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.
Learn more about our transplantation research milestones and our research aimed at improving the success of transplantation for patients.
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 multiple myeloma or 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 graft-versus-host disease.
Researchers at Memorial Sloan Kettering are developing techniques to train a patient’s T cells to recognize and kill cancer cells as well as normal cells that have been infected with viruses after a transplant. After extracting some of the patient’s T cells, our investigators expose them to artificial cells exhibiting specific proteins called tumor antigens.
The T cells learn to “see” the cancer cells as diseased, and when re-introduced into the patient, they can seek out and destroy the cancer cells. Memorial Sloan Kettering investigators have pioneered the use of donor cells as treatment for patients who develop viral infections after a transplant or have their disease return.
Treatment to prepare patients for traditional transplants, known as myeloablative therapy, utilizes very high doses of chemotherapy and radiation to totally eradicate a patient’s bone marrow cells. Such regimens are associated with additional side effects and poorly tolerated by older and sicker patients.
Memorial Sloan Kettering researchers are investigating reduced-intensity conditioning regimens — which are better tolerated because they utilize lower doses of chemotherapy and/or radiation therapy. The goal is to get rid of all cancer cells while blood stem cells from an allogeneic (donor-provided) transplant mount an attack against the patient’s tumor cells. This type of treatment capitalizes on an immune mechanism known as the graft-versus-tumor effect. Our researchers are conducting a variety of clinical trials using reduced-intensity conditioning regimens for patients with certain solid tumors, leukemias, and lymphomas.
Our physicians are developing treatment strategies to identify which patients will benefit from either an autologous transplant or an allogeneic transplant. We are also working to determine the best timing of each procedure.
Working closely with our colleagues in the Leukemia, Lymphoma, and Myeloma Services, we are developing personalized approaches for each patient, including ways to determine which treatment or clinical trial is the best option for that patient. Now under way are trials investigating the optimal dose of stem cells to infuse; the timing and type of transplant for lymphoma; the role of consolidation chemotherapy for patients with myeloma; the use of T cell depletion followed by cells targeting WT-1, a protein produced in leukemia cells; and many others.
Lymphocytes that react to self-recognition 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. We are now analyzing the clinical significance of these disparities 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.
GVHD, which may occur when cells from a donated stem cell graft attack the normal tissue of the transplant patient, has been a major obstacle in allogeneic (donor-provided) stem cell transplantation. Among adults who receive unmodified bone marrow transplants from an HLA-matched donor, the risk of severe GVHD remains 30 to 56 percent, despite the use of drugs to suppress the immune system. GVHD is initiated by T cells, a type of immune cell, but the mechanisms by which T cells cause disease are poorly understood. Researchers at Memorial Sloan Kettering are investigating the role of T cells in GVHD.
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 antileukemia 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.
Research has 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.
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 resulted from 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 GVHD. This indicates that at least in some diseases like AML, the competing processes of GVHD and graft-versus-leukemia can be uncoupled.
Encouraged by these results, we are currently investigating the outcome of T-cell-depleted transplantation from related or unrelated donors for patients with high-risk and/or relapsed multiple myeloma.
The graft-versus-leukemia effect was first discovered in patients with chronic myelogenous leukemia (CML) who had relapsed after receiving an allogeneic bone marrow transplant from an HLA-matched donor. The patients could be induced into durable molecular remissions by giving high doses of peripheral blood mononuclear cells derived from the original transplant. These studies provided the first evidence that enhanced resistance to leukemia accrued through a marrow allograft, as shown by comparing relapse rates following syngeneic and HLA-matched allogeneic transplants, was mediated by cells in the donor graft.
Donor leukocyte infusions have also been attempted for acute myeloid leukemia relapses following allogeneic marrow transplants. Antileukemic effects of donor lymphocyte infusion have been less consistently observed, and are often less durable, than in patients treated for CML.
In patients with multiple myeloma, several observations suggest that donor T lymphocytes can mediate graft-versus-myeloma immune activity following allogeneic transplantation. The existence of a graft-versus-myeloma effect has been more directly confirmed by donor lymphocyte infusion in patients who relapsed after failure allografts.
We are currently investigating cellular immunotherapeutic approaches for patients with leukemia and multiple myeloma. To improve the outcome of such therapies, we are also characterizing the effector cells that mediate leukemia resistance associated with marrow allografts, and developing novel strategies for generating donor T cells against antigens/alloantigens uniquely or differentially expressed by malignant versus normal hematopoietic cells.
One of the problems in treating brain tumors is that standard doses of chemotherapy drugs do not penetrate well into the brain, due to the blood-brain barrier. Because of the modest efficacy of chemotherapy in patients with brain tumors, treatment relies heavily on radiotherapy — which in long-term survivors can be associated with severe side effects, including decreased memory and dementia that can be life-threatening. High-dose chemotherapy followed by autologous stem cell transplant (HDCASCT) provides the opportunity to deliver very high doses of chemotherapy that can overcome the blood-brain barrier and address brain tumors in a more effective way.
We have launched two clinical trials to investigate whether HDCASCT can replace radiotherapy in the treatment of two types of brain tumors: primary central nervous system lymphomas and oligodendrogliomas. In these diseases, many patients are expected to survive more than five years with standard chemotherapy and radiotherapy, and some develop severe dementia from the radiation. We are hoping that the use of HDCASCT following standard chemotherapy will improve treatment efficacy for these brain tumors, and spare patients from radiotherapy-related side effects.
Memorial Sloan Kettering clinicians are now 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.
Autologous transplantation can cure many patients with aggressive non-Hodgkin lymphoma, even when the disease has relapsed after initial treatment. At Memorial Sloan Kettering, researchers are exploring ways to maximize the safety and efficacy of this intensive treatment.
Our efforts include a nationwide clinical trial of a new antibody therapy called ofatumumab in combination with standard chemotherapy, which our researchers are leading in an attempt to improve the effectiveness of treatment of relapsed aggressive non-Hodgkin lymphoma. For slower-growing (indolent) non-Hodgkin lymphomas that need treatment with autologous transplantation, multiple clinical trials continue to advance our ability to treat relapsed lymphomas prior to transplantation.
We are also developing trials to improve the procedures by which a patient’s peripheral blood stem cells are filtered and frozen before autologous transplant; to increase the safety and efficacy of standard high-dose therapy; and to develop new post-transplant treatments that improve the impact of the high-dose therapy. For patients with low-grade follicular lymphoma, treatment post-transplant with combined antibody and immune-boosting therapy is being investigated as a possible way to increase effectiveness even further.