Immunotherapy of cancer for the elderly patient: does allogeneic bone marrow transplantation after nonmyeloablative conditioning provide a new option?

Abstract

The critical role of antigen-specific T cells in cancer immunotherapy has been amply demonstrated. Though success of clinical trials still remains far behind expectations, the continuous improvement in our understanding of the biology of the immune response will provide the basis for optimized cancer vaccines. This review focuses on active therapeutic vaccination after allogeneic bone marrow cell transplantation with nonmyeloablative conditioning. This approach could provide a major breakthrough in cancer immunotherapy, particularly of elderly patients. The senescent immune system, mainly the T-cell compartment, displays reduced responsiveness, and this has to be overcome if therapeutic vaccination is to be of benefit for the patient. Although the defects are quite well characterized, the inducing factors and ways to overcome them are still to be explored in more detail. Many questions also remain to be answered in the field of allogeneic bone marrow transplantation after nonmyeloablative conditioning to optimize this therapeutic setting in cancer immunotherapy. Current considerations to improve engraftment and to reduce graft-versus-host disease while strengthening graft-versus-tumor reactivity will be briefly reviewed. Finally, I will discuss whether tumor-reactive T cells can be "naturally" maintained during the process of T-cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, a T-cell vaccine will meet a pool of virgin T cells in the allogeneically reconstituted host, which are tolerant toward the host but not anergized toward tumor antigens presented by MHC molecules of the host. Inevitably, the problem of the aged immune system would be circumvented.

Natural Killer Cell-Enriched Donor Lymphocyte Infusions from A 3-6/6 HLA Matched Family Member following Nonmyeloablative Allogeneic Stem Cell Transplantation

“…15 As the majority of spontaneous tumors are typically non-immunogenic, the elicitation of NK cell mediated major histocompatability complex unrestricted cytotoxicity may be helpful in inducing significant antitumor responses while this cell type does not appear to induce aGVHD. 18,19,20 …”

CD44 promotes progenitor homing into the thymus and T cell maturation

“…Thymus involution, starting soon after birth, does not create health problems in adults as a result of maintenance of rudimentary function [4] and the higher proportion of memory T cells [5,6]. However, when adults require a therapeutic replacement of the hematopoietic system, the failure of appropriate T cell education poses a serious problem on this therapeutic setting [7][8][9]. Thus, repopulation of the thymus and intrathymic T cell maturation are important in BMC reconstitution.…”

Thymocyte expansion and maturation: crosstalk of CD44v6 on thymocytes and panCD44 on stroma cells

“…This requires intrathymic maturation of graft‐derived T cells, to become tolerant toward the host. However, intrathymic T‐cell maturation is severely impaired in the elderly because of thymic involution 41 . We report here that re‐acquisition of immunocompetence and tolerance induction can be accelerated by over‐expression of CD44v6, which supported by the thymic stroma, facilitates early steps of thymocyte maturation.…”