Abstract
The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES. However, utilization of these cells in current therapy protocols is hampered due to high complexity in production, relatively low cell numbers, and rapid T cell exhaustion.In order to provide off-the-shelf products in the future, we successfully generated HLA-A*02:01-restricted T cell receptor (TCR) transgenic T cells directed against CHM1319 by retroviral transduction.After short-term expansion a 100% purified CHM1319-TCR-transgenic T cell population expressed a CD62L+/CD45RO and CD62L+/CD45RA+ phenotype. These cells displayed specific in vitro IFNg and granzyme B release in co-culture with HLA-A*02:01+ ES cell lines expressing CHM1. When co-injected with ES cells in Rag2−/−ɣc−/− mice, CHM1-specific TCR-transgenic T cells significantly inhibited the formation of lung and liver metastases in contrast to control mice. Lungs and livers of representative mice displayed CD8+ T cell infiltration in the presence (control group treated with unspecific T cells) and in the absence (study group) of metastatic disease, respectively. Furthermore, mice receiving unspecific T cells showed signs of graft-versus-host-disease in contrast to all mice, receiving CHM1319-TCR-transgenic T cells.CHM1319 specific TCR-transgenic T cells were successfully generated causing anti-ES responses in vitro and in vivo. In the future, CHM1319-TCR-transgenic T cells may control minimal residual disease rendering donor lymphocyte infusions more efficacious and less toxic.
Highlights
Oncogene addiction provides ideal targets for immunotherapy
CHM1-4B4 was only positive for the variable α-chain TRAV13-1*02, detected by the Vα8 primer and the variable β-chain TRBV13*01, detected by the Vβ23 primer and was considered clonal
Loss of target antigen is a major mechanism of resistance to immunotherapy of cancer, e.g. loss of CD19 expression during CD19 directed CAR T cells in leukemia treatment [20]
Summary
Oncogene addiction provides ideal targets for immunotherapy. We have described the BRICHOS chaperon domain containing endochondral bone protein Chondromodulin-I (CHM1) being directly up-regulated by the Ewing sarcoma (ES) causing the fusion oncogene product EWS-FLI1. CHM1 maintains an undifferentiated, invasive phenotype and is required for pulmonary metastatic spread of ES [1]. The generation of tumor specific TCR transgenic donor CD8+ T cells for adoptive transfer is a promising immunotherapeutic tool to control cancer [2]. Allorestricted T cell receptor (TCR) responses represent a powerful mechanism in evolution [3]. Given the unknown accessibility of CHM1 by drugs or chimeric antigen receptor transgenic T cells (CARs), we tested the targetability of CHM1 by allo-restricted, peptide specific T cells
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