When gene therapy meets adoptive cell therapy: better days ahead for cancer immunotherapy?

Evaluation of: Johnson LA, Morgan RA, Dudley ME et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3), 535-546 (2009). Effective cancer immunotherapy requires large numbers of antitumor lymphocytes with effective homing and effector functions over a prolonged time. Adoptive cell therapy (ACT) has proven a promising immunotherapy approach by achieving clinical responses in patients bearing metastatic melanoma. ACT expands a cancer patient's own cytotoxic lymphocytes in vitro and reinfuses them in vivo. Identifying cytotoxic T lymphocytes directed against cancer cells can, however, be a tedious endeavor. The paper under evaluation overcomes this hurdle and proposes a highly effective gene therapy approach to transduce a patient's lymphocytes with a high-avidity T-cell receptor, thus turning reinfused lymphocytes into strong effector cells directed against cancer. Furthermore, transgenic mice were used to broaden the repertoire of human transduced T-cell receptor to evasive tumor-associated antigens. Patients bearing metastatic melanoma were successfully treated with ACT using peripheral blood lymphocytes transduced with Mart-1 and gp100 tumor-associated epitopes. Objective clinical response rates of 30 and 19% were obtained in patients treated with the human and mouse T-cell receptors, respectively. Gene-engineered cells persisted in all patients at high level for 1 month after treatment. These findings have two major implications: first, transgenic mice can be used to obtain high-avidity T-cell receptors specific for elusive tumor-associated antigens, bypassing the need for frustrating immunizations attempts. Second, a gene therapy approach to ACT allows for an efficient transduction of patient's lymphocytes into highly avid tumor-specific cytotoxic cells, eliminating the requirement for identification and selection of tumor-specific lymphocytes in individual patients. Taken together, these results mark a step towards standardized immunotherapy protocols open to all patients and that will be able to deliver consistent clinical results.