To assess the importance of CD4+ T cell help, Tähtinen and Feola et al. engrafted melanomas s.c. into naïve mice or mice pre-immunized with human tetanus toxoid (TT), followed by tumor implantation and intratumoral vaccination with TT vaccine and/or a human adenovirus coated with MHC-II pathogen and/or MHC-I tumor peptides. TT pre-vaccination plus dual MHC-II pathogen/MHC-I tumor antigen vaccination increased tumor control, pathogen-specific CD40L+CD4+ Th1 cells, and APC maturation in draining lymph nodes and tumor-infiltrating DCs, effector memory CD4+ and less exhausted CD8+ T cells intratumorally, and synergized with anti-PD-1.

Contributed by Paula Hochman

ABSTRACT: Due to the high coverage of international vaccination programs, most people worldwide have been vaccinated against common pathogens, leading to acquired pathogen-specific immunity with a robust memory T cell repertoire. While CD8+ anti-tumor cytotoxic T lymphocytes (CTL) are the preferred effectors of cancer immunotherapy, CD4+ T cell help is also required for an optimal anti-tumor immune response to occur. Hence, we investigated whether the pathogen-related CD4+ T cell memory populations could be re-engaged to support the CTLs, converting a weak primary anti-tumor immune response into a stronger secondary one. To this end, we used our PeptiCRAd technology that consists of an oncolytic adenovirus coated with MHC-I-restricted tumor-specific peptides, and developed it further by introducing pathogen-specific MHC-II-restricted peptides. Mice pre-immunized with tetanus vaccine were challenged with B16.OVA tumors and treated with the newly developed hybrid TT-OVA-PeptiCRAd containing both tetanus toxoid- and tumor-specific peptides. Treatment with the hybrid PeptiCRAd significantly enhanced anti-tumor efficacy and induced TT-specific, CD40 ligand-expressing CD4+ T helper cells and maturation of antigen presenting cells (APCs). Importantly, this approach could be extended to naturally occurring tumor peptides (both tumor-associated antigens and neoantigens), as well as to other pathogens beyond tetanus, highlighting the usefulness of this technique to take full advantage of CD4+ memory T cell repertoires when designing immunotherapeutic treatment regimens. Finally, the anti-tumor effect was even more prominent when combined with the immune checkpoint inhibitor anti-PD1, strengthening the rationale behind combination therapy with oncolytic viruses.

Author Info: (1) University of Helsinki. (2) Faculty of Pharmacy, University of Helsinki. (3) University of Helsinki. (4) University of Helsinki. (5) Faculty of Science, Leiden University. (6)

Author Info: (1) University of Helsinki. (2) Faculty of Pharmacy, University of Helsinki. (3) University of Helsinki. (4) University of Helsinki. (5) Faculty of Science, Leiden University. (6) Division of Pharmaceutical Biosciences, University of Helsinki. (7) University of Helsinki. (8) University of Helsinki. (9) University of Helsinki. (10) University of Padua. (11) Experimental Oncology, ISTITUTO NAZIONALE TUMORI IRCCS - Fondazione Pascale. (12) University of Helsinki. (13) University of Helsinki. (14) Drug Research Program, Faculty of Pharmacy, University of Helsinki. (15) ValoTherapeutics. (16) Experimental Oncology, ISTITUTO NAZIONALE TUMORI IRCCS - Fondazione Pascale. (17) Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, University of Helsinki vincenzo.cerullo@helsinki.fi.