Invited lecture: Vaccines against cancer
(2008) WHO Global Vaccine Research Forum and Parallele Satellite Symposia — Location: Institut Pasteur, Paris, France (29.June.2008)
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- Abstract
- Therapeutic vaccination of cancer patients is a promising approach for cancer therapy. It is based on the molecular definition of tumor antigens recognized by cytolytic T lymphocytes (CTL). These antigens correspond to peptides resulting from intracellular degradation of tumor-specific proteins. The peptides are presented to CTL by MHC class I molecules at the surface of tumor cells. Cancer vaccines aim at increasing immune responses against those tumor antigens in order to induce immune rejection of the tumor. A number of vaccination strategies have been tested in clinical trials, including peptides, recombinant viruses, recombinant proteins with various adjuvants, and antigen-loaded dendritic cells. These trials mainly addressed melanoma, for which a high number of tumor antigens have been defined, including those encoded by the MAGE family of cancer germline genes. Regressions of metastatic melanomas were observed in 10-20% of the patients, in the absence of any toxicity. A detailed analysis of the anti-tumor CTL response in treated patients indicated a massive infiltration of tumor sites by anti-tumor CTL. This infiltration was already observed before vaccination, and appears to results from a spontaneous CTL response, which became inefficient at the tumor site. Thus, an important factor limiting the efficacy of immunotherapy is the development of mechanisms allowing tumors to resist immune rejection. The challenge is to identify such mechanisms and design therapeutic approaches to overcome it. A powerful tumor resistance mechanism is based on the expression by tumor cells of Indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that catalyses rapid tryptophan degradation, resulting in a local tryptophan depletion that severely affects T lymphocyte proliferation and is thereby profoundly immunosuppressive. We showed that many human tumors express IDO in a constitutive manner. We confirmed that tumoral IDO was enzymatically active. Making use of a preclinical model system, we also showed that this constitutive expression of IDO endows tumor cells with the ability to resist immune rejection by preventing T cell attack in vivo. Importantly, this effect was partly reverted by systemic treatment of mice with 1-methyl-L-tryptophan, an inhibitor of IDO. These results suggest that the efficacy of therapeutic vaccination of cancer patients could be improved by concomitant administration of an IDO inhibitor. Huijbers I, Krimpenfort P, Chomez P, van der Valk MA, Song J-Y, Inderberg-Suso E-M, Schmitt-Verhulst A-M, Berns A, Van den Eynde BJ. An inducible mouse model of melanoma expressing a defined tumor antigen. Cancer Res 2006 ; 66 : 3278-86. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Med 2003 ; 9 : 1269-74. Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde BJ. An antigenic peptide produced by peptide splicing in the proteasome. Science 2004 ; 304 : 587-90. Warren EH, Vigneron NM, Coulie PG, Gavin MA, Stroobant V, Chapiro J, Dalet A, Tykodi SS, Xuereb SM, Mito JK, Riddell SR, Van den Eynde BJ. A minor histocompatibility antigen produced in the proteasome splicing of non-contiguous peptide fragments in the reverse order. Science 2006 ; 313 : 1444-47.
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Van den Eynde, B. (2008). Invited lecture: Vaccines against cancer. WHO Global Vaccine Research Forum and Parallele Satellite Symposia, Institut Pasteur, Paris, France. https://hdl.handle.net/2078.5/50258