The purpose of our research is to more safely perform allogeneic stem cell transplants across HLA barriers so that virtually all patients will have an available related donor, and to establish the necessary hematopoietic chimerism for our tolerance-induction protocols. The development of these research protocols is the result of a longstanding collaboration with the MGH Transplantation Biology Research Center (TRBC). Novel transplant strategies, based on exciting observations in preclinical models of nonmyeloablative stem cell transplantation and tolerance induction, have been implemented and are strong evidence of ongoing translational efforts between the basic science and clinical sections of the program. Specific clinical protocols include:
Nonmyeloablative Allogeneic Stem Cell TransplantationMassachusetts General Hospital was one of the first hospitals to employ a nonmyeloablative preparative strategy for allogeneic stem cell transplantation. The purpose of this strategy was to induce mixed lympho-hematopoietic chimerism to reduce the risk of GVHD and to serve as an immunological platform for adoptive cellular therapy (via donor lymphocyte infusions, or DLI). This approach is associated with substantially less toxicity than conventional myeloablative transplant approaches, and has allowed for the transplantation of patients who are older or with significant comorbidity. The induction of sustained mixed chimerism following HLA-mismatched transplantation was demonstrated with this approach for the first time. Potent antitumor responses have been observed in a significant number of patients with advanced chemorefractory hematologic malignancies. DLI have resulted in conversion of mixed chimerism to full donor hematopoiesis with no, or manageable, GVHD in most cases of HLA-matched stem cell transplantation. Recent changes in the protocol for HLA matched transplantation have included the substitution of peripheral blood for bone marrow as the source of hematopoietic progenitor cells to enhance the probability of sustained chimerism and the stratification of DLI according to patterns of chimerism to reduce the risk of GVHD. Given our exciting observations in the field of HLA-mismatched transplantation, in which GVHD has been effectively prevented by ex vivo T cell depletion of peripheral blood stem cells, a similar strategy will be adopted in the HLA-matched transplant setting in the near future.
Nonmyeloablative Haploidentical Stem Cell Transplantation
Because of a high risk of graft versus host disease (GVHD) with our initial nonmyeloablative transplant strategy, we have modified our protocol. It now includes ex vivo T cell depletion of the peripheral blood stem cell graft and the substitution of MEDI 507 (a monoclonal anti-CD2 antibody) for antithymocyte globulin to effect a more complete in vivo host and donor T-cell depletion (to prevent both graft rejection and GVHD). With this approach, mixed chimerism has been reliably achieved with minimal or no GVHD. Some patients have received DLI with conversion of their T cell chimerism. Sustained antitumor responses have been observed in patients with chemorefractory non-Hodgkin's lymphoma. Studies of immune reconstitution and mechanisms of tolerance induction are presently being performed in the laboratory of Megan Sykes, MD, of the Transplantation Biology Research Center (TBRC).
Combined HLA matched bone marrow and kidney transplantation for end-stage renal disease secondary to multiple myeloma:
This clinical strategy is based on a number of preclinical models from the TBRC in which donor-specific tolerance for an organ graft was reliably induced following the establishment of even transient mixed lymphohematopoietic chimerism. Over the past five years, five patients have received a combined HLA-matched kidney and bone marrow transplant for multiple myeloma with renal failure. Evidence of tolerance for the organ graft has occurred in each case. Sustained antimyeloma responses have been observed in three patients. This treatment is now being offered under the auspices of an NIH Immune Tolerance Network-sponsored multicenter trial. Combined haploidentical bone marrow and kidney transplantation for renal failure (without underlying malignancy).
Given the potential advantages of donor-specific tolerance induction (i.e., the avoidance of long-term immunosuppressive therapy), the establishment of mixed chimerism following nonmyeloablative conditioning for tolerance induction has been extended to patients with renal failure without an underlying malignancy. This protocol is also being conducted under the auspices of the Immune Tolerance Network. Evidence of donor specific tolerance has been achieved in the first of two patients who have been enrolled on this trial.
Cord Blood Transplantation
Under the direction of Dr. Karen Ballen, a series of cord blood transplant protocols have been developed. In an effort to overcome the problem of graft rejection in adult patients receiving cord blood, two closely matched cord blood units have been used as the source of stem cells following both nonmyeloablative and myeloablative conditioning regimens. Encouraging survival probabilities with minimal GVHD have been demonstrated in patients with hematologic malignancies. Based on an important discovery in the laboratory of Dr David Scadden in which favorable effects of human parathyroid hormone (PTH) on stem cell development were shown, a cord blood protocol utilizing post-transplant PTH to enhance hematologic and immunologic reconstitution is in progress.
