Ryotaro Nakamura, M.D.

December 18, 2015 | by City of Hope

Hematologic Malignancies

Originally from the south of Japan, Ryotaro Nakamura, M.D., received his medical degree at the Kumamoto University School of Medicine, after which he performed residencies at the University Hospital and associated Iizuka Hospital. He subsequently moved to the United States to pursue a residency at Thomas Jefferson University Hospital in Philadelphia, and subspecialty training in hematology/oncology at National Institutes of Health in Bethesda, Maryland. In 2002, Nakamura then made a trip to the west coast to join City of Hope, where he now serves as an associate professor in the Department of Hematology & Hematopoietic Cell Transplantation and associate chair of the Cancer Protocol Review and Monitoring Committee. City of Hope was an excellent match for Nakamura not only because it maintains an outstanding

transplant program, but also because of the incredible climate of Southern California, which reminds him and his wife of the south of Japan.

Nakamura, who has extensive training in hematopoietic stem cell transplantation (HCT), sees patients at City of Hope, typically for aplastic anemia, myelodysplastic syndrome, leukemia, lymphoma and related hematological malignancies. He is dedicated to serving this population, many of whom are involved in clinical trials. In addition, Nakamura co-chairs City of Hope’s HCT/GVHD Committee, and he represents City of Hope as a steering committee member for the Blood and Marrow Transplant Clinical Trial Network — a cooperative research group sponsored by the National Heart, Lung, and Blood Institute and National Cancer Institute focused on transplant-related clinical trials. In these ways, Nakamura has been committed to advancing the state of the art and the standard of care for transplant patients.

In this context, Nakamura’s research focuses on immunological interventions for hematological malignancies. HCT is a critical form of immunotherapy used for high-risk/relapsed leukemia, which can be associated with significant toxicities such as graft-versus-host disease (GVHD) caused by immune attack on healthy tissues of the host by infused donor immune cells. Because patients’ immune systems may not be strong immediately after the transplant procedure, other challenges associated with HCT include the risk of relapse and opportunistic infections such as cytomegalovirus (CMV). Nakamura’s research broadly encompasses studies to augment immune responses against leukemia and infection while minimizing immune-related toxicities, such as GVHD.

In the therapeutic arena, Nakamura is collaborating with Don J. Diamond, Ph.D., to develop vaccine products to produce a host immune response against CMV in HCT patients. In addition to mitigating the morbidity and mortality associated with CMV infection, a goal is also to address some of the limitations (e.g., severe adverse effects) of current antiviral treatments. The team has worked together on a phase I pilot safety trial of CMV PepVax, a peptide-based vaccine (HLA-A2-restricted pp65 epitope), which is moving into Phase II therapeutic studies supported by a recently awarded R01 grant. In an effort to expand the target population for this approach, the team also developed a strategy involving a delivery system expressing full-length CMV antigens (pp65, IE1, IE2) based on a modified vaccinia virus Ankara (CMV-MVA Triplex). This R01 supported effort will involve two clinical trials of the CMV-MVA vaccine to: 1) evaluate the vaccine’s safety and the immune responses in healthy volunteers (recently completed) and 2) evaluate efficacy in preventing CMV infection and safety in HCT recipients at high risk for CMV reactivation.

Nakamura has led or participated in a number of institutional and multicenter trials for prevention/treatment of GVHD. He and his colleagues are one of the first groups to develop new GVHD prophylaxis using tacrolimus and sirolimus, reporting early promising results and unique and important complication, thrombotic microangiopathy. In collaboration with Samer Khaled, M.D., and Jeffrey Weitzel, M.D., his team identified a potential link between certain genetic variants involved in drug metabolism of tacrolimus/sirolimus and blood drug levels and clinical outcome such as GVHD.

