Survivin is a tumor-associated antigen (TAA) that inhibits apoptosis and is widely overexpressed in cancer cells; therefore, survivin has potential as a target for cancer immunotherapy. Application of HLA-A2–restricted survivin-specific T cell receptors (TCRs) isolated from allogeneic HLA–mismatched TCR repertoires has, however, been impeded by the inability of these TCRs to distinguish healthy cells expressing low levels of survivin from cancer cells with high survivin expression levels. Here, we identified an HLA-A2–restricted survivin-specific TCR isolated from autologous TCR repertoires that targets tumor cells in vitro and in vivo but does not cause fratricidal toxicity. Molecular modeling of the TCR-peptide-HLA ternary complexes and alanine scanning revealed that the autologously derived TCRs had tighter interactions with the survivin peptide than did fratricidal TCRs. Similar recognition patterns were observed among 7 additional TAA-specific TCRs isolated from allogeneic versus autologous repertoires. Together, the results from this study indicate that maximal peptide recognition is key for TCR selectivity and likely critical for reducing unwanted off-target toxicities. Moreover, isolating TCRs from autologous repertoires to maximize TCR selectivity has potential as a useful strategy to identify and select other shared tumor- and self-antigen–specific TCRs and ensure selective antitumor activity.
Caroline Arber, Xiang Feng, Harshal Abhyankar, Errika Romero, Meng-Fen Wu, Helen E. Heslop, Patrick Barth, Gianpietro Dotti, Barbara Savoldo
Submitter: Mads Hald Andersen | mads.hald.andersen@regionh.dk
Herlev Hospital, Department of Hematology, Center for Cancer Immune Therapy, 2730 Herlev
Published December 10, 2014
In a very important study published in the Journal of Clinical Investigation, Arber and colleagues re-establish survivin as an attractive target for anti-cancer immunotherapy (1). Previously, this concept was challenged by findings showing that lymphocytes expressing high-avidity transgenic T cell receptors (TCRs) recognizing survivin underwent apoptosis over time (2). Expression of survivin in activated T cells was suggested to result in self-recognition and fratricide. However, Arber and colleagues were able to isolate autologous repertoires of survivin-specific TCRs that did not target normal hematopoietic progenitor cells, but only tumor cells. These findings are supported by several previous pre-clinical and clinical studies based on autologously-generated T cells.
In 2003, Smidt and colleagues showed that even though activated B- and T-cells express survivin, these cells were not recognized by survivin-specific cytotoxic T lymphocytes ex vivo (3). Similarly, survivin-specific T cells did not lyse stimulated T cells in a murine lymphoma model (4). Furthermore, in vitro generated survivin-specific T cells, stimulated with full-length dominant-negative survivin, did not affect the hematopoietic colony formation of CD34+ purified progenitor cells (5). When used as a vaccine target in preclinical studies, the survivin-directed immune response affected both tumor cells and tumor-associated angiogenesis and eradicated pulmonary metastases without toxicity, including no effects on wound healing or fertility (6, 7).
Also of consideration are the spontaneous existences of survivin-specific T cells that have been described in patients with a variety of different malignancies, both in the peripheral tissues and among tumor-infiltrating lymphocytes (8-15). In fact, survivin was first described as a tumor antigen because of spontaneous immunity, i.e. clonal expansion of T cells in vivo, in melanoma and chronic lymphocytic leukemia almost 15 years ago (9). Furthermore, survivin-specific T-cell reactivity was found at all time points examined in a longitudinal examination conducted for over seven years in a melanoma patient who was in complete remission following IL-2-based immunotherapy (16). The data demonstrated that survivin-specific T cells may persist in vivo for extended periods in the absence of the clinical manifestation of disease as well as autoimmunity.
Survivin is a very interesting tumor antigen because it is prominently expressed in virtually every human malignancy (17-23). Thus, one of the most significant features of survivin is its preferential expression in tumor versus normal tissues. Accordingly, a survivin-specific T-cell clone isolated from a breast cancer patient efficiently lysed a large panel of malignant cell lines of different origins (24). In addition, down regulation of survivin as a means of escaping the impact of therapy would severely affect the survival capacity of malignant cells. Finally, very simple survivin-based vaccination approaches have already demonstrated interesting clinical effects in a few patients in small clinical trials (25, 26). Hence, more potent survivin-based vaccines or adoptive T cell therapy with genetically engineered anti-survivin TCRs could be interesting novel treatment modalities for cancer treatment.
References
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