Small RNA enhances Anti-tumor T-cell Cancer Therapy

Adoptive T-cell transfer is an effective form of anticancer immunotherapy in which patients receive infusions of cytotoxic T cells that seek out and destroy targeted cancer cells. This type of therapy is usually preceded by a lymphodepleting chemotherapy regimen and combined with high doses of the cytokine interleukin-2 (IL-2) to eliminate immunosuppressive and other immune cells and to enhance the survival and activity of the transplanted cells. Unfortunately, these high-intensity treatments often lead to severe side effects, such as a prolonged reduction of white blood cells, an increased risk of clotting events, or an accumulation of fluid in the tissues, which limit the pool of patients healthy enough to receive the treatment and can result in prolonged hospitalization and higher health care costs. New approaches that are less toxic but equally effective could allow for more widespread use of adoptive T-cell transfer.
Luca Gattinoni, M.D, of CCR’s Experimental Transplantation and Immunology Branch, and his colleagues, including Nicholas Restifo, M.D., of CCR’s Surgery Branch, and Thomas Waldmann, M.D., of CCR’s Lymphoid Malignancies Branch, decided to examine the activity of the microRNA miR-155 in adoptive T-cell transfer, given its essential role in cytotoxic T-cell responses against tumors. The researchers transduced cytotoxic T cells that recognize gp100, an antigen on the surface of some melanomas and normal melanocytes, with retroviruses expressing GFP and miR-155, GFP and a scrambled microRNA (scr), or GFP alone. They infused the modified cells into mice with intact immune systems bearing subcutaneous melanomas along with a recombinant vaccinia virus expressing gp100, which is necessary for tumor regression in this model system. Encouragingly, the investigators observed a significant reduction in tumor size in mice that received the GFP-miR-155 over-expressing cells but not the GFP or GFP-scr cells.

These studies demonstrate that ove-rexpression of miR-155 in cytotoxic T cells was sufficient to replace immunodepletion and high dose cytokine administration to enhance the anti-tumor activity of adaptively transferred T cells. Though further studies will be required, expressing miR-155 in T cells may eliminate the need for highly toxic preparative therapies and make adoptive T-cell transfer available to a broader spectrum of cancer patients.