Functional properties and antigen specificity of expanded T-cells are crucial for the efficacy of adoptive cell transfer-based therapies in cancer. Most current strategies involve nonspecific expansion of bulk tumor-infiltrating lymphocytes, often providing growth preference to co-infiltrated virus specific T-cells and driving an exhausted phenotype of the expanded T-cell product.A potential way to resolve this challenge, is the use of artificial antigen-presenting scaffolds providing both an antigen specific stimulation through peptide-MHC interaction and additional the required co-stimulatory and growth signals through associated stimulatory molecules and cytokines. We have designed such antigen-presenting scaffolds; build on a dextran-polysaccharide, carrying both peptide-MHC and relevant stimulatory molecules. The artificial antigen-presenting scaffolds interacts specifically with T-cells based on recognition of the peptide-MHC molecule and effectively expand and functionally stimulate specific T-cells in a peptide-MHC-directed fashion, while leaving all other T-cell specificities untouched. Results from in vitro experiments have showed that antigen specific CD8 T-cells stimulated with these artificial antigen-presenting scaffolds express a less differentiated phenotype and low PD-1 expression, associated with high proliferation potential and enhanced antitumor effect in vivo. Furthermore, this expansion strategy provides a high frequency of multifunctional antigen specific CD8 T-cells expressing IFN-γ, TNF-α, and CD107a upon target recognition and provide improved cancer cell killing over IL2-driven expansion of tumor-infiltrating lymphocytes. Furthermore, the current strategy allows for simultaneous expansion of numerous different T-cell populations, required to generate T-cell products with broad recognition profiles based on the personal cancer-antigen and mutational profile. All of these characteristics are of significant importance for in vivo tumor cell killing following adoptive transfer of expanded T-cell products. Thus, the present strategy represents an optimized method for expansion of cancer-restricted T-cells for adoptive cell therapy.
Citation Format: Vibeke Mindahl Rafa, Mona Bodenhöfer, Amalie Kai Bentzen, Tripti Tamhane, Marco Donia, Inge Marie Stentoft Svane, Søren Nyboe Jakobsen, Christian Schmess, Sine Reker Hadrup. Peptide-MHC-directed expansion of multifunctional antigen-responsive T-cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B039.