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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., Competing Interests: Author HL, SS, KK, XQ, AH, KS, UB, JR, SA-E, TS, FS, IM and KKO are employees of Hookipa and own stock. CI is an employee of Hookipa who received travel funds and owns stock. DP owns stock in Hookipa and received funding from Hookipa for scientific consultancy, travel funds, writing support, and patent licensing fees. The authors declare that this study received funding from Hookipa Pharma Inc. The funder had the following involvement with the study: study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication., (Copyright © 2021 Lauterbach, Schmidt, Katchar, Qing, Iacobucci, Hwang, Schlienger, Berka, Raguz, Ahmadi-Erber, Schippers, Stemeseder, Pinschewer, Matushansky and Orlinger.)