Allogeneic and Autologous Transplantation Therapy of Cancer: Converging Themes

Abstract

Effective adoptive T-cell therapy of cancer occurs after allogeneic bone marrow transplantation, and is now increasingly observed after autologous transplantation. As the clinical practice of each field evolves and the biologic underpinnings of these two seemingly disparate approaches are elucidated, four converging themes have emerged. (1) T-cell antigen specificity. The alloreactive T-cell graft-versus-tumor response is difficult to dissociate from potentially lethal graft-versus-host disease (GVHD); as such, efforts are underway to enhance antigen-specificity after allogeneic transplantation. By comparison, the field of autologous T-cell therapy has now largely redefined itself by use of highly specific T-cell receptor reactivities, which may ultimately prove limiting in terms of tumor escape mechanisms; efforts are therefore underway to broaden antigenic reactivities after autologous transplantation. (2) Host conditioning. Myeloablative conditioning used in allogeneic transplantation causes significant morbidity and mortality even in young and healthy patients, thereby limiting broader application to the majority of cancer patients; in response, less intensive and better tolerated nonmyeloablative regimens are being developed. By comparison, autologous T-cell therapy has been primarily limited by lack of efficacy, and in response, investigators have increased host conditioning to myeloablative levels to create immune space that facilitates T-cell expansion and effectiveness in vivo. (3) T-cell function. The evolving discipline of T-cell biology will continue to enhance the efficacy of both autologous and allogeneic transplantation therapy. The quality of the T-cell response is of paramount importance, and is determined by T-cell differentiation status, apoptotic tendency, and cytokine phenotype vis-à-vis Th1, Th2, Treg, and Th17 balance; modulation of this balance for therapeutic gain will depend upon an ability to understand and control an emerging phenomenon termed T-cell plasticity. (4) T-cell-mediated immune pathology. GVHD after allogeneic transplantation has been an instrumental model system for understanding T-cell path ology; importantly, cellular and molecular mechanisms underlying GVHD may also contribute to toxicities observed after effective autologous T-cell therapy. As such, both allogeneic and autologous immunotherapies are now confronted with an overall goal of maximizing T-cell efficacy while limiting T-cell toxicity. Attainment of such enhanced therapeutic windows may be facilitated by recent developments in immune cell modulation, including use of cell fate control genes and use of inhibitors of the mammalian target of rapamycin (mTOR) and JAK/STAT pathways. In conclusion, converging themes in autologous and allogeneic transplantation therapy indicate that a bright future will emerge for T-cell therapies, the success of which will be realized through advances in T-cell biology and T-cell engineering.