Towards clinical TCR gene therapy: tumor models and receptors

During the past few decades great progress has been made in the field of cancer immune therapy. There has been increased understanding on strategies tumors use to induce immune tolerance and evade immune responses, which enabled the design of clinical immune therapy trials. Two recent approaches that either oppose or circumvent immune tolerance towards tumors have successfully been tested in phase I clinical trials. First, immune tolerance can be opposed by monoclonal antibodies that block T cell inhibitory molecules. For example, Ipilimumab and MDX-1106 block Cytotoxic T-Lymphocyte Antigen- 4 (CTLA-4) and Programmed Death-1 (PD-1) receptor, respectively, and administration of these antibodies resulted in anti-tumor activities in patients with metastatic melanoma and renal cell carcinoma. In fact, the combination of Ipilimumab and Dacarbazine (DTIC, currently the standard first-line treatment for melanoma) increased the response rates by three-fold. These results have encouraged further testing of dosing and combinations of these immune modulating reagents. Second, immune tolerance can be circumvented by adoptive transfer of autologous and ex-vivo expanded tumor infiltrating lymphocytes (TILs). TIL therapy preceded by non-myeloablative lymphodepletion resulted in objective response rates in about 50% of advanced metastatic melanoma patients in two different medical centers, suggesting, but not yet proving anti-melanoma activity. Equally interesting were the complete responses observed in TIL therapy that ranged between 10 and 22% and seem higher than those observed for other treatments of melanoma (see Table 1). Recently, a simpler and faster method was developed to generate ‘young’ TILs that harbor characteristics associated with improved T cell persistence and in vivo survival. This young TIL culture protocol yields bulk T cells, omits the extensive in vitro testing of tumor reactivity, enriches for CD8+ T cells and depletes suppressive T cells (Treg cells). Next to TILs, adoptive transfer of tumor specific T cell clones generated from autologous peripheral T cells resulted in objective responses in 8 out of 10 metastatic melanoma patients. Notably, Butler and colleagues ‘educated’ peripheral T cells using artificial antigen-presenting cells loaded with HLA-A2-restricted tumor antigens. This protocol yielded tumor-specific T cells that are clinically long-lived and effective in melanoma patients. Collectively, the above-mentioned studies show the potential of immune therapy and especially the successes of adoptive therapy with tumor-specific T cells.

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