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

Geertruida Straetemans, Miriam Coccoris, Cor Berrevoets, Elike Westerlaken, Csilla Scholten, Debby van Eck - Schipper, Timo ten Hagen, Reno Debets

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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.
Original languageUndefined/Unknown
Pages (from-to)187-201
Number of pages15
JournalHuman Gene Therapy
Issue number2
Publication statusPublished - 2012

Research programs

  • EMC MM-03-47-11
  • EMC MM-03-86-08

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