Cancer and Blood Disorders Research

The Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta is proud to have participated in the chimeric antigen receptor (CAR) T cell clinical trials for the treatment of pediatric CD19 positive acute lymphoblastic leukemia (ALL) sponsored by Novartis, that resulted in U.S. Food and Drug Administration (FDA) approval of this ground breaking therapy (Tisagenlecleucel—trade name Kymriah).

We are one of a limited number of centers designated as a certified treatment site. Our team has developed expertise in the delivery of this therapy, treating patients across Georgia and from surrounding and remote states. In addition, our research team is adapting this concept to target other brain tumors and neuroblastoma, which we hope to have in open clinical trials to provide options to patients with resistant disease.

AflacLL1602/ENCERT: A Phase 1 trial using everolimus in combination with nelarabine, cyclophosphamide and etoposide in relapsed T cell lymphoblastic leukemia and lymphoma (T-ALL/T-LLy)

Current therapy options for patients with relapsed T-ALL or T-LLy yield only a 30 percent complete remission rate. The addition of everolimus, an mTOR inhibitor with activity in T cell disease, may improve those rates. The study's main goal is to determine a safe pediatric dose of everolimus and establish a safety profile for everolimus when given in combination with standard chemotherapy.

AflacST1603: A Phase 1 study using nab-paclitaxel (Abraxane) in combination with gemcitabine for pediatric relapsed and refractory solid tumors

Relapsed and refractory non-central nervous system (non-CNS) solid tumors have poor outcomes and novel therapies are needed. We hypothesize the combination of gemcitabine and nab-paclitaxel, an albumin-bound, solvent-free taxane that allows higher dosing and shorter infusion duration than solvent-bound taxanes, as well as increased drug delivery to tumors through increased albumin-initiated transcytosis, will improve the anti-tumor efficacy observed with gemcitabine and docetaxel in relapsed and refractory solid tumors. The study's main goal is to determine a safe pediatric dose of nab-paclitaxel, in combination with gemcitabine, and define a toxicity profile for this combination of chemotherapy.

AflacST1402: A Phase I study using simvastatin in combination with topotecan and cyclophosphamide in relapsed and/or refractory pediatric solid and CNS tumors (NCT02390843)

Independent of cholesterol inhibition, simvastatin has been found to inhibit signal transducer and activator of transcription 3 (STAT3). STAT3 is a protein that stimulates chemotherapy resistance, which is a major cause of treatment failure and death among pediatric and adolescent patients. The study's primary objective is to define the toxicity of high dose simvastatin in combination with chemotherapy to treat solid tumors with abnormal STAT3 activation by restoring tumor sensitivity to routine chemotherapeutic agents.

AflacST1501: A Phase 1 study using abemaciclib in children with newly diagnosed diffuse intrinsic pontine glioma, and in children with recurrent and refractory solid tumors, including malignant brain tumors (NCT02644460)

Abemaciclib represents a selective and potent CDK4/6 dual inhibitor with broad anti-tumor activity. There is existing biologic data demonstrating dysregulation of the CDK4/6 pathway in pediatric high-grade tumors, including malignant brain tumors. Presently, there are not any established treatments that provide effective therapy for patients with progressive disease or patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). Abemaciclib is an attractive agent for these patients, given the strong preclinical data on blood-brain barrier penetration, oral bioavailability and its anti-tumor activity. The study's primary objective is to estimate the maximum tolerated dose of abemaciclib in this patient population.

AflacST1502: A Phase II study of sirolimus in combination with metronomic chemotherapy in children with recurrent and/or refractory solid and CNS tumors (NCT02574728)

Sirolimus is a potent immunosuppressive drug that has been found to inhibit cell growth and have anti-tumor activity in previous studies involving pediatric solid tumors. This Phase II study will investigate the time of progression in children with recurrent and refractory solid tumors, including brain tumors, when oral sirolimus is given in combination with metronomic chemotherapy.

