Bone Marrow Transplantation Research
The program in Bone Marrow Transplantation (Drs. David E. Avigan, Jon Arnason, Vassiliki Boussiotis, Robin M. Joyce, James D. Levine, Jacalyn Rosenblatt, Dimitrios Tzachanis, and Jeffrey I. Zwicker) is largely involved with clinical and translational research activities.
A fundamental mission of the Hematological Malignancies and Bone Marrow Transplantation program is to enhance our understanding of the basic biology of blood cancers and to translate this knowledge towards the development of effective therapies. The program conducts a broad array of research studies directed towards enhancing and refining existing therapies, as well as examining the efficacy of new treatment approaches. These include the development of clinical protocols that are conducted through the Dana-Farber/Harvard Cancer Center (DF/HCC), the Eastern Cooperative Oncology Group (ECOG), and the Clinical Trials Network. These efforts are supported by a large infrastructure of research staff required for patient monitoring, data collection, and research analysis of studies.
A central area of translational scientific investigation has been the development of novel immune based therapies for the treatment of blood cancers. Bone marrow transplantation is uniquely curative for many patients with hematological malignancies due to the targeting of tumor cells by the transplanted donor immune system. However, the risks associated with this approach are considerable due to treatment related toxicity, transplant related infections, and the lack of specificity of the anti-tumor response resulting in damage of the normal tissues by the infused donor cells.
Investigations into these risks have led to the development of novel strategies to minimize transplant-associated toxicity while preserving its unique efficacy. We have developed several approaches for allogeneic transplantation with reduced intensity chemotherapy regimens in which anti-tumor effects are primarily mediated by donor immune cells. This approach allows for the adoption of this potentially curative therapy in older and infirm patients who would not be able to tolerate a traditional transplant. We are also studying newer regimens that will enhance the reduction of the leukemia cell burden prior to the transplant burden, and have focused our efforts on examining how the pattern of immune recovery post-transplant effects patient outcomes.
There has been strong interest in harnessing the patient's own immune system to target and eliminate cancer cells. However, tumor cells actively prevent their recognition by the immune system by creating an immunosuppressive milieu that inhibits cellular immune function. Research efforts led by Dr. David Avigan, the Program Director, and Dr. Jacalyn Rosenblatt have focused on the development of tumor vaccines that would effectively reverse the cancer cell's ability to suppress the immune system, stimulate anti-tumor immune responses, eradicate existing disease and provide long-term protection against recurrence through the development of immunologic memory against the tumor. To accomplish this effect, we are using potent immune stimulating cells known as dendritic cells (DCs), which are the native "teachers of the immune system". DCs present antigens in the context of potent costimulatory signals that are necessary for the induction of primary immune responses. As the central mediators of immune stimulation, DCs demonstrate the capacity to overcome tumor associated immune tolerance.
Through our preclinical work, we developed a vaccination system using DCs fused to whole tumor cells to produce a fusion cell that carries a broad array of tumor targets, including targets that are specific to a particular patient. Applied initially in a mouse model, we demonstrated that mice vaccinated with fusion cells developed strong anti-tumor responses, were protected from a lethal challenge of tumor cells, and, most importantly, demonstrated complete regression of established metastatic disease. We then demonstrated that fusions created with patient derived tumor cells and dendritic cells induced powerful immune responses, in vitro, against a variety of human tumors including breast cancer, ovarian cancer, and multiple myeloma.
We have subsequently received approval from the FDA to study the safety and effectiveness of the fusion vaccine in patients with cancer. We established an immunotherapy program at BIDMC in which patient specific fusion vaccines are generated in our clinical immunotherapy and cell manipulation facility. This program is multidisciplinary, drawing upon the expertise of members of the Departments of Medicine (specifically, the Bone Marrow Transplant and Oncology programs), Surgery and Pathology as well as other investigators at the Harvard Cancer Center. We have successfully completed phase I/II studies in breast and renal cancer and have demonstrated immunologic and clinical responses in a subset of patients. We are currently focusing our efforts on improving the efficacy of the vaccines and have received grant support from the National Cancer Institute, Department of Defense and the Leukemia Society to study our cancer vaccine in patients with blood cancers as well as breast, melanoma, renal and ovarian carcinoma. We are conducting two studies for patients with multiple myeloma including a protocol in which patients undergo vaccination following autologous transplantation in an effort to eliminate post-transplant residual disease. Our pre-clinical work is currently focusing on efforts to reverse tumor-mediated suppression of the immune system. We are developing strategies to expand tumor reactive T cells ex vivo in an effort to generate T cell therapies for patients with acute leukemia. We are also developing other approaches for producing cancer vaccines including the use of viruses that have been manipulated to contain tumor specific genes.
Another area of investigation concerns the identification of cancer stem cells in patients with blood cancers. One of the fundamental challenges of eradicating malignancy is that tumor cells are derived from a small number of stem cells that are distinct from the majority of tumor cells and appear to be more resistant to existing therapies. This may account for the observation that patients with blood cancers may respond to chemotherapy but subsequently succumb to disease recurrence. Bone marrow transplantation is potentially effective in eliminating blood cancer stem cells through their replacement by normal donor hematopoiesis. However, the chemotherapy treatment and the subsequent disruption of the patient's immune system results in significant treatment associated morbidity and mortality. Drs Rosenblatt and Avigan are examining approaches to selectively identify and isolate tumor stem cells so that we could develop novel therapeutic strategies to target these cells.
Under the direction of Dr. Robin Joyce, the program has also led efforts to develop antibody-mediated therapies for non-Hodgkin's lymphoma. We have completed a study, which demonstrated disease free survival in a majority of patients treated with Rituxamab in conjunction with autologous stem cell transplantation. Dr. Joyce has also been on the forefront in studies examining the effect of anti-lymphoma antibodies bound to a radioactive material in the treatment of patients with low grade and aggressive lymphoma.
Dr. Boussiotis and her laboratory are interested in: the molecular mechanisms of T cell tolerance, the role of p27kip1 in T helper and cytolytic responses, the regulation of T cell immune responses by Rap1, PI3K and its downstream pathways as therapeutic targets for T-ALL, and the reconstitution of T cell immunity after unrelated cord blood transplantation in patients with hematological malignancies.