Our Research Program in Transplantation

Research Milestones Three decades of achievements in the advancement of therapy more

Collaborations between Basic & Clinical Scientists

Memorial Sloan-Kettering's team approach to transplantation extends beyond the bedside to the laboratory. All of the physicians in our transplant group are also clinical investigators and many conduct laboratory research as well. Clinical and laboratory researchers are collaboratively studying the mechanisms underlying healthy immune reactions and how these can go wrong in someone with cancer. They are also using information that has come out of research in other areas such as cancer vaccines to develop new strategies for immunotherapy after transplantation. Researchers who are studying how immune cells called T cells develop are uncovering important findings on how the immune system reconstitutes after transplantation.

T Cell Infusions

Memorial Sloan-Kettering investigators are now evaluating leukocyte infusions administered in a calculated schedule to allow the delivery of specific doses of T lymphocytes to patients whose leukemia has relapsed after an allogeneic bone marrow transplant. By increasing the number of T cells given in each treatment in a controlled manner, they hope to identify a dose of T cells that will have the desired effect on leukemia cells without causing significant GvHD.

Mini-Transplants

Mini-transplants (also called reduced intensity transplants, nonmyeloablative stem cell transplants, or mixed chimera transplants) are allogeneic transplants in which the cytoreductive regimen does not completely destroy the patient's marrow, blood, and immune systems. Treatment to prepare patients for traditional transplants, in contrast, is fully myeloablative (marrow eradicating) and does completely destroy the patient's blood and immune systems.

The goal of a mini-transplant is to help the donor immune system cells to mount an attack against the patient's tumor cells. This capitalizes on the graft-versus-tumor effect of an allogeneic transplant.

Physicians use a moderately marrow suppressive regimen and then infuse the patient with the donor cells. In the months that follow, the patient and donor's immune cells coexist, but eventually the donor immune system takes over. Although mini-transplants entail a significant risk of chronic GvHD, they are potentially much more tolerable for patients because they are less toxic than a standard transplant, especially for normal cells. Our researchers have begun clinical trials of this type of transplant for patients with certain solid tumors, leukemias, and lymphomas.

Donor Leukocyte Infusions

CML patients sometimes relapse after receiving unmodified bone marrow grafts. Further infusions of stem cells from the same donor can return these patients to remission, research at Memorial Sloan-Kettering and other cancer centers has shown. Unfortunately, when these infusions contain the full complement of T cells, they also lead to severe GvHD in as many as 75 percent of patients. But when the number of T cells in each infusion is reduced, our investigators have shown, the incidence of acute GvHD also drops (to 3 percent), and more than 90 percent of these patients achieve long-lasting remissions.

Engineered T Cells

Researchers at Memorial Sloan-Kettering are developing techniques to train patients' T cells to recognize and target cancer cells. After extracting some of the patient's T cells, they expose them to artificial cells exhibiting specific proteins called tumor antigens. In this specialized context, the T cells learn to "see" the cancer cells as diseased. When these cells are readministered to the patient, they should seek out and destroy the cancer cells. To make this process even more effective and less toxic, researchers are working toward making the T cells sensitive to a relatively nontoxic drug like the antiviral agent ganciclovir. Should the readministered T cells begin to cause GvHD, physicians could eliminate them by giving the patient ganciclovir. Memorial Sloan-Kettering will soon begin clinical trials of these specially engineered T cells.

Risk-Adapted Therapy

Physicians are working to develop treatment strategies that best identify which patients will benefit from autologous stem cell rescue, and which patients should be treated with other approaches. Clinical trials now under way here include a study testing different chemotherapeutic regimens in combination with transplantation for patients with non-Hodgkin's lymphoma. There is also a study that will examine the efficacy of transplantation as a first-line therapy in patients who are otherwise expected to do poorly with standard therapy.

Transplantation in Germ Cell Tumors

Memorial Sloan-Kettering clinicians are currently evaluating whether combining chemotherapy with bone marrow or peripheral stem cell transplantation is more effective than combination chemotherapy alone in treating men with germ cell tumors. Through another trial, researchers are hoping to determine whether a treatment regimen that includes transplantation allows them to give higher doses of chemotherapy and kill more tumor cells.

Immune Recognition of Genetic Disparities

Lymphocytes that react to alloantigens mediate graft rejection (by host lymphocytes) and graft-versus-host disease (GvHD, by donor lymphocytes). Memorial Sloan-Kettering investigators have studied the genetic bases for alloantigenic disparities that elicit potentially serious reactions. This group pioneered the development of DNA sequence-specific typing of human leukocyte antigen (HLA) class I alleles. These techniques have identified multiple genetic microvariants that are important in a transplant setting. The clinical significance of these disparities is now being analyzed both retrospectively and prospectively.