Our clinical and translational researchers are investigating:

• Alternative donor transplant for sickle cell disease, using novel cell and immunotherapy to improve outcomes
• Transplant for adults with sickle cell disease (STRIDE-II)
• Examining late effects of transplant for sickle cell disease
• An online decision aid about treatments for sickle cell disease
• Novel cell and immunotherapy to reduce the risk of or to treat graft-versus-host-disease (GVHD)

Additionally, we are:

• One of a select group of centers offering gene therapy for sickle cell disease
• One of small number of centers offering CAR-T cell treatment for relapsed and refractory B ALL patients (Novartis)
• Members of the Primary Immune Deficiency Treatment Consortium (PIDTC), Pediatric Blood and Marrow Transplant Consortium (PBMTC), Blood and Marrow Transplant Clinical Trials Network (BMT CTN) and Sickle Transplant Alliance for Research (STAR)
• Offering haploidentical transplant with gene modified T-cells post-transplant to aid immune recovery (Bellicum)

The focus of our basic research is to:

• Identify the molecular pathways linked to the development and evolution of acute and chronic GVHD.
• Develop novel, nongenotoxic targeted conditioning for hematopoietic cell transplantation (HCT).
• Develop immunobiology of immune dysregulation.
• Develop gene therapy for hemophagocytic lymphohistiocytosis (HLH). 

Our researchers are investigating the metastasis (spread of cancer to another part of the body) of medulloblastoma, a type of brain tumor that occurs in infants and young children. In addition, they’re exploring safer, more effective methods of treatment for children with brain tumors.

Our clinical and translational research includes:

• Targeted therapeutics: The discovery of new medicines (targets) to change the way cancer cells behave. Our doctors are conducting clinical trials to test identified targeted therapeutics for children with brain tumors. 
• Genomic biomarkers: Insights into the biology of children’s brain tumors that have led to clinical trials to test new medicines. 
• Nanotechnology: The study and creation of targeted, molecular-sized nanoparticles to treat diseases. Nanomedicine has the potential to revolutionize the treatment and care of—and ultimately cure—childhood diseases and conditions.

Basic research includes:

• Regulation of medulloblastoma metastasis: Research to develop a drug therapy that stops the spread of medulloblastoma as an alternative to the often-damaging whole-brain radiation therapy, which follows surgery to remove a brain tumor. Currently, Tobey MacDonald, M.D., is studying medulloblastoma. However, if the approach is successful, it could potentially be applied to any kind of tumor anywhere in the body.
• Oncogenic signaling in medulloblastoma: A study to find a gentler cure for medulloblastoma. Robert Castellino, M.D., is researching a gene called wild-type p53-induced phosphatase (WIP1).

Our grant-funded clinical research studies aim to better understand, detect and manage late effects of cancer therapy. Additionally, we aim to improve our ability to educate, empower and promote health in survivors.

Health-related outcomes

Our researchers are exploring:

• Patient-reported outcomes and quality of life
• Type and severity of late effects most commonly seen in survivors
• Cardiac late effects and models of coordinated care with cardiologists
• Ovarian and testicular late effects and how they relate to delayed puberty and infertility
• Skin cancer and the genetics of skin cancer
• Impact of treatment on body mass index (BMI), both underweight and overweight
• Physical activity and its impact on adolescent survivors’ health and quality of life using technology (smartphones, Fitbit Flex) and community-based exercise programs (local YMCAs)
• Survivor and family related barriers to participation in survivor healthcare
• Risky health behaviors in adolescent and young adult survivors and how to encourage a healthy lifestyle
• How to prevent late effects through early interventions (medications or physical therapy)
• Research methodology and statistical applications around clinical outcomes research

Our researchers also have leadership roles in the Children’s Oncology Group Long-Term Follow-Up Guidelines Task Force and the International Late Effects of Childhood Cancer Guideline Harmonization Group. These groups are national and international experts in survivorship that develop the guidelines used to help detect and prevent late effects in survivors.

Communication

We’re seeking new ways to inform and educate survivors about their health risks and improve their health and quality of life by:

• Tailoring evidence based communication strategies to increase survivors’ knowledge of survivor care and adherence to long-term follow up healthcare
• Developing methods of communicating infertility risk to adolescent and young adult survivors
• Educating Georgia primary healthcare providers about survivor care
• Using social media to improve adolescent and young adult transition

Cancer SurvivorLink

Cancer SurvivorLink is an online resource designed to support care for survivors of childhood cancer. It provides educational materials to improve awareness of survivorship issues, best practices in survivor care, and a secure way to electronically store and share health documents.

