Live-attenuated lymphocytic choriomeningitis virus-based vaccines for active immunotherapy of HPV16-positive cancer

Abstract

Infection with human papillomavirus (HPV) is associated with a variety of cancer types and limited therapy options. Therapeutic cancer vaccines targeting the HPV16 oncoproteins E6 and E7 have recently been extensively explored as a promising immunotherapy approach to drive durable antitumor T cell immunity and induce effective tumor control. With the goal to achieve potent and lasting antitumor T cell responses, we generated a novel lymphocytic choriomeningitis virus (LCMV)-based vaccine, TT1-E7E6, targeting HPV16 E6 and E7. This replication-competent vector was stably attenuated using a three-segmented viral genome packaging strategy. Compared to wild-type LCMV, TT1-E7E6 demonstrated significantly reduced viremia and CNS immunopathology. Intravenous vaccination of mice with TT1-E7E6 induced robust expansion of HPV16specific CD8 + T cells producing IFN-γ, TNF-α and IL-2. In the HPV16 E6 and E7-expressing TC-1 tumor model, mice immunized with TT1-E7E6 showed significantly delayed tumor growth or complete tumor clearance accompanied with prolonged survival. Tumor control by TT1-E7E6 was also achieved in established largesized tumors in this model. Furthermore, a combination of TT1-E7E6 with anti-PD-1 therapy led to enhanced antitumor efficacy with complete tumor regression in the majority of tumor-bearing mice that were resistant to anti-PD-1 treatment alone. TT1-E7E6 vector itself did not exhibit oncolytic properties in TC-1 cells, while the antitumor effect was associated with the accumulation of HPV16-specific CD8 + T cells with reduced PD-1 expression in the tumor tissues. Together, our results suggest that TT1-E7E6 is a promising therapeutic vaccine for HPV-positive cancers.

Lymphocytic Choriomeningitis—Emerging Trends of a Neglected Virus: A Narrative Review

“…Schmidt et al (2020) constructed a new vaccine TT1-E7E6 based on replicating attenuated LCMV encoding a non-oncogenic version of oncoproteins E7 and E6 of human papillomavirus type 16 (HPV-16). Evaluation of TT1-E7E6 in a mouse model showed vector clearance, induction of CD8+ T-cells specific for HPV-16 and tumor control, suggesting that the LCMV-based TT1-E7E6 vaccine might represent an excellent candidate for the immunotherapy of HPV-16-positive cancers [110].…”

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

“…Therefore, a key goal of immunotherapy is to convert non-inflamed tumors, so called “cold” tumors, into inflamed “hot” tumors, which are characterized by high levels of TILs and other markers of immune activation ( 38 ). Mouse tumor models have shown that therapeutic treatment can promote this “cold” to “hot” transition by activating antigen-specific CD8 + T cells that travel to and infiltrate the tumor and release pro-inflammatory cytokines in the TME ( 4 , 39 ).…”

“…These genetic modifications should not affect tropism of the resulting vector because proteins influencing tropism such as the viral surface protein were left unchanged. The safety of these engineered arenaviral vectors has been extensively documented in preclinical studies, and an encouraging safety profile is emerging from clinical trials ( 4 , 5 , 39 , 41 ).…”

“…Taken together, these properties make arenaviruses a particularly attractive platform for use as cancer therapies. In this review, we describe systemically administered, replication-competent arenaviral vectors, which induce high levels of tumor-specific CD8 + T cell responses ( 4 , 5 , 39 ). Data from cancer models using arenavirus vectors expressing self- or non–self-antigens and results from vectors in clinical development for the treatment of advanced or metastatic human papilloma virus positive (HPV+) cancers will be summarized.…”

“…Data from cancer models using arenavirus vectors expressing self- or non–self-antigens and results from vectors in clinical development for the treatment of advanced or metastatic human papilloma virus positive (HPV+) cancers will be summarized. More details on the results and methods used in these experiments have been previously published or presented ( 4 , 5 , 39 , 41 , 42 ).…”