Our researchers have documented that CD8+ cytotoxic T cells from the host can recognize unique microvariants of HLA-B and HLA-C alleles. More recently, techniques have been developed to assess the role of disparities of genes located outside the major histocompatibility complex (MHC), including minor alloantigens such as HA-1. The potential role of genetic disparities of KIR expression in engraftment, GvHD, and the leukemia resistance conferred by a marrow allograft is now being evaluated.

Graft-versus-Host Disease

GvHD has been a major obstacle in allogeneic hematopoietic cell transplantation. Among adults who receive unmodified HLA-matched marrow transplants, the risk of severe GvHD remains 30 to 56 percent, despite the use of immunosuppressants. T cells against alloantigens initiate GvHD, but the mechanisms used by T cells are poorly understood.

Increasing Efficacy & Decreasing Toxicity of Transplants

Memorial Sloan-Kettering scientists have demonstrated a central role for the Fas/Fas ligand pathway in GvHD mediated by CD4+ T cells. Recent studies have also suggested that the death receptor TRAIL plays a role in the pathogenesis of GvHD. Most importantly, the critical anti-leukemia effects of transplanted T cells (graft versus tumor) require integrity of the perforin pathway, but are independent of the Fas and TNF pathways. These results suggest that uncoupling of effector pathways of T cells that mediate graft versus tumor from GvHD could increase therapeutic efficacy and decrease toxicity of transplants.

The Role of Dendritic Cells

Several lines of evidence have also demonstrated that bone marrow-derived antigen-presenting cells can stimulate T cells against major and minor alloantigens. The critical antigen-presenting cells are called dendritic cells, and the reactive T cells can in turn mediate GvHD or graft rejection. Our investigators have pioneered the development of techniques for generating and isolating different classes of human dendritic cells. In the context of hematopoietic transplantation, this group is examining the capacity of different types of dendritic cells to play pivotal roles in the competing processes of graft rejection, GvHD, graft-host tolerance, and immune reconstitution. These investigators are also using dendritic cells to stimulate active immunity against cancer.

Novel Methods to Promote Recovery Current investigations to enhance immune reconstitution more

T-Cell Depletion Investigations

Initially, the benefits from T-cell depletion in GvHD prevention were counterbalanced by a high risk of graft failure. Our researchers demonstrated that graft failures were mainly ascribable to the re-emergence of cytotoxic host CD8+ or CD4+ T cells after transplant that were specifically reactive against single HLA class I or II alleles or minor alloantigens of the donor. This team has conducted a series of phase II trials testing stepwise introductions of immunosuppressive agents into the cytoreduction regimen. With the current regimen, the incidence of graft failures has been reduced to less than 2 percent after HLA-matched related or unrelated transplants, and to 8 percent after two to three HLA allele-disparate grafts.

The success of T-cell-depleted bone marrow transplants in the treatment of adults with acute leukemia has been striking. For example, in patients with acute myelogenous leukemia (AML), 72 percent of patients transplanted during the first remission and 66 percent of those transplanted in the second remission have achieved extended disease-free survival. Only 7 percent of patients have relapsed by seven years, which is not different from the rate of relapse in patients with acute leukemia who received unmodified transplants. In fact, it is substantially less than the relapse rates for AML reported by many other centers using unmodified or conventional allografts. This has also been achieved without causing significant acute or chronic graft-vs-host disease (GvHD). This indicates that at least in some diseases like AML, the competing processes of GvHD and graft-vs-leukemia (GvL) can be uncoupled.

In contrast, in patients with chronic myelogenous leukemia (CML), transplantation with T-cell-depleted grafts leads to an unacceptably high relapse rate: 43 percent at six years. These results are consistent with the notion that in CML, but not in acute leukemias, lymphocytes within the graft provide important therapeutic graft-versus-leukemia effects.

Adoptive Cellular Therapy

Early studies conducted in Munich, and rapidly confirmed at Memorial Sloan-Kettering and other centers, have shown that patients with CML who relapse after allogeneic transplants can be reinduced into durable molecular remission by infusion of high doses of peripheral blood leukocytes from the donor. Unfortunately, leukocyte infusions also lead to severe GvHD in up to 75 percent of treated patients. Our researchers have shown, however, that low doses of donor T cells administered late after transplant lead to a low incidence of acute GvHD (3 percent), but induce molecular remissions in more than 90 percent of relapsed CML patients.

Donor leukocyte infusions have rarely been effective in the treatment of acute leukemias, however. We have therefore developed a collaborative program to (a) characterize effector cells mediating leukemia resistance associated with marrow allografts; (b) develop novel strategies for generating donor T cells against antigens/alloantigens uniquely or differentially expressed by malignant versus normal hematopoietic cells; and (c) explore strategies employing alloantigen-reactive T cells transduced to express a "suicide" gene for a controlled, reversible GvHD response that can potentiate engraftment and eradication of residual leukemia.