine related adverse events and activity encouraging, with 4 PRs, 1 SD and only 1 PD as best response. Immune responses were evaluated by ex–vivo interferon–gamma ELISpot on PBMC collected at baseline, post pembrolizumab, and post vaccination. Vaccine immunogenicity was demonstrated in all evaluable patients receiving the prime/boost regimen (n=4), with a mean of T cell response of ~ 650 IFN–γ spot forming cells (SFC) per million of PBMC (range 380–1,250 SFC/106) and with observed induction of both CD4 and CD8 T cell responses which lasted for at least 6 months. By analyzing the intratumoral TCR repertoire, we found increase of T cells by ~3 fold on average post treatment with NOUS–PEV in all evaluable patients (n=3), with expansion and diversification of intratumoral T cell clones. Vaccine–induced TCR clonotypes were found in on–treatment tumor biopsies of 2 vaccinated patients, providing the proof–of–concept for neoantigen induced T cells homing and infiltrating into the tumor. Overall, these data show that NOUS–PEV continues to be safe, and elicits a robust long lasting immune response and clinical activity. Citation Format: Oliver Bechter, Anna Morena D'Alise, Guido Leoni, Gabriella Cotugno, Loredana Siani, Rosa Vitale, Valentino Ruzza, Irene Garzia, Laura Antonucci, Elisa Micarelli, Sven Gogov, Alessia Capone, Juan Martin-Liberal, Emiliano Calvo, Victor Moreno, Stefan Symeonides, Elisa Scarselli. NOUS-PEV, a personalized cancer immunotherapy targeting neoantigens, induces long lasting, tumor infiltrating memory T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB196.

Development of a Potency Assay for Nous-209, a Multivalent Neoantigens-Based Genetic Cancer Vaccine

“…Genetic vaccines encoding neoantigen-based transgenes represent a novel and promising therapeutic option for cancer therapies [ 19 ], with a number of examples in clinical development, including off-the-shelf (i.e., Nous-209) and personalized-approach vaccines [ 15 , 32 ]. As for Nous-209, the synthetic nature of the neoantigen transgenes can pose complexity for the development of relevant potency assays based on protein expression.…”

Personalized Cancer Vaccines Go Viral: Viral Vectors in the Era of Personalized Immunotherapy of Cancer

“…GAd is still similar to human Ads, but markedly differs in its antigenic determinants particularly in its hexon Hyper Variable Regions (HVRs) and fiber protein domains, leading to a notably less seroprevalence in human populations worldwide [39]. Currently, two GAd vectors are in clinical development as cancer vaccines: a Chimpanzee Adenovirus (species E ChAd68 serotype) and a Gorilla Adenovirus (species C GAd20 serotype), which have both been proven to be capable of inducting optimal T cell immunity in cancer patients [40][41][42].…”

“…In the context of personalized neoantigen vaccines, two major technologies are currently used to boost GAd primed T cell immunity; one is based on self-amplifying RNA [40], and the second one on MVA vectors [41].…”

“…In a phase I clinical trial (NCT04990479), NOUS-PEV was administered in combination with pembrolizumab to patients with metastatic malignant melanoma and NSCLC (n = 6). Vaccination was feasible and safe, and immunogenicity was demonstrated in all the evaluable patients who received the prime-boost regimen, with the detection of robust neoantigen-specific immune responses to multiple neoantigens in the peripheral blood comprising both CD4 and CD8 T cells [41]. The expansion and diversification of vaccineinduced TCR clonotypes were observed in the post-treatment biopsies of the patients with clinical response, providing evidence for the homing and infiltration of neoantigen-induced T cells into the tumor [41].…”

“…Vaccination was feasible and safe, and immunogenicity was demonstrated in all the evaluable patients who received the prime-boost regimen, with the detection of robust neoantigen-specific immune responses to multiple neoantigens in the peripheral blood comprising both CD4 and CD8 T cells [41]. The expansion and diversification of vaccineinduced TCR clonotypes were observed in the post-treatment biopsies of the patients with clinical response, providing evidence for the homing and infiltration of neoantigen-induced T cells into the tumor [41]. A similar approach based on GAd/MVA (NOUS-209) is also currently employed to target shared neoantigens in metastatic patients with a deficiency of dMMR/MSI.…”