Peptides-Coated Oncolytic Vaccines for Cancer Personalized Medicine.

Oncolytic Viruses (OVs) work through two main mechanisms of action: the direct lysis of the virus-infected cancer cells and the release of tumor antigens as a result of the viral burst. In this sc.enario, the OVs act as in situ cancer vaccines, since the immunogenicity of the virus is combined with tumor antigens, that direct the specificity of the anti-tumor adaptive immune response. However, this mechanism in some cases fails in eliciting a strong specific T cell response. One way to overcome this problem and enhance the priming efficiency is the production of genetically modified oncolytic viruses encoding one or more tumor antigens. To avoid the long and expensive process related to the engineering of the OVs, we have exploited an approach based on coating OVs (adenovirus and vaccinia virus) with tumor antigens. In this work, oncolytic viruses encoding tumor antigens and tumor antigen decorated adenoviral platform (PeptiCRAd) have been used as cancer vaccines and evaluated both for their prophylactic and therapeutic efficacy. We have first tested the oncolytic vaccines by exploiting the OVA model, moving then to TRP2, a more clinically relevant tumor antigen. Finally, both approaches have been investigated in tumor neo-antigens settings. Interestingly, both genetically modified oncolytic adenovirus and PeptiCRAd elicited T cells-specific anti-tumor responses. However, in vitro cross-representation experiments, showed an advantage of PeptiCRAd as regards the fast presentation of the model epitope SIINFEKL from OVA in an immunogenic rather than tolerogenic fashion. Here two approaches used as cancer oncolytic vaccines have been explored and characterized for their efficacy. Although the generation of specific anti-tumor T cells was elicited in both approaches, PeptiCRAd retains the advantage of being rapidly adaptable by coating the adenovirus with a different set of tumor antigens, which is crucial in personalized cancer vaccines clinical setting.

Characterization of a novel OX40 ligand and CD40 ligand-expressing oncolytic adenovirus used in the PeptiCRAd cancer vaccine platform.

Oncolytic viruses (OVs) have been shown to induce anti-cancer immunity and enhance cancer immunotherapies, such as immune checkpoint inhibitor therapies. OV therapies can be further improved by arming OVs with immunostimulatory molecules, including various cytokines or chemokines. Here, we have developed a novel adenovirus encoding two immunostimulatory molecules: cluster of differentiation 40 ligand (CD40L) and tumor necrosis factor receptor superfamily member 4 ligand (OX40L). This novel virus, designated VALO-D102, is designed to activate both innate and adaptive immune responses against tumors. CD40L affects the innate side by licensing antigen-presenting cells to drive CD8+ T cell responses, and OX40L increases clonal expansion and survival of CD8+ T cells and formation of a larger pool of memory T cells. VALO-D102 and its murine surrogate VALO-mD901, expressing murine OX40L and CD40L, were used in our previously developed PeptiCRAd cancer vaccine platform. Intratumoral administration of PeptiCRAd significantly increased tumor-specific T cell responses, reduced tumor growth, and induced systemic anti-cancer immunity in two mouse models of melanoma. In addition, PeptiCRAd therapy, in combination with anti-PD-1 immune checkpoint inhibitor therapy, significantly improved tumor growth control as compared to either monotherapy alone.

Viral Nanoparticles: Cancer Vaccines and Immune Modulators.

In the last decades, viruses have gained great interest in the field of immuno-oncology (I-O) for their ability of interacting both with the immune system and the tumour microenvironment. Those pathogens have naturally evolved and been evolutionary to specifically infect hosts, replicate, deliver their genome, and spread. These properties, initially considered a disadvantage, have been investigated and edited to turn viruses into precious allies for molecular biology serving as gene therapy vectors, adjuvants for the immune system, drug cargos, and, lately, anticancer therapeutics. As anticancer drug, one interesting option is viral engineering. Modification of either the viral genome or the outer shell of viruses can change infectivity and tissue targeting and add new functions to the viral particle. Remarkably, in the field of cancer virotherapy, scientists realized that a specific viral genomic depletion would turn the normal tropism of viruses to conditionally replicate in cancer cells only. This category of viruses, named 'Oncolytic viruses', have been investigated and used for cancer treatment in the past decades resulting in the approval of the first oncolytic virus, a herpes simplex virus expressing a stimulating factor, named T-Vec, in 2015. As such, oncolytic viruses achieved positive outcome but still are not able to completely eradicate the disease. This has brought the scientific community to edit those agents, adding to their ability to directly lysate cancer cells, few modifications to mainly boost their interaction with the immune system. Viruses experienced then a renaissance not only as infecting agent but as nanoparticle and cancer vaccines too. These strategies bring new life to the concept of using viruses as viral particles for therapeutic applications.