Description

Development of a vaccine platform for cancer immunotherapy using autologous genetically modified T cells

Joshua R. Veatch, Brenda Jesernig, Stanley R Riddell*

Fred Hutchinson Cancer Research Center, Seattle. WA

*Corresponding Author

Multiple lines of evidence suggest that T cells specific for self and/or mutated antigens (neoantigens) mediate the antitumor responses that are observed in some patients that receive tumor infiltrating lymphocyte therapy or checkpoint blockade. This suggests that the responses to CPB might be improved by enhancing preexisting or inducing new tumor-reactive T cell responses by vaccination prior to or concurrently with checkpoint blockade. We have developed a vaccine platform for inducing T cell immunity using autologous T cells to systemically deliver tumor antigens to prime and boost T cell immunity. T cells genetically modified with immunogenic antigens (T-APC) are efficient at priming and boosting robust T cell responses to the transgene product in human patients, non-human primates and mice. An attractive feature of T-APC as a vaccine platform is that they are easy to obtain, can deliver antigen widely to lymph node sites, and can be easily genetically modified with “adjuvants” that augment immunogenicity. We show that systemic administration of T-APC expressing ovalbumin can prime and boost robust CD8⁺ T cell responses in mice, and that immunogenicity does not require direct presentation of antigen by the T-APC. Modifying T-APC with a membrane tethered IL-12 or to produce GM-CSF locally greatly augmented CD8⁺ and CD4⁺ T cell priming, and the combination of these cytokines was synergistic. Therapeutic vaccination with T-APC augmented with IL-12 expression markedly reduced tumor growth in the B16F10 transplantable melanoma model. This vaccine platform is now being extended to neoantigen targets in autochthonous tumor models.