Description:
<jats:title>Abstract</jats:title>
<jats:p>The demonstration that antibodies can be used to treat cancers has revolutionized the field of cancer immunotherapy and gave hope to many patients. Originally targeting tumor-specific antigen, new therapeutic antibodies target now immune checkpoint markers expressed on T cells. The advantage is to generate an active and long-lasting antitumor immunity with the achievement of a broad and polyclonal antitumor immunity, addressing better the heterogeneity of cancers and reducing the chances of immune escape. The development of such highly specific molecules is particularly challenging however when it comes to preclinical safety assessment and efficacy studies. An ideal animal model needs to possess the target so that the drug product is pharmacologically active. Moreover, such model should ideally provide further insight in determining the pharmacological action of the product and the determination of safety to maximize the usefulness in animal studies. Intriguingly, no equivalent of the traditional T-cell-dependent antibody response (TDAR) assay, which evaluates mainly the CD4+ T cells response, is currently available for the CD8+ T cell response. The goal of this study is to fill this gap with a Non-Human Primate (NHP) challenge model that will elicit a potent CD8+ T cell response. MHC I-genotyped Mauritian cynomolgus macaques (MCMs) were immunized with 3 replication incompetent recombinant adenovirus serotype 5 (Ad5) vectors encoding Gag, Nef or Pol SIV proteins. MCMs were distributed into 3 groups and received two intramuscular injections of adenoviruses 4 weeks apart. One group received the anti-PD-L1 Atezolizumab and a second received a molecule in early development targeting another immune checkpoint molecule. T cell activation was monitored with blood samples taken on a weekly basis for 8 weeks. Blood samples were used to characterize the T cell immunophenotypes and to correlate them with some functional assays. Vaccination was well tolerated and could be conducted on standard safety toxicology studies without compromising other endpoints. Adv5-SIVs modulated total T cells 2 weeks after a single vaccination, induced T-cell activation, T-cell proliferation and the expression of several checkpoint molecules. Moreover, functional assays confirmed that T-cell activation profile correlated with an antigen-specific CD8 T-cell response. Compounds administered differently enhanced the profile of T-cell activation, the upregulation of immune checkpoint molecules and antigen specific responses of their T cells. Moreover, both compounds extended the cytolytic activity of the antigen-specific CD8+ T cell up to 8 weeks. Taken together, the vaccination model we developed seems appropriate to study the pharmacology of new protein-based therapeutics targeting CD8+ T cells.</jats:p>
<jats:p>Citation Format: Richard Graveline, Morad Haida, Carolyne Dumont, Dominic Poulin, Florence Poitout-Belissent, Rana Samadfan, Sven Kronenberg, Franziska Regenass-Lechner, Rodney Prell, Marie-Soleil Piche. A simian challenge model to evaluate the CD8-positive T cell response with cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB097.</jats:p>