Our researchers are studying how SurvivorLink can improve access to survivorship care and patient knowledge about important survivor issues. We are:

• Evaluating the abilities of young adult (18-21 years old) patients to use SurvivorLink to manage their health records
• Assessing the impact of SurvivorLink on adherence to cancer survivor care and late effects visits and screening.
• Using iterative feedback to continuously enhance and improve SurvivorLink

Learn more about how to sign up and use SurvivorLink

Survivor health self-management and transition to adult care

The Children’s Oncology Group (COG) recommends that survivors receive ongoing survivor-specific care throughout their lives. When pediatric survivors grow up and become young adults, they need to be ready to manage their survivor care and transfer care from Children’s and the Aflac Cancer & Blood Disorders Center to adult doctors. Our team is conducting research to understand how we can best help survivors get ready for these responsibilities. Our projects focused on survivor health self-management and transition include:

• Adapting and validating the Readiness to Transition Questionnaire (RTQ), a survey measure of transition readiness that assesses shifts in healthcare responsibility from parents to adolescents
• Characterizing barriers to transition of survivor care and the subpopulations of survivors at risk for non-adherence post-transfer
• Evaluating the impact of transition clinics and meeting adult providers on successful transition to adult care
• Establishing a network of college health providers, who are knowledgeable of the needs of survivors, at colleges and universities throughout Georgia.

Partnership

• Childhood Cancer Survivor Study (CCSS): This National Cancer Institute funded study explores health problems that develop later in life as a result of cancer treatment, also known as late effects.
• Consortium for Pediatric Intervention Research: Consortium to support the feasibility of delivering intervention and develop opportunities for definitive clinical trials.

Gene therapy is a technique that uses genes to treat or prevent disease. Using this therapy, researchers insert one or more corrective genes, which have been designed in the lab, into the genetic material of a patient's cells to correct the effects of a disease-causing mutation.

Our basic research in gene therapy focuses on inherited diseases, such as hemophilia, sickle cell disease and hemophagocytic lymphohistiocytosis (HLH), and cancer.

Inherited diseases

Our researchers are focusing on introducing corrective genes into bone marrow stem cells to treat several diseases caused by single gene defects.

• Recombinant viral vectors, which are used to deliver genetic materials into cells, have the potential to be a cure for hemophilia A, sickle cell disease and HLH.
• Using high-expression elements and optimized gene sequences can enhance protein expression and enable the use of several gene transfer plaftforms. For example, enhanced expression of factor VIII (the protein mutated in hemophilia A) can reduce the cost of recombinant fVIII production. Approximately 70 percent of patients with hemophilia A aren’t treated due to cost constraints, so a reduction in the cost producing fVIII will increase access to the protein.

Cancer

Our researchers are pioneering an approach to treat cancer using novel immunotherapies—treatments that use the patient’s own immune cells to kill cancer.

• One strategy that is being developed has been termed drug resistance immunotherapy (DRI). Our scientists are exploring whether immunocompetent cells (those with a normal immune response) can be genetically engineered to withstand the toxic effects of chemotherapy, and, if so, whether the genetic modification makes it possible to use both chemotherapy and cell-based immunotherapy. The ability to use both types of treatment, rather than a single approach, could improve survival rates.
• A second approach is to genetically engineer immunocompetent cells with genes that direct the cellular killing mechanisms to the cancer. This approach, termed chimeric antigen receptor modified T cells (or CAR T), has been successfully used to treat cancers originating in the blood. Our researchers are focused on cancers that affect children, such as neuroblastoma and leukemia.

The focus of our clinical research on hemostasis (stoppage of bleeding or hemorrhage) and thrombosis (blood clotting) includes rare bleeding disorders like hemophilia and von Willebrand disease (VWF)/low VWF, qualitative platelet disorders and deep vein thrombosis and pulmonary emboli.

Hemophilia
Hemophilia is a rare bleeding disorder in which the blood doesn't clot normally may lead to internal bleeding into muscles and joints. Our researchers are exploring:

• Treatment of severe hemophilia A with primary and secondary prophylaxis, which involves the infusion of new clotting factors to prevent bleeding
• Risk factors due to low bone density in hemophilia patients 
• Factor VIII (fVIII) inhibitors—which prevent blood from clotting normally—in patients with hemophilia undergoing surgery
• Mechanisms of fVIII inhibitor development 
• Developing liver directed gene therapy and stem cell-based gene therapy for hemophilia A
• Platelet function in hemophilia
• Clinical trial evaluating a new subcutaneous non factor product in babies with severe hemophilia A
• Clinical trial evaluating a new regimen for treating inhibitors in hemophilia A

In addition, researchers are studying:

• Rare bleeding disorders and the efficacy and safety of recombinant fXIII, a medicine that prevents bleeding
• Platelet dysfunction of immune and nonimmune (drug induced) thrombocytopenia, a deficiency of platelets in the blood that causes abnormal bleeding
• Risk factors for the development of thrombosis (blood clots) in young children and determining the optimal length of anticoagulation therapy

Our basic and translational research focus includes:

• Mechanisms of fVIII inhibitor formation and its ability to cause disease
• Regulation of fVIII expression
• Development of fVIII products, which prevent bleeding
• Mechanisms of platelet activation and clearance, and VWF

Our researchers are investigating safer, less toxic and more effective methods of treatment for children with leukemia and lymphoma.

