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Antigen-specific TIL therapy for melanoma: a flexible platform for personalized cancer immunotherapy
© Kelderman et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
Adoptive cell therapy (ACT) for melanoma has shown to be an effective treatment modality with clinical responses in approximately 50% of stage IV disease patients. However, durable complete responses are observed in only a small proportion (10-20%) of patients. Recent data have demonstrated that the tumor-infiltrating lymphocyte (TIL) infusion products used for therapy harbor only low frequencies of T cells reactive against presently known shared melanoma-associated epitopes. Furthermore, ongoing studies indicate that T cell reactivity against patient-specific mutated antigens may be common in human melanoma. Collectively, these two observations suggest that the development of a clinically applicable approach that allows the selection of defined tumor-reactive T cell populations in a patient-specific manner would be of value. Here we develop such a platform technology and demonstrate its value in a preclinical model. First, reversible (strep-tagged) HLA-A*0201 molecules for clinical use were produced with a UV-sensitive peptide ligand, and the resulting MHC class I monomers could be loaded with peptides of interest in straightforward peptide exchange reactions. To subsequently evaluate the potential of these MHC exchange streptamers for antigen-specific T cell enrichment, we performed individual or combined enrichments of melanoma-reactive T cell populations from TIL populations. Enrichment of both high (1≥%) and low frequency (<1%) tumor-specific T cell populations, either alone or combined, was shown to be feasible with a mean enrichment factor of 27 and 56. To evaluate the potential of this technology for the generation of T cell products that recognize patient-specific neo-antigens, we performed combined enrichments of two HLA-A*0201 restricted T cell responses, directed against neo-antigens in the CDK4 (2.2% of CD8+ cells) and GCN1L1 (0.58% of CD8+ cells) gene products that we identified by exome sequencing. Combined enrichment of these two patient-specific T cell populations resulted in a neo-antigen specific cell product with a purity of 92.4%. Functional analysis of the neo-antigen selected T cell product against autologous tumor in NSG mice showed superior tumor control and survival compared to non-selected ‘standard’ TIL. Together, these data demonstrate that selection of (panels of) antigen-specific T cells using the combination of UV-induced ligand exchange and reversible streptamer technology is feasible. In combination with exome-driven analysis of tumor-specific T cell reactivity in human cancer, this strategy forms a highly flexible platform for the development of antigen-specific cell products for personalized cancer immunotherapy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.