T-Cell Receptor Gene Therapy in Human Melanoma-Bearing Immune-Deficient Mice: Human but not Mouse T Cells Recapitulate Outcome of Clinical Studies

Adoptive cell therapy using T-cell receptor (TCR)–engineered T cells is a clinically feasible and promising approach to target tumors, but is currently faced with compromised antitumor efficacies in patients. Here, we extensively validated immune-deficient mice to facilitate further development of the therapeutic potential of TCR-engineered T cells. Treatment of human melanoma-bearing SCID or NSG mice with high doses of human T cells transduced with an hgp100/HLA-A2-specific TCR did not result in antitumor responses irrespective of chemotherapeutic preconditioning. Imaging of human green fluorescent protein–labeled T cells demonstrated significant T-cell accumulation in intratumoral vasculature directly upon T-cell transfer, which was followed by loss of T cells within 72 hr. Peripheral persistence of human T cells was highly compromised and appeared related to T-cell differentiation. On the contrary, adoptive transfer (AT) of relatively low numbers of hgp100/HLA-A2 TCR-transduced mouse T cells resulted in rapid clearance of large established human melanomas. Unexpectedly and in contrast to reported studies with chimeric antibody receptor–engineered T cells, antitumor activity and homeostatic expansion of T cells were independent of TCR transgene as evidenced in two SCID strains and using two different human melanoma cell lines. Interestingly, the xeno-reactive melanoma response of mouse T cells appeared to be dictated by CD4+ tumor-infiltrating lymphocytes and did not require in vitro T-cell activation, retroviral gene transfer, or subcutaneous interleukin-2 support. Taken together, AT of human but not mouse T cells in human melanoma-bearing immune-deficient mice is in close accordance with clinical studies. Straetemans and colleagues evaluate immune-deficient mouse models to test the anti-human melanoma efficacy of adoptively transferred human as well as mouse T cells engineered with a human gp100/HLA-A2-specific T cell receptor (TCR). They report that unlike human TCR T cells, mouse TCR T cells are efficacious against human melanoma cells in severe combined immunodeficiency (SCID) mice and nonobese diabetic (NOD) SCID gamma (NSG) mice and that the antitumor responses and homeostatic expansion of mouse T cells are independent of the TCR transgene.

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