Blood and Bone Marrow Transplant Program

Ken Cooke, M.D.

Director of the BMT Program
Professor of Oncology and Pediatrics

Dr. Cooke joined the faculty of the Sidney Kimmel Cancer Center in 2013. He was recruited as the Herman and Walter Samuelson Professor in Oncology to serve as the overall director of Pediatric BMT Program. Dr. Cooke’s scientific and clinical interests have been directed toward understanding the immunologic mechanisms that contribute to the development of graft-versus-host disease (GVHD) and non-infectious lung injury both in the acute and chronic settings.

His laboratory focuses on four major areas: First, we are studying the role of endovascular injury and activation in the recruitment of donor myeloid and lymphoid effector cells to sites of target organ injury, specifically the lung. We also have demonstrated that TNFα functions as both an effector and facilitator of lung inflammation in experimental IPS, and that inflammation can be mitigated with TNFα neutralization. These observations led to the development of clinical trials, wherein neutralization of TNFα has been shown to provide a therapeutic benefit in pediatric transplant recipients with IPS.

Second, we are exploring physiologic mechanisms responsible for chronic inflammation, dysregulated repair and collagen deposition during the development of fibrotic lung injury after BMT. Third, in collaboration with investigators from Case Western, the laboratory has uncovered a heretofore unknown role for Cdk5, a ubiquitously expressed serine/threonine kinase, in T cell activation, migration and the generation of memory. Using novel chimeric and T cell-restricted Cdk5 gene deleted mice, we are currently exploring the contribution of Cdk5 in the induction of GVHD and graft-versus-leukemia activity following BMT. Finally, subsets of non-blood forming but bone marrow-derived stem cells called mesenchymal stem cells or MSCs have recently been discovered and can be expanded ex vivo while retaining their pluripotency. These cells have the capacity to both suppress the immune system and repair damaged tissue. While the co-administration of such cells has shown promise in optimizing transplantation outcomes in early phase clinical studies, the mechanisms by which these cells are protective remain enigmatic. The laboratory is using established animal models to identify the key points in the pathogenesis of GVHD and lung dysfunction where MSCs are operative.
 

Heather Symons, M.D., M.H.S.

Assistant Professor of Oncology and Pediatrics
Clinical Director

Dr. Symons’ research focuses on the development of novel immunotherapies for hematologic and high-risk solid tumors and on overcoming traditional limitations to donor selection. Her focus is on using haploidentical donors for blood stem cell transplantation; she is working toward strategies to identify and select the best half-matched donor available. Dr. Symons is the principal investigator of several haploidentical BMT trials for patients with hematologic malignancies, solid tumors and non-malignant disorders. She is also the lead investigator on a national, multi-institutional trial using haploidentical BMT for pediatric and young adult patients with leukemia and lymphoma. In the laboratory, she is investigating the scope and pace of immune reconstitution that occurs in patients who have received blood stem cells from half-matched donors and post-transplant cyclophosphamide. Dr. Symons is the recipient of an Alex’s Lemonade Stand Grant as well as a Hyundai Scholar Award.

Learn about Heather Symon's personalizing cancer care.

Allen Chen, M.D., Ph.D., M.H.S.

Associate Professor of Oncology and Pediatrics

Children with metastatic or recurrent malignancies have a poor prognosis despite initially chemoresponsive disease. There is a steep linear relationship between the dose of many cytotoxic agents and the log tumor cell kill. For agents whose major dose-limiting toxicity is myelosuppression, hematopoietic stem cell rescue may permit five to 10 times dose escalation, which would produce several times more cell killing. The Childrens Cancer Group has demonstrated in a prospective, randomized, controlled study in patients with high-risk neuroblastoma that purged autologous bone marrow transplantation (BMT) produces superior three-year event-free survival (EFS), compared with conventional dose-intensive chemotherapy as consolidation in first response. Although prospective randomized trials have yet to be completed for other pediatric solid tumors, autologous BMT appears to produce survival at least equivalent to longer courses of intensive conventional chemotherapy, and the major risk remains tumor progression. Therefore, additional agents and modalities that are not cross-resistant with current therapies are needed. Dr. Chen is investigating tandem transplantation and autologous GVHD as alternative approaches to provide improved control of pediatric solid tumors.

