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. 2020 Jun 15;80(12):2575-2585.
doi: 10.1158/0008-5472.CAN-19-2062. Epub 2020 Feb 27.

Exploiting Preexisting Immunity to Enhance Oncolytic Cancer Immunotherapy

Siri Tähtinen #  1 , Sara Feola #  1 , Cristian Capasso  1 , Netta Laustio  1 , Christianne Groeneveldt  2 , Erkko O Ylösmäki  1 , Leena Ylösmäki  1 , Beatriz Martins  1 , Manlio Fusciello  1 , Marta Medeot  3 , Maria Tagliamonte  4 , Jacopo Chiaro  1 , Firas Hamdan  1 , Karita Peltonen  1 , Tuuli Ranki  5 , Luigi Buonaguro  4 , Vincenzo Cerullo  6   7   8
Affiliations

Exploiting Preexisting Immunity to Enhance Oncolytic Cancer Immunotherapy

Siri Tähtinen et al. Cancer Res. .

Abstract

Because of 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. Although CD8+ antitumor cytotoxic T lymphocytes (CTL) are the preferred effectors of cancer immunotherapy, CD4+ T-cell help is also required for an optimal antitumor immune response to occur. Hence, we investigated whether the pathogen-related CD4+ T-cell memory populations could be reengaged to support the CTLs, converting a weak primary antitumor 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 preimmunized 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 antitumor efficacy and induced TT-specific, CD40 ligand-expressing CD4+ T helper cells and maturation of antigen-presenting cells. 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 antitumor effect was even more prominent when combined with the immune checkpoint inhibitor anti-PD-1, strengthening the rationale behind combination therapy with oncolytic viruses. SIGNIFICANCE: These findings establish a novel technology that enhances oncolytic cancer immunotherapy by capitalizing on pre-acquired immunity to pathogens to convert a weak antitumor immune response into a much stronger one.

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