The Philadelphia (Ph) chromosome, resulting from the t(9;22) translocation, is characteristic of chronic myeloid leukemia (CML). As a result of this translocation, two novel chimeric genes are generated and the bcr/abl and abl/bcr fusion proteins expressed. The bcr/abl fusion mRNA is present in all CML patients, whereas the reciprocal abl/bcr fusion mRNA is detectable in about 80% of the Ph + CML patients. These fusion proteins may undergo enzymatic degradation in the cytosol and give rise to MHC class I restricted peptide epitopes originating from the junctional regions of the translocation products, which thus may serve as novel tumor specific antigens. Previously, other groups have tested peptides corresponding to the junctional region of the bcr/abl protein for their binding capacity to HLA class I molecules and have identified a few candidate epitopes. Peptides originating from the abl/bcr fusion protein have on the other hand so far been neglected, for no apparent reason. We have now extended these studies to include also the reciprocal abl/bcr translocation product by testing a large panel of synthetic peptides corresponding to the junctional regions of both the abl/bcr and the bcr/abl fusion proteins for their ability to stabilize HLA class I molecules. We find that the abl/bcr translocation product may be an even more important source of CML specific peptide antigens and together the junctional sequences of both these proteins contain peptide sequences which bind efficiently to a number of HLA molecules (HLA-A1, -A2, -A3, -A11, -B7, -B27, -B35) and thus may serve as candidate CML specific tumor antigens. Leukemia (2000) 14, 419-426.
BackgroundCCL22 is a macrophage-derived chemokine that exerts immunosuppressive functions by the recruitment of regulatory T cells (Treg) through the CCL22/CCR4 axis. It has been described to play a key role in the suppression of anti-cancer immunity in different cancer types including ovarian, breast, or pancreatic cancer and is thought to promote the suppression of anti-cancer immunity by Treg recruitment. Recently, we described that CCL22-specific T cells generated from cancer patients can kill CCL22-expressing tumor cells and directly influence the level of CCL22 in vitro.1 In this study, we provide PoC data for a CCL22-targeting vaccine by assessing the immunotherapeutic efficacy of this approach in syngeneic mouse tumor models.Materials and MethodsPeptide vaccines that induce expansion of CCL22-specific T cells were identified by measurement of vaccine-induced ex vivo response (IFNγ ELISpot) in BALB/c and C57BL/6 mice. The antitumor efficacy was evaluated in CT26, Pan02 and B16 syngeneic models. To investigate the vaccine’s mode of action, the tumor immune infiltration was analyzed through flow cytometry and qPCR.ResultsVaccination with CCL22-specific peptide vaccines induced expansion of primarily CD8+, CCL22-specific T cell responses (assessed by ex vivo IFNγ ELISpot). Treatment with CCL22 vaccines reduced tumor growth and increased survival in CT26, Pan02 and B16 tumor models. Assessment of gene expression in the tumors indicated that vaccination leads to a reduction of CCL22 expression in the tumor microenvironment (TME), as well as the expression of other immune-suppressive molecules such as IDO. Furthermore, vaccinated mice harbored an increased CD8+ T cell infiltration with a concomitant increase in M1/M2 ratio within the TME.ConclusionsThis study provides evidence that targeting CCL22 expressing cells by vaccination induces immune modulation in the TME, leading to augmentation of anti-tumor responses - thus provides a rationale for a novel immunotherapeutic approach in cancer.Disclosure InformationI. Lecoq: A. Employment (full or part-time); Modest; IO Biotech. K.L. Kopp: A. Employment (full or part-time); Modest; IO Biotech. R. Christensen: A. Employment (full or part-time); Modest; IO Biotech. E. Martinenaite: A. Employment (full or part-time); Modest; IO Biotech. A.W. Pedersen: A. Employment (full or part-time); Modest; IO Biotech. M.H. Andersen: A. Employment (full or part-time); Modest; IO Biotech.
BackgroundIndoleamine 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 MethodsIDO1-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.ResultsThe 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.ConclusionsAs 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.ReferenceSørensen 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): 2200–10Disclosure InformationS. 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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