Scientists supposed two ways how this problem can be solved. The first way is following. New chimeric receptor is «suspended» upon T-cell surface. The receptor has external structure similar to that of antibodies, and it has a cytosolic domain transmitting a signal into the cell. That construction can retarget T-cells in vitro and force them to attack neoplasms. The second way is following. T-cells can be modified so they can express the natural heterodimer αβTCR detecting tumor cells. In the first clinical trial, T-cells with surface TCR specific to glycoprotein 100 (gp100) were created. A patient suffered from melanoma got an injection with those T-cells and IL-2 admixture. The aim of that method was to generate additional receptors through pairing transgenic TCR chains with natural ones. Scientists did not observe any toxic side effects. However, investigations show that expression level of gp100-specipic TCRs falls that can reduce TCR avidity and therefore minimize effector functions. Another important restriction of this method lies in the fact that every TCR is particular for the given peptide-MHC complex. Transplantation of T-lymphocytes is successfully used in various clinical cases deal with immunodeficiency and neoplasms. However, this treatment is less effective when a tumor has deficiency in the antigens. Prospective lines of the treatment based on the transplantation of modified immune cells is creation of T-cells insensitive to HIV. Preclinical trials show that such a cure is possible but its safety still should be established.
Place of employment — University of Pennsylvania School of Medicine, USA.
Contacts — 421 Curie Boulevard, Philadelphia,Pennsylvania 19104–6160(215) 573–5745 cjune@mail.med.upenn.edu .
Publications — Principles of adoptive T cell cancer therapy. Carl H. June. J Clin Invest. 2007 May Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T cell immunotherapy in murine acute myeloid leukemia. Qing Zhou, Christoph Bucher, Meghan E Munger, Steven L Highfill, Jakub Tolar, David H Munn, Bruce L. Levine, Megan Riddle, Carl H. June, Daniel A. Vallera, Brenda J. Weigel, and Bruce R Blazar. Blood. 2009 Sep.
