Abstract LB-269: Development of a vaccine model to track the CD8-specific response in Mauritius cynomolgus monkey

Abstract

Abstract Introduction Manipulating the immune system to achieve therapeutic efficacy in cancer treatment has led to a new class of drugs that brought lasting remissions to many patients who had run out of options. The development of new immunotherapy aimed at targeting cancer cells requires the ability to monitor specifically the immune response. Although CD8 T cells play a crucial role in this process, no equivalent of the traditional T-cell-dependent antibody response (TDAR) assay, which evaluates the T-helper immune response, is currently available. Since cancer immunotherapy agents are often tested in non-tumor bearing NHP for safety assessment, the animal models currently available do not allow monitoring of potential exaggerated pharmacology and efficacy of these new drug candidates. Objectives The goal of this study was to develop an NHP vaccination model that specifically elicits a CTL response, in order to evaluate the efficacy in exacerbating the Cytotoxic T Lymphocyte (CTL) response. Experimental Procedures To reach this goal, MHC-genotyped Mauritian cynomolgus macaques (MCMs) were immunized with 3 replication incompetent recombinant adenovirus serotype 5 (Ad5) vectors, each containing the coding sequence for Gag, Nef or Pol SIV proteins. Such model allowed monitoring of the CD8 T cell activation in lieu of a tumor or live virus model. MCMs were distributed into 3 groups: one control group and 2 groups which received two intramuscular injection of the adenovirusrs spaced by 4 or 8 weeks. The immune response was monitored with blood samples taken on a weekly basis for up to 12 weeks. Blood samples were used to 1) characterize the different CD8-positive sub-populations by Tetramer staining and Immunophenotyping; 2) to correlate the immunophenotyping profile obtained with functional assays such as ex vivo recall response and IFNγ ELIspot. Results Of the three groups tested, MCM monkeys receiving 2 injections 8 weeks apart showed the more robust CD8 T cell response. This response was mainly characterized by a proliferation profile (Ki67-positive cells), the expression of activation markers at the surface of CD8 T cells and antigen specific responses of the CD8 T cells. Of the three Gag, Pol and Nef proteins, immunization with Nef gave the most robust response, as observed by the IFNγ ELIspot results and by the presence of a Nef-specific CD8-specific subpopulation observed by tetramer staining. No changes in the distribution of T, B, NK, Treg or Memory T cells was observed between the 3 groups. Conclusion The results obtained during the course of this study suggests that the described CD8-specific vaccination model using Mauritius cynomolgus macaques is a promising model to evaluate the efficacy and potential exaggerated pharmacology of new drug candidates targeting CD8 T cells. Citation Format: Richard Graveline, Morad Haida, Carolyne Dumont, Rana Samadfam, Dominic Poulin, Marie-Soleil Piche. Development of a vaccine model to track the CD8-specific response in Mauritius cynomolgus monkey [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-269.