In allogeneic BMT, nonablative preparative regimens can produce engraftment with less preparative-regimen-related toxicity, but at a price of more graft versus.host disease. In fact, GVHD is a major limitation of the success of BMT for all indications, but its morbidity and mortality are offset in patients with hematologic malignancies by an improved graft-versus-leukemia effect. Therefore, for patients with nonmalignant diseases, such as inherited hematologic and metabolic diseases that present during childhood, preventing GVHD is particularly important. Rodent models indicate that cyclophosphamide administered at a critical interval after mismatched BMT can specifically destroy alloreactive T cell clones, and Dr. Leo Luzniks trial in adult patients undergoing haploidentical BMT for hematologic malignancies supports a role for cyclophosphamide treatment after graft infusion to produce tolerance. Dr. Chen will test whether cyclophosphamide administered after graft infusion will allow long-term engraftment without GVHD in immune-competent patients with hemoglobinopathies receiving nonmyeloablative BMT.

Christopher Gamper, M.D. Ph.D.

Assistant Professor of Oncology and Pediatrics

Dr. Gamper’s research seeks to identify factors critical for regulating the activation of specialized immune cells called T lymphocytes or T cells. After activation, T cells can more efficiently target and destroy infected tissues and tumor cells. Tumors are capable, however, of becoming resistant to T cells. One mechanism that appears to contribute to this process is the permanent silencing of genes, including immune hormones called cytokines, by DNA methylation. Experiments designed to identify genes whose expression is increased ineffective T cells demonstrated that DNA Methyltransferase 3a (DNMT3a), is highly expressed in ineffective cells. Dr. Gamper generated mice that have T cells lacking DNMT3a to study novel ways to reawaken desirable anti-tumor activity and enhance vaccine strategies that can be used in the management of cancers that are difficult to treat. Dr. Gamper is working with Dr. Brian Ladle to translate these findings into improved immunotherapies that can be used after BMT.

From a clinical perspective, Dr. Gamper is developing clinical trials to identify novel approaches to treat acute GVHD that fails to respond to steroids. Additionally, some patients require BMT for non-cancerous conditions such as sickle cell anemia. Such patients do not require the anti-cancer benefit of high dose chemotherapy, and GVHD can only cause them serious side effects. Efforts are underway to develop safer “reduced intensity” protocols for such patients using half-matched parents or siblings as donors, based on the safety and success of such an approach developed by colleagues Drs. Javier Bolanos-Meade and Robert Brodsky in the adult BMT program at Johns Hopkins. By using such half-matched donors, bone marrow transplantation to cure sickle cell anemia could become much more widely available than relying on fully matched sibling donors. Early results from this trial are promising and were published in the journal Blood.

Elias Zambidis, M.D. Ph.D.

Associate Professor of Oncology and Pediatrics

The Zambidis laboratory at the Johns Hopkins Institute for Cell Engineering focuses on studying the biology of very primitive (pluripotent) stem cells that have the capacity to develop into many different tissues, including blood cells and cells that line the blood vessels. As a fellow, Dr. Zambidis was one of the very first investigators at Johns Hopkins to work with human embryonic stem cells (hESC), and began working with them immediately after the federal government made them available to the biomedical community in 2002. After joining the faculty at Johns Hopkins in 2005, he published his novel experimental system which models the events of early human hemo-vasculogenesis (Zambidis et al, 2005, and Zambidis et al, 2008).

Dr. Zambidis has developed a way to generate pluripotent stem cells from mature human tissue. These “induced” pluripotent stem cells (or iPSC) have opened doors to multiple lines of investigation and overcome ethical challenges related to the use of embryonic stem cells. To this end, the Zambidis laboratory recently developed novel methods to generate highly efficient, nonviral, human iPSC lines from myeloid progenitors (Park et al., PLoS One, 2012). In collaboration with other investigators from Johns Hopkins, Dr. Zambidis has used these robust iPSC to create vascular progenitors that may heal damaged blood vessels (Park et al, Circulation, 2014), and to investigate the epigenetics in cancer in the context of cellular reprogramming. As a pediatric BMT/oncology physician-scientist, his ultimate goal is to use iPSC technology toward treating severe hematologic/oncologic and vascular diseases and to overcome some of the complications associated with blood stem cell transplantation.

David Loeb, M.D., Ph.D.