Our team is investigating safer, less toxic and more effective methods of treatment for children with leukemia (cancer of the blood) and lymphoma (cancer of the lymphatic tissues). The Aflac Cancer Center Leukemia Biorepository is led by Sharon Castellino, MD, MSc, and Deb DeRyckere, PhD, and is a resource for the study of rare leukemia.

Our researchers are studying aberrant signaling pathways and novel medicines, and combinations. Their research includes:

• MERTK-Targeted Therapies: The lab of Douglas K. Graham, MD, PhD, and Dr. Deryckere focuses on understanding roles for the MERTK protein in leukemia and other cancers. They are developing and optimizing drugs to target MERTK in tumor cells and the immune system. MRX-2843, a first-in-class MERTK-selective inhibitor resulting from this effort, is currently in Phase I clinical trials.
• Nuclear MERTK: Katherine Minson’s, MD, research focuses on the role MERTK plays in the nucleus of leukemia cells. MERTK has been studied on the cell surface, but it’s role in the nucleus of cancer cells may affect genes influencing growth and survival. Study of the biology of MERTK in the nucleus could lead to advances in understanding how leukemia develops and how to better treat it.
• CALM-AF10 biology in leukemia: The lab of Daniel S. Wechsler, MD, PhD, and Waitman Aumann, MD, studies the role of CALM-AF10 in the development of leukemia. They are focusing on novel therapeutic interventions for aggressive CRM1- and HOXA dependent leukemias.
• Tyrosine kinase inhibitor (TKI) therapies: Dr. Castellino and Himalee Sabnis, MD, MSc, are studying the late effects of TKI therapy on growth in children, and on how these therapies may impact immune function and long term cardiovascular health in pediatric patients.
• Outcomes in patients with leukemia and lymphoma: Dr. Castelllino’s team uses epidemiological methods and patient reported outcomes to evaluate side effects of therapy and long term health for populations with leukemia or Hodgkin lymphoma. She also studies late effects on the heart in childhood cancer survivors toward finding biomarkers for cardiovascular late effects.
• Cancer Control and Supportive Care during Leukemia Therapy: Tamara Miller, MD, MSCE, is focused on understanding side effects of treatment for pediatric leukemia during therapy. She is using electronic medical record data and bioinformatics to develop novel approaches of reporting on clinical trials. This will improve our understanding of the rates of side effects and enhance epidemiologic approaches to studying the benefits of therapy for pediatric leukemia.
• Experimental therapeutics for PTPN11-associated leukemia: Cheng-Kui Qu's, MD, PhD lab studies molecular mechanisms by which activating mutations of PTPN11 (SHP2) cause childhood juvenile myelomonocytic leukemia and other leukemia. Research in his lab is focused on understanding cell signaling and metabolic regulation of cell development and leukemogenesis with a focus on tyrosine and lipid phosphatases in normal hematopoietic stem cells and leukemic stem cells.
• Chronic inflammation, immunity, and leukemia development: Curtis Henry, PhD, studies the role of chronic inflammation, aging, and obesity on leukemogenesis, immunity, and therapeutic responses. Identified modulators that induce resistance to chemotherapies or immunotherapies are being examined to determine their therapeutic potential in high-risk populations.
• Molecular mechanisms of leukemogenesis and treatment resistance: Christopher Porter’s, MD, lab studies WEE1 as a chemosensitizing target in acute myeloid leukemia. They are also studying the transcription factor ETV6 for it’s role in leukemogenesis.
• Targeting MDM2 in cancer treatment: Muxiang Zhou, MD, and Lubing Gu, MD, are searching for small-molecule compounds that can induce degradation of MDM2 oncoprotein, and thereby lead to novel targeted-therapies.
• Normal and leukemic cytokine signaling: Kevin Bunting, PhD, is studying the biology of signal transducer and activator of transcription 5 (STAT5) and its role in normal production of blood cells. His lab is also focused on targeting persistently activated STAT5 in leukemia using novel calcium-modulating drugs delivered to the bone marrow via receptor-targeted nanoparticles. In addition, Dr. Bunting is studying the Grb2-associated binding (Gab) protein family and their role in hematopoietic stem cell homeostasis and immune cell activation through compound mutant mice lacking Gab1, Gab2, and Gab3.
• Chimeric antigen receptor (CAR)-based cellular therapies: Sunil Raikar, MD, is working on developing novel CARs specifically for T-cell leukemia. Dr Raikar is utilizing innovative CRISPR/Cas9 genome editing technology to knockdown surface expression of target antigens on CAR-T cells thus enabling its use in T-cell disease.
• Innovative therapy in pediatric leukemia and lymphoma: Dr. Sabnis is leading a Phase I clinical trial using everolimus with chemotherapy to improve survival in patients with relapsed T cell acute lymphoblastic leukemia or lymphoma. This trial funded by the CURE Childhood Cancer Foundation will include four other participating pediatric cancer institutions.