In effort to better understand factors determining treatment outcomes Nakamura has worked on many immunologic or genetic correlative studies. During his training at National Institutes of Health he observed oligoclonal expansion of T cells in patients with myelodysplastic syndrome (MDS) and reported an association between HLA-DR15 and treatment response to immunosuppressive therapy in MDS, which has been adopted to the National Comprehensive Cancer Network guidelines. At City of Hope, in collaboration with Diamond, John Zaia, M.D., and Stephen Forman, M.D., he reported a number of observations including, but not limited to: reduction of leukemia relapse with higher transplant CD34+ cell dose, an association between CD8 T cell responses against HY-based minor antigens and chronic GVHD, prediction of leukemia relapse by molecular quantitative monitoring of a leukemia antigen, WT1, and an association between CMV infection and memory NK cells (NKG2C+NK). The latter is of particular interest since his team also observed that the risk of leukemia relapse after HCT may be reduced when patients experience CMV reactivation. One can hypothesize that CMV infection may be shaping the immune system early after HCT and providing a beneficial landscape for T cells and NK cells, which may lead to an immune environment that controls leukemia from recurring. The ongoing CMV vaccine trials described above will likely shed more light on this intriguing question.

Given this impressive portfolio of clinical and research activities, it may seem that Nakamura has time only for work and no play. Nevertheless, he is committed to the Blade Runners — an extramural soccer team built up by John Rossi, Ph.D. — and their quest for the cup in their “over 40” league. Under the leadership of team manager Ralf Buettner, Ph.D., the team’s exceptional prowess and the efforts of star player Nakamura (who has been playing since he was nine through college) have made them a formidable force. Nakamura greatly enjoys playing with a diverse group and getting yelled at in myriad different languages. Part of the secret to his success — don't resist getting knocked over — in this way, you can avoid injury and be ready for your next match!

 

Publication Highlights:

Nakamura R, La Rosa C (co-1st author), Longmate J, Drake J, Slape C, Zhou Q, Lampa MG, O’Donnell M, Cai J, Farol L, Salhotra A, Snyder DS, Aldoss I, Forman SJ, Miller JS, Zaia JA, Diamond DJ. 2015. Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol: in press.

Nakamura R, Franck A, Gallez-Hawkins G, Jeannet L, Li X, Forman SJ, Zaia JA. 2014. Phenotypic and Functional Characteristics of NK Cells Associated with Cytomegalovirus (CMV) Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation (HCT). Biol Blood Marrow Transplant (2):S145.

Israyelyan A, La Rosa C, Tsai W, Kaltcheva T, Srivastava T, Aquino L, Li J, Kim Y, Palmer J, Streja L, Senitzer D, Zaia JA, Rosenwald A, Forman SJ, Nakamura R (co-senior author), Diamond DJ. 2013. Detection and preliminary characterization of CD8+T lymphocytes specific for Wilms' tumor antigen in patients with non-Hodgkin lymphoma. Leuk Lymphoma 54(11):2490-9.

Rodriguez R, Nakamura R (co-1st author), Palmer JM, Parker P, Shayani S, Nademanee A, Snyder D, Pullarkat V, Kogut N, Rosenthal J, Smith E, Karanes C, O'Donnell M, Krishnan AY, Senitzer D, Forman SJ. 2010. A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood 115(5):1098-105.

Zhou W, Longmate J, Lacey SF, Palmer JM, Gallez-Hawkins G, Thao L, Spielberger R, Nakamura R, Forman SJ, Zaia JA, Diamond DJ. 2009. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood 113(25):6465-76.

Nakamura R, Auayporn N, Smith DD, Palmer J, Sun JY, Schriber J, Pullarkat V, Parker P, Rodriguez R, Stein A, Rosenthal J, Wang S, Karanas C, Gaal K, Senitzer D, Forman SJ. 2008. Impact of graft cell dose on transplant outcomes following unrelated donor allogeneic peripheral blood stem cell transplantation: higher CD34+ cell doses are associated with decreased relapse rates. Biol Blood Marrow Transplant 14(4):449-57.

Saunthararajah Y, Nakamura R (co-1st author), Nam JM, Robyn J, Loberiza F, Maciejewski JP, Simonis T, Molldrem J, Young NS, Barrett AJ. 2002. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 100(5):1570-4.

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