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.
Highlights
Immunization strategies that induce clinically effective cytotoxic T cell responses against tumors have the potential to address critical unmet needs in the treatment of cancer
Data with other replication-competent lymphocytic choriomeningitis virus (LCMV) vectors, including an LCMV vector expressing ovalbumin, support these findings with respect to the induction of a polyfunctional effector CD8+ T cell pool and release of IL-33. These results demonstrate that arenavirusmediated dendritic cells (DCs) and T cell interactions, in combination with the presence of IL-33 and other pro-inflammatory cytokines, lead to a marked increase in antigen-specific, polyfunctional CD8+ T cells with antitumor activity
We have shown that engineered replicationcompetent arenavirus vectors target APCs to deliver encoded tumor antigens, induce potent antigen-specific CD8+ T cell responses, and enhance T cell infiltration into tumors
Summary
Administering an alternating sequence of two vectorized arenaviruses of distant genealogical relationship (such as a combination of Old World LCMV vectors and New World PICV vectors) impedes efficient boosting of vector backbone–directed CTL responses and focuses immune responses on the common transgene cargo Applying this strategy in mice, alternating vector therapy using a LCMV vector (HB-201) and a PICV vector (HB-202) induced HPV16 E7/E6specific CD8+ T cell responses that accounted for up to 50% of circulating CD8+ T cells, with similar levels observed when targeting tumor self-antigens such as P1A [4]. The median survival time of vaccinated mice was >59 days (exceeding the duration of the study) versus 24 days for mice in the control group [39] Preclinical experiments using this HPV16 E7/E6expressing vector showed direct links between immunogenicity, including increased levels of antigen-specific T cells and TILs, and antitumor activity [39]. 1/2 study, described in the Discussion section, will evaluate the efficacy of HB-201/HB-202 alone and in combination with a PD1 inhibitor to determine if these preclinical data translate to the clinic [3]
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