Sickle cell disease is an inherited blood disorder that causes red blood cells to change shape.

Our researchers are seeking ways to improve outcomes and quality of life for children with this disease through blood and marrow transplantation (BMT) and transfusion medicine (the transfer of blood and blood components).

Our clinical and translational researchers are seeking a cure and looking for ways to improve treatments and the quality of life for children with the disease. They’re studying:

• Health outcomes and new therapies, such as hydroxyurea (a medicine) and stem cell transplantation 
• Prevention of sickle cell disease complications, such as kidney damage, pain and stroke
• Red blood cell alloimmunization, an undesired immune response that occurs after BMT 
• Micronutrients (vitamins and minerals)

Our basic researchers are exploring:

• Whether angiogenic growth factors (promote blood vessel formation) play a protective or destructive role in the structure of the lining of blood vessels in the lungs and in leg ulcers in sickle cell disease
• Antioxidant enzymes that protect the vessels in the lungs from oxidant-induced changes in the structural resistance of vessels in sickle cell disease pulmonary hypertension
• Cellular interactions in sickle cell disease to determine their relative contributions to blocked blood vessels, blood cell rupture or destruction, and the formation of reactive oxygen species (a natural byproduct of normal oxygen metabolism)
• The development of sickle cell disease in respect to the generation, prevention and treatment of organ dysfunction—specifically the role of endothelial (inner lining of blood vessel) cells in the generation of kidney disease
• Genetic association studies to identify markers that influence the incidence of pulmonary hypertension and leg ulcers in sickle cell disease
• Nanotechnology—the study and creation of targeted, molecular-sized nanoparticles to treat diseases—which has the potential to revolutionize the treatment and care of childhood conditions and could ultimately lead to cures

A solid tumor is an abnormal clump of cells that doesn't contain any liquid or cysts. They can occur in bones, tissues and organs.

Our researchers are looking for new ways to improve the health and quality of life for children with solid tumors by exploring:

• New medicines to change the way cancer cells behave, also called targeted therapeutics 
• New combinations of medicines
• Mechanisms involved in chemoresistance, a trait found in some cancers that make them less likely to respond to chemotherapy
• High-risk neuroblastoma therapy and outcomes 

Our basic research focus includes:

• Improving the effectiveness of chemotherapy in neuroblastoma treatment by targeting molecular structures that protect neuroblastoma cells 
• Biologic validation of Phase I agents 

Transfusion medicine involves transfusion of blood or blood components. It’s used to treat diseases such as bone cancer, leukemia, sickle cell disease and others.

Our clinical researchers are exploring ways to improve transfusion treatments and minimize potential complications by investigating:

• Transfusion-transmitted cytomegalovirus (CMV), a common virus that causes infection and can be dangerous for people with weakened immune systems
• Potential adverse effects of stored red blood cells
• Alloimmunization (an undesired immune response that can occur after transfusion) in sickle cell patients
• Development of a pediatric transfusion medicine training curriculum
• Transfusion medicine and hemostasis (stopping bleeding or hemorrhage) network trials

Our basic research focus includes:

• Red blood cell alloimmunization
• Blood and marrow transplantation (BMT) rejection primed by red blood cell or platelet transfusions
• Red blood cell autoimmunity (an immune response against an organism’s own cells and tissues)
• Red blood cell antigen loss