Background Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that contributes to immunoregulation at many levels, including suppressing effector T cells and inducing/activating regulatory T cells. Thus far, several therapeutic approaches to target IDO1 enzymatic activity have shown promise in preclinical models, however, results from the first major clinical trial were disappointing. The present study seeks to provide preclinical PoC data for the conceptually unique idea of developing an IDO1-targeted vaccine based on our earlier findings that humans exhibit intrinsic T cell reactivity against IDO1 epitopes1 suggesting the existence of a T cell-mediated, counter-regulatory mechanism directed against cells that express IDO1.
Materials and Methods IDO1-derived peptide vaccines were identified by measurement of vaccine-induced ex vivo response (IFNγ ELISpot) and demonstration of anti-tumor responses in CT26 tumor-bearing mice. To understand the vaccine’s mode of action, resected tumors were analyzed by immunofluorescence microscopy and flow cytometry.
Results The CT26 colon carcinoma model was selected for these studies based on evidence of high levels of IDO1 expression and responsiveness to IDO1 inhibition reported for these tumors. In silico-predicted H2d MHC class I and II-restricted IDO1 peptide sequences were tested and vaccine candidates were chosen after confirming ex vivo response and anti-tumor response in CT26. Therapeutic treatment of established CT26 tumors with MHC class I- and II-directed, IDO1-derived peptide vaccines elicited anti-tumor responses when administered alone, and the effect was further pronounced when combined, suggesting distinct mechanisms of action. In addition, a combination of IDO1 vaccine with anti-PD-1 antibody produced a combinatorial anti-tumor response beyond what was achieved with either agent alone. Consistent with this observation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth in treatment naïve mice. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component indicative of antigen spread. Examination into the tumors in vaccinated mice indicated that IDO1 vaccine treatment exerts its effect by selective reduction of IDO1 expression in the tumor microenvironment and concomitant expansion of activated CD4+ and CD8+ T cells.
Conclusions As noted in humans, our data demonstrate that IDO1 is immunogenic in mice confirming that this endogenous protein is excluded from normal tolerance mechanisms. The observed immunotherapeutic efficacy of IDO1 peptide vaccines on their own and in combination with anti-PD-1 antibody support the rationale for ongoing clinical development of IDO1 peptide vaccine-based therapy. Future studies include further differentiation of the vaccine platform against other IDO1-targeting approaches, as well as decoding the underlying mechanism of cooperativity between anti-PD-1 antibody and IDO1 peptide vaccines.
Sørensen RB, Hadrup SR, Svane IM, Hjortsø MC, Thor Straten P, Andersen MH. Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 2011; 117(7): 2200–10
Disclosure Information S. Dey: None. E. Sutanto-Ward: None. K.L. Kopp: A. Employment (full or part-time); Significant; IO Biotech. J.B. DuHadaway: None. A. Mondal: None. I. Lecoq: A. Employment (full or part-time); Significant; IO Biotech. M. Zocca: A. Employment (full or part-time); Significant; IO Biotech. M.H. Andersen: A. Employment (full or part-time); Significant; IO Biotech. A.W. Pedersen: A. Employment (full or part-time); Significant; IO Biotech. A.J. Muller: F. Consultant/Advisory Board; Modest; IO Biotech.
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