Abstract and Introduction
Allogeneic hematopoietic stem cell transplantation (HCT) is currently the standard of care for most patients with high-risk acute leukemias and some other hematologic malignancies. Although HCT can be curative, many patients who undergo allogeneic HCT will later relapse. There is, therefore, a critical need for the development of novel post-HCT therapies for patients who are at high risk for disease recurrence following HCT. One potentially efficacious approach is adoptive T-cell immunotherapy, which is currently undergoing a renaissance that has been inspired by scientific insight into the key issues that impeded its previous clinical application. Translation of the next generation of adoptive T-cell therapies to the allogeneic HCT setting, using donor T cells of defined specificity and function, presents a unique set of challenges and opportunities. The challenges, progress and future of adoptive T-cell therapy following allogeneic HCT are discussed in this review.
Allogeneic hematopoietic stem cell transplantation (HCT) can be curative and is the standard of care for many chemotherapy-refractory and high-risk hematologic malignancies including acute myeloid leukemia, acute lymphoid leukemia, chronic lymphoid leukemia (CLL), non-Hodgkin's lymphoma and Hodgkin's lymphoma. Unfortunately, a significant fraction of patients who undergo allogeneic HCT will later relapse, and the development of novel post-HCT therapies for patients who are at high risk for disease recurrence following HCT is an important objective of current research. The pre-HCT radiation and/or chemotherapy that are administered to the recipient to enable donor hematopoietic stem cell engraftment also provide potent anti-tumor activity, particularly when delivered at myeloablative intensity. However, seminal studies have shown that patients who received allogeneic HCT with T-cell-replete grafts from HLA-matched sibling donors had a lower incidence of relapse compared with those who received T-cell-depleted grafts.[2,3] This result confirmed predictions from murine models that illustrated the importance of donor T cells for a curative graft-versus-leukemia/tumor (GVL/T) effect and led to the logical assumption that T-cell immunotherapy may be a powerful tool to prevent and treat disease relapse after HCT. Although donor T cells are critical to the GVL/T effect, their presence is also associated with a significantly increased risk of graft-versus-host disease (GVHD). Thus, a major challenge is how to implement T-cell therapy to prevent or treat relapse after allogeneic HCT in such a way as to avoid GVHD.
Several advances in distinct areas of research have culminated in the development of strategies for utilizing the adoptive transfer of T cells to selectively target malignant cells. These advances include the identification of target antigens on cancer cells, the development of tools for introducing genes that encode tumor-targeting receptors into T cells and insights into T-cell biology that may provide for more reproducible engraftment and function after adoptive T-cell transfer. Thus, adoptive T-cell immunotherapy can, in principle, provide precise control of the targeted antigen and rapidly increase the number and avidity of T cells in the patient that can recognize the tumor. The application of adoptive T-cell therapy after allogeneic HCT, particularly with genetically modified donor T cells, presents unique challenges because the patients are typically receiving immunosuppressive drugs, and the infusion of donor T cells has the potential to cause GVHD. Here, the authors review current efforts to define appropriate targets for adoptive T-cell therapy to treat hematologic malignancies and establish platforms for graft engineering and gene transfer to facilitate safe and effective T-cell therapy in allogeneic HCT recipients.
Expert Rev Hematol. 2012;5(4):409-425. © 2012 Expert Reviews Ltd.