Associate Professor of Oncology and Pediatrics
Director of the Musculoskeletal Tumor Program

Dr. Loeb has active laboratory and clinical research efforts. In the laboratory, Dr. Loeb studies a gene called WT1. High levels of WT1 convey a poor prognosis for patients with osteosarcoma and soft tissue sarcomas. Dr. Loeb's laboratory has shown that WT1 expression is regulated, in part, by the amount of oxygen in a tumor, and that low oxygen levels lead to higher WT1 expression, which in turn leads to an increase in the ability of tumor cells to cause new blood vessels to form. The laboratory is studying both the mechanism by which oxygen levels control WT1 expression and the way WT1 regulates blood vessel growth.

In another project, Dr. Loeb’s laboratory is investigating the role of an enzyme called RNA Helicase DDX3 in sarcoma biology.  His laboratory discovered that sarcoma cells contain high levels of DDX3, that DDX3 plays an important role in both sarcoma growth and in the ability of sarcoma cells to repair damaged DNA, and that DDX3 may be an important new target for developing novel treatments for sarcomas. Dr. Loeb has conducted a series of clinical trials investigating the use of a radiopharmaceutical, Samarium-153, to treat high-risk osteosarcoma patients whose tumors are visible on bone scan. The current study involves combining Samarium-153 with conventional radiation therapy to deliver potentially curative doses of radiation to tumors while sparing surrounding normal tissues exposure to toxic levels of radiation.

Jeffrey Huo, M.D. Ph.D.

Instructor of Oncology and Pediatrics

Dr. Huo recently joined the BMT program after completing his fellowship training at Johns Hopkins. Dr. Huo’s work begun under the mentorship of Dr. Elias Zambidis and has two major scientific areas of focus: The first, in collaboration with the laboratory of Dr. Stephen Baylin, is studying the epigenetics of directed reprogramming of differentiated cells backwards to induced pluripotent stem cells (iPSC). This process of directed reprogramming has important parallels to the aberrant transformation of normal tissues into cancer stem cells. Understanding the underlying mechanisms will both provide important insights into the epigenetic origins of cancer, and help make iPSC cell engineering safer for clinical use. The second, in continuing collaboration with Drs. Maria Canto-Soler and Gerard Lutty of the Wilmer Eye Institute, is using iPSC technology to create a developmental model of retinoblastoma. This will allow us to dissect the earliest stages in retinoblastoma genesis, and ultimately develop new targeted therapies for this often devastating infant and child tumor. Dr. Huo is the recent recipient of a Postdoctoral Fellowship award from the Maryland Stem Cell Research Fund and an Alex’s Lemonade Stand Young Investigator Award.

Nicolas J Llosa, M.D.

Instructor of Oncology and Pediatrics

Dr. Llosa recently joined the BMT program after completing his fellowship training at Hopkins. His research focuses on understanding how the immune system interacts with cancer cells from sarcoma tumors. Sarcoma is a type of cancer that can occur in various locations in the body; it is a general term for a broad group of cancers including tumors that form in the bones and in the soft tissues. Sarcomas affect people of all ages and some, such as rhabdomyosarcoma, neuroblastoma, Ewing sarcoma and osteosarcoma, are more common in children and adolescents.

Dr. Llosa concentrates on the immunotherapy of sarcomas. Immunotherapy (also called biologic therapy or biotherapy) is a type of cancer treatment designed to boost the body's natural defenses to fight the cancer and it is currently one of the most promising approaches for treating some types of solid tumors. His specific area of interest is the use of drugs that target immune system checkpoints, activity that keeps the immune system from attacking other normal cells in the body. Cancer cells sometimes take advantage of these checkpoints to avoid being attacked by the immune system. CTLA-4 and PD-1/PD-L1 are checkpoint molecules found on immune system cells (T cells) that can be blocked with drugs, leading to a general increase in the patient’s immune system that helps it attack cancer cells. He wants to use immune checkpoint inhibitors for attacking sarcomas with the goal of obtaining excellent, long-lasting responses.

Nancy Robey, PA

Physician Assistant
Clinical Care Provider

Mary Jo Holuba, NP

Nurse Practitioner
Clinical Care Provider

Kim Drucis, NP

Patient Coordinator

Hetal Patel, MSN

Patient Coordinator

Michelle Kokoszka, RN

Discharge Coordinator

Nicole Dores, PharmD

BMT Specialty Pharmacist

Patrice McMullen RN

Insurance Specialist