Future Protocol Development
Other transplant strategies that are being evaluated in the Bone Marrow Transplant Program include:
Rasburicase for the prevention of GVHD:
Given the possible role of uric acid as a danger signal in the activation of host antigen presenting cells, rasburicase will be given during conditioning therapy for allogeneic stem cell transplantation in an effort to prevent GVHD. Studies of immune reconstitution post-transplant will be undertaken in an attempt to discern the mechanism of GVHD protection.
Recipient lymphocyte infusions (RLI) for the intentional rejection of donor chimerism following nonmyeloablative haploidentical stem cell transplantation
An unexpected outcome following our initial nonmyeloablative bone marrow transplants was that approximately one third of our patients rejected their grafts. Surprisingly a substantial proportion of these patients achieved sustained remissions of their chemorefractory hematologic malignancy. In an effort to determine the mechanism of these anti-tumor responses a murine MHC-mismatched nonmyeloablative transplant model was conducted in the laboratory of Dr Megan Sykes in which RLI were given after mixed chimerism was established. Improved tumor-free survival was observed in the mice whose grafts were rejected by the RLI and who subsequently received a tumor challenge. Host-specific anti-tumor responses were believed to be responsible for the improved tumor-free survival. This protocol represents very well the bench to bedside (and back to the bench) translational research that is being conducted by investigators at the TBRC and the clinical Bone Marrow Transplant program of the Massachusetts General Hospital.
1 Ballen KK, King R, Carston M, Kollman C, Nelson G, Lim S, Reece D, Giralt S, Vesole DH
Outcome of unrelated transplants in patients with multiple myeloma.
Bone Marrow Transplant. 03/23/2005; 35(7); 675-81.
2 Ballen KK
Advances in umbilical cord blood transplantation.
Curr Stem Cell Res Ther. 01/28/2008; 1(3); 317-24.
3 Shaffer J, Villard J, Means TK, Alexander S, Dombkowski D, Dey BR, McAfee S, Ballen KK, Saidman S, Preffer FI, Sachs DH, Spitzer TR, Sykes M
Regulatory T-cell recovery in recipients of haploidentical nonmyeloablative hematopoietic cell transplantation with a humanized anti-CD2 mAb, MEDI-507, with or without fludarabine.
Exp Hematol. 06/25/2007; 35(7); 1140-52.
4 Noronha V, Berliner N, Ballen KK, Lacy J, Kracher J, Baehring J, Henson JW
Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: case study and review of the literature.
Neuro Oncol. 07/06/2006; 8(3); 280-3.
5 Ballen KK, Spitzer TR, Yeap BY, McAfee S, Dey BR, Attar E, Haspel R, Kao G, Liney D, Alyea E, Lee S, Cutler C, Ho V, Soiffer R, Antin JH
Double unrelated reduced-intensity umbilical cord blood transplantation in adults.
Biol Blood Marrow Transplant. 01/15/2007; 13(1); 82-9.
6 Dey BR, Shaffer J, Yee AJ, McAfee S, Caron M, Power K, Ting DT, Colby C, Preffer F, Ballen K, Attar E, Saidman S, Tarbell N, Sachs D, Sykes M, Spitzer TR
Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen.
Bone Marrow Transplant. 06/20/2007; 40(1); 19-27.
7 Spitzer TR, McAfee S, Sackstein R, Colby C, Toh HC, Multani P, Saidman S, Weyouth DW, Preffer F, Poliquin C, Foley A, Cox B, Andrews D, Sachs DH, Sykes M
Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies.
Biol Blood Marrow Transplant. 12/01/2000; 6(3A); 309-20.
8 Spitzer TR, McAfee SL, Dey BR, Colby C, Hope J, Grossberg H, Preffer F, Shaffer J, Alexander SI, Sachs DH, Sykes M
Nonmyeloablative haploidentical stem-cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies.
Transplantation. 06/02/2003; 75(10); 1748-51.
9 Dey BR, McAfee S, Colby C, Cieply K, Caron M, Saidman S, Preffer F, Shaffer J, Tarbell N, Sackstein R, Sachs D, Sykes M, Spitzer TR
Anti-tumour response despite loss of donor chimaerism in patients treated with non-myeloablative conditioning and allogeneic stem cell transplantation.
Br J Haematol. 01/25/2005; 128(3); 351-9.
10 Dey BR, Spitzer TR
Current status of haploidentical stem cell transplantation.
Br J Haematol. 10/25/2006; 135(4); 423-37.
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