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

Abstract

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.

Keywords::

• adoptive cell therapy
• cancer immunotherapy
• engineered lymphocytes
• gene therapy
• melanoma
• T-cell receptor

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.