Role of Human Dendritic Cells in Transplant and Tumor Immunity

Marco Mielcarek, M.D.

Fred Hutchinson Cancer Research Center

Funded in December, 2006: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Do Immune Dendritic Cells Both Help and Hinder Bone Marrow Transplant Effects?

This study will explore whether innate immune dendritic cells (DCs) in the skin of patients undergoing bone marrow transplantation for leukemia or lymphoma are responsible for initiating not only positive cancer-fighting actions, but also negative “graft-versus-host disease” (GVHD). If so, the findings may lead to ways to minimize their negative role by changing the balance between donor and host DCs in patients. Bone marrow or blood stem cell transplants for patients with the blood cancers leukemia or lymphoma, provide a new source of donor immune cells to fight and potentially cure these cancers. The transplant, however, often precipitates an attack by the transplanted tissue (the graft) on the patients' (host) tissues. This is usually manifested by severe and sometimes deadly inflammation in the skin or intestine. Physicians currently try to suppress these excessive immune responses caused by donor immune cells by giving medications that suppress donor immune cells after transplantation. Although this reduces the risk of GVHD, it also increases the likelihood of infection.

The researchers have found in mice studies, however, that even the most stringent pre-transplant efforts to kill the patients' immune cells fail to eradicate the host's immune DCs in the skin. Importantly, they also found that the hosts' DCs initiate and regulate both the anti-cancer attacks and the GVHD attacks. Moreover, larger host DC levels are associated with greater severity of GVHD.

Based on these surprising animal model findings, the researchers now seek to determine whether the same situation occurs in patients. They also want to determine whether the time it takes to replace the patient's own skin DCs with those originating from the grafted cells might depend on the intensity of the chemotherapy given in preparation for the transplant.

The investigators at the Fred Hutchinson Cancer Research Center (FHCRC) will collect skin, blood, and bone marrow samples from approximately 100 patients with leukemia or lymphoma prior to, and for several months after transplantation. They will then measure the balance between donor and host-derived DCs in blood and marrow, and assess patients' clinical outcomes data (i.e. severity of GVHD). The Mount Sinai investigators will determine, from the skin samples, whether the patients' own DCs persist and renew in the skin, and whether patients with greater numbers of donor DCs, relative to host DCs have better outcomes. If so, the investigators will try to identify specific “chemokines” (molecules that guide the actions of cells) present in the patients' skin. Such chemokines might be capable of shifting the balance of power from the hosts' DCs to the donor DCs, improving cancer outcomes while reducing the severity of GVHD.

Significance: If this research demonstrates that immune DCs in patients with leukemia or lymphoma are responsible for initiating and regulating immune attacks against both the cancer and normal host tissues by transplanted immune cells, the findings could lead to new approaches aimed at changing the balance between donor and host DCs to decrease GVHD while continuing to marshal immune attacks against the cancer.

ABSTRACT

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Role of Human Dendritic Cells in Transplant and Tumor Immunity

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative treatment for many patients with high-risk hematologic malignancies. The success of allo-HCT is largely based on immunologic graft-versus-tumor (GVT) effects mediated by allogeneic T lymphocytes present in the graft. Unfortunately, this beneficial effect is counterbalanced by the occurrence of graft versus host reactions directed against normal host tissues resulting in graft versus host disease (GVHD), a potentially life-threatening complication that limits the success of allo-HCT. GVHD may manifest as inflammation of the skin, liver and gut with the skin being the most frequently affected organ. According to the degree of genetic disparity between allogeneic donor and recipient, GVHD may occur in up to 75%, and may lead to death in up to 20% of transplant recipients.

Therefore, while preserving beneficial GVT effects, a major objective in allo-HCT is the prevention of GVHD. Using mouse allo-HCT models, we and others have identified host dendritic cells (DCs) as the key initiators and regulators of GVHD and GVT effects. However, the role of host DCs in human patients undergoing allo-HCT remains poorly understood. This proposal is based on the hypothesis that host DCs are key regulators of GVHD and GVT effects in human patients after allo-HCT. Thus, the overall goal of this application is to explore whether modulation of host DC function can be harnessed to favorably influence the balance between beneficial GVT effects and detrimental GVHD.

INVESTIGATOR BIOGRAPHIES

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Marco Mielcarek, M.D.

Marco Mielcarek received his M.D. from the Freie Universitat Berlin, Germany, in 1986. He completed a residency in Internal Medicine followed by a fellowship in Hematology/Oncology at the Freie Universitat Berlin and then joined the Fred Hutchinson Cancer Research Center in Seattle as a research fellow in 1994. His early research in the laboratories of Drs. Beverly Torok-Storb and Rainer Storb focused on immunosuppressive monocytes in growth-factor (G-CSF)-mobilized stem cell products, including their relevance in allogeneic stem cell transplantation. Between 1998 and 2003, Dr. Mielcarek pursued additional residency and fellowship training in Internal Medicine and Medical Oncology, respectively, at the University of Washington/ Fred Hutchinson Cancer Research Center in Seattle, where he joined the faculty as an Assistant Professor in Medical Oncology in 2005. He is a board-certified medical oncologist and attending physician taking care of patients with hematologic cancers who are treated by bone marrow and peripheral blood stem cell transplantation.

His research interests include preclinical and clinical aspects of nonmyeloablative stem cell transplantation (“mini”-transplants) including novel strategies for donor/host tolerance-induction, and prevention and treatment of graft-versus-host disease (GVHD).

Miriam Merad received her M.D. degree from the University of Algiers, her residency training in Hematology and Oncology from the University of Paris, and her Ph.D. degree in Immunology from Stanford University and the University of Paris. Miriam Merad is now an Assistant Professor at the Mount Sinai Medical School in New York, where her lab studies the dynamic of dendritic cells and the influence of these dynamics on adaptive immunity.

Dr. Merad discovered that LCs, in contrast to other dendritic cell population, self-renew in quiescent skin throughout life and are replaced by circulating precursors only in injured skin. Dr. Merad's laboratory is now trying to identify the nature and the niche of the skin-resident LC precursor. Dr. Merad has also discovered that Langerhans cells are radio-resistant and therefore persist in the recipient skin after allogeneic hematopoietic cell transplantation (allo-HCT).

Allo-HCT is a standard treatment for numerous hematological malignancies and is based on the capacity of donor alloreactive T lymphocytes to recognize and eradicate tumor cells. Unfortunately, this beneficial effect is counterbalanced by the occurrence of graft versus host reactions directed against normal host tissues resulting in graft versus host disease (GVHD), a potentially life-threatening complication that limits the success of allo-HCT with the skin being one of the major organ affected by GVHD. Using clinically relevant animal models of allo-HCT, Miriam Merad found that recipient Langerhans cells play a major role in cutaneous GVHD and that elimination of recipient LCs can protect from cutaneous GVHD. Based on these studies, Dr. Merad together with Dr. Mieclarek (FHRCC) are now examining whether these findings also apply to patients that receive allo-HCT. If these results are confirmed in humans, Dr. Merad's laboratory will start developing novel targeted therapies aiming at eliminating recipient tissue DCs to prevent GVHD.