Our clinical and laboratory researchers are collaboratively studying how immune reactions work and how these can go wrong in people with cancer. We are using information that has come out of research in other areas, such as cancer vaccines, to develop new strategies for immunotherapy after transplantation.
Memorial Sloan Kettering investigators are testing infusions with specific doses of T cells in people whose multiple myeloma or leukemia has come back after an allogeneic stem cell transplant. By increasing the number of T cells given in each treatment in a controlled way, we hope to find a dose of T cells that will destroy leukemia cells without causing significant graft-versus-host disease.
Treatment to prepare people for traditional transplants is called a preparative regimen or conditioning. It uses very high doses of chemotherapy and radiation that get rid of bone marrow cells. The treatment can have additional side effects and is hard for older and sicker patients.
MSK researchers are investigating reduced-intensity conditioning regimens. These are easier for patients because they use lower doses of chemotherapy and radiation therapy. The goal is to get rid of all of the cancer cells while the allogeneic transplant stem cells mount an attack against the tumor. Our researchers are doing a variety of clinical trials using reduced-intensity conditioning regimens for people with certain leukemias and lymphomas.
Our doctors are developing treatment strategies to identify who will benefit from either an autologous transplant or an allogeneic transplant. We are also working to find out the best timing of each procedure.
We work closely with our colleagues in the Leukemia, Lymphoma, and Myeloma Services to develop personalized approaches for each person we care for. These include ways to find out which treatment or clinical trial is the best option for that person.
How well a donor’s T cells match the patient can affect graft rejection (by patient T cells) and graft-versus-host disease (by donor T cells). MSK investigators have studied the genetic reasons that immune differences may cause serious reactions. We pioneered the development of DNA sequence-specific typing of human leukocyte antigen (HLA) class I alleles. This technique identifies the many small genetic changes that are important in a transplant setting. We are now studying the significance of these differences.
Our researchers have found that CD8+ cytotoxic T cells from the patient can recognize unique small changes in HLA-B and HLA-C alleles. New techniques look at the effects of genes located outside the major histocompatibility complex (MHC), including minor alloantigens such as HA-1. The potential role of genetic differences of KIR expression in engraftment, graft-versus-host disease, and the leukemia resistance conferred by a marrow allograft is now being evaluated.
In GVHD, donated stem cells attack the normal tissues in the patient. It has been a major obstacle in allogeneic (donor-provided) stem cell transplantation. Among adults who have unmodified stem cell transplants from an HLA-matched donor, the risk of severe GVHD remains 30 to 56 percent, even with drugs that shut down the immune system. GVHD is started by the T cells, a type of immune cell, but how they cause the disease is poorly understood. Researchers at MSK are studying the role of T cells in GVHD.
MSK scientists have shown there’s 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 important, the critical antileukemia effects of transplanted T cells (graft versus tumor) require the integrity of the perforin pathway but are independent of the Fas and TNF pathways. These results suggest that uncoupling of the effector pathways of T cells that mediate graft versus tumor from GVHD could improve who well treatments work and decrease the toxicity of transplants.
Research has shown that stem-cell-derived antigen-presenting cells can stimulate T cells against major and minor alloantigens. The critical antigen-presenting cells are called dendritic cells. The reactive T cells can in turn help stop 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 stem cell transplants, we are examining how much of a role different types of dendritic cells have in the competing processes of graft rejection, GVHD, graft-host tolerance, and immune reconstitution. We are also using dendritic cells to stimulate active immunity against cancer.
Initially, the benefits of T cell depletion in preventing GVHD were balanced by a high risk of graft failure. Now, graft failures has been reduced to less than 2 percent after HLA-matched related or unrelated transplants, and to 8 percent after two or three HLA allele-disparate grafts.
The success of T-cell-depleted transplants in the treatment of adults with acute leukemia has been striking. For example, in people with acute myelogenous leukemia (AML), 72 percent of them 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 them have relapsed within seven years. This is the same rate of relapse in people with acute leukemia who had unmodified transplants. In fact, it is substantially less than the relapse rates for AML reported by many other centers using unmodified or conventional allografts.
Importantly, this regimen also has resulted in lower rates of GVHD.
Encouraged by these results, we are currently studying the outcome of T-cell-depleted transplantation from related or unrelated donors for people with high-risk or relapsed multiple myeloma.
The graft-versus-leukemia effect was first seen in people whose chronic myelogenous leukemia (CML) had relapsed after receiving an allogeneic stem cell transplant from an HLA-matched donor. They could be induced into a remission with high doses of peripheral blood mononuclear cells that came from the original transplant. These studies provided the first evidence that enhanced resistance to leukemia after a transplant was due to the donated cells. This was shown by comparing relapse rates following syngeneic and HLA-matched allogeneic transplants.
Donor T cell infusions have also been tried for acute myeloid leukemia relapses following allogeneic marrow transplants. The antileukemic effects of donor T cell infusion have been less consistently observed. Often, these effects don’t last as long in people with acute myeloid leukemia as in those with CML.
In people with multiple myeloma, several observations suggest that donor T cells can control graft-versus-myeloma immune activity following allogeneic transplantation. The existence of a graft-versus-myeloma effect has been more directly confirmed by donor T cell infusion in people who relapsed after failed allografts.
We are currently studying cellular immunotherapeutic approaches for people with leukemia and multiple myeloma. To improve the outcome of such therapies, we are also characterizing the effector cells that mediate the leukemia resistance associated with marrow allografts, and we are developing novel strategies for generating donor T cells against antigens and alloantigens uniquely or differentially expressed by cancer versus normal blood cells.
MSK doctors are studying whether combining chemotherapy with stem cell transplantation is better than combination chemotherapy alone for men with germ cell tumors. In another trial, researchers are hoping to find out whether a care plan that includes transplantation allows them to give higher doses of chemotherapy and kill more tumor cells.
Autologous transplantation can cure many people with aggressive non-Hodgkin lymphoma. This can be the case even when the disease has come back after initial treatment. At MSK, researchers are exploring ways to maximize the safety and effectiveness of this treatment.