Development and Characterization of a Novel Non-Lytic Cancer Immunotherapy Using a Recombinant Arenavirus Vector Platform

Abstract

Engineered viral vectors represent a promising strategy to trigger antigen-specific antitumor T cell responses. Arenaviruses have been widely studied because of their ability to elicit potent and protective T cell responses. Here, we provide an overview of a novel intravenously administered, replication-competent, non-lytic arenavirus-based vector technology that delivers tumor antigens to induce antigen-specific anti-cancer T cell responses. Preclinical studies in mice and cell culture experiments with human peripheral blood mononuclear cells demonstrate that arenavirus vectors preferentially infect antigen-presenting cells. This, in conjunction with a non-lytic functional activation of the infected antigen-presenting cells, leads to a robust antigen-specific CD8+ T cell response. T cell migration to, and infiltration of, the tumor microenvironment has been demonstrated in various preclinical tumor models with vectors encoding self- and non–self-antigens. The available data also suggest that arenavirus–based vector therapy can induce immunological memory protecting from tumor rechallenge. Based on promising preclinical data, a phase 1/2 clinical trial was initiated and is currently ongoing to test the activity and safety of arenavirus vectors, HB-201 and HB-202, created using lymphocytic choriomeningitis virus and Pichinde virus, respectively. Both vectors have been engineered to deliver non-oncogenic versions of the human papilloma virus 16 (HPV16) antigens E7 and E6 and will be injected intravenously with or without an initial intratumoral dose. This dose escalation/expansion study is being conducted in patients with recurrent or metastatic HPV16+ cancers. Promising preliminary data from this ongoing clinical study have been reported. Immunogenicity data from several patients demonstrate that a single injection of HB-201 or HB-202 monotherapy is highly immunogenic, as evidenced by an increase in inflammatory cytokines/chemokines and the expansion of antigen-specific CD8+ T cell responses. This response can be further enhanced by alternating injections of HB-202 and HB-201, which has resulted in frequencies of circulating HPV16 E7/E6-specific CD8+ T cells of up to 40% of the total CD8+ T cell compartment in peripheral blood in analyses to date. Treatment with intravenous administration also resulted in a disease control rate of 73% among 11 evaluable patients with head and neck cancer dosed every three weeks, including 2 patients with a partial response.

Replication-attenuated r3LCMV vectors potentiate tumor control via IFN-I

“…Due to their high immunogenicity, LCMV vectors have been explored as vaccine candidates for various diseases ( 8–10 ). In these prior studies, LCMV vectors have been genetically modified to include a foreign antigen to prime antigen-specific immune responses.…”

Oropharyngeal cancer and human papillomavirus: a visualization based on bibliometric analysis and topic modeling

“…A study evaluated the efficacy of HB-200 arenavirus-based immunotherapy combined with pembrolizumab for first-line treatment of HPV16-positive head and neck cancer patients. HB-200 can express non-oncogenic HPV16 E7-E6 fusion protein, inducing E6- and E7-specific CD8+ T cell responses ( Lauterbach et al, 2021 ). The results showed that the combination therapy exhibited promising clinical activity in the first-line treatment setting, with an overall response rate of 43% ( Nabell et al, 2023 ).…”

An attenuated lymphocytic choriomeningitis virus vector enhances tumor control in mice partly via IFN-I

“…Due to their high immunogenicity, LCMV vectors have been explored as vaccine candidates for various diseases (8)(9)(10). In these prior studies, LCMV vectors have been genetically modified to include a foreign antigen to prime antigen-specific immune responses.…”