Cellular Therapy and Stem Cell Transplantation
Carrie L. Kitko, MD1*, Catherine M Bollard, MBChB2,3,4, Mitchell S. Cairo, MD5, Joseph Chewning, MD6, Terry J. Fry, MD7,8, Michael A. Pulsipher, MD9, Shalini Shenoy, MBBS10, Donna A. Wall, MD11, John E. Levine, MD, MS12
1 Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN
2 Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC
3 GW Cancer Center, George Washington University, Washington, DC
4 Division of Blood and Marrow Transplantation, Children’s National Hospital, Washington, DC
5 Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Maria Fareri Children’s Hospital, Westchester Medical Center, New York Medical College, Valhalla, New York, NY
6 Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
7 Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
8 Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO
9 Division of Hematology and Oncology, Intermountain Primary Children’s Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine, Salt Lake City, UT
10 Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University, St Louis, MO
11 Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Canada
12 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
*Corresponding Author : Carrie L. Kitko, MD, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN. Email: carrie.l.kitko@vumc.org
Word count:
Abstract: 160
Manuscript: 3499
Figures: 2
Tables: 4
Funding support: Grant support from the National Institute of Health, U10CA180886, U10CA180899, U10CA098543, U10CA098413.
Abstract : Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children’s Oncology Group cellular therapy-based trials for advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T cell depletion is used and the depth of remission as measured by next-generation sequencing based minimal residual disease assessment pre-transplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.
Introduction : The Cellular Therapy and Stem Cell Transplantation (CT) committee is a domain within the Children’s Oncology Group (COG) and as such develops its own trials in addition to collaborating with other diseases committees, domains, and disciplines as well as external groups such as the Pediatric Transplant and Cellular Therapy Consortium (PTCTC) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN; Figure 1) in areas related to transplant and cellular therapy for pediatric cancer. For some COG studies, the primary research question concerns cellular therapy practice such as the best donor source, e.g., ASCT2031, haploidentical vs unrelated donor), preparative regimen intensity for juvenile myelomonocytic leukemia (JMML) (ASCT1221), or whether the inclusion of sirolimus in graft-vs-host disease (GVHD) prophylaxis can improve outcomes for patients with minimal residual disease (MRD) prior to transplant (ASCT0431). Such studies are best run by the CT committee directly; in other cases, the cellular therapy component may be one block of a larger treatment plan for specific diseases, such as ACNS0333 and ANBL0532 (tandem autologous transplant as consolidation following induction chemotherapy for brain tumors and neuroblastoma respectively). Studies focused on supportive care may be more appropriate for the Cancer Control and Supportive Care domain portfolio, such as ACCL0934 or ACCL1131, testing different infection prophylaxis strategies early post-HCT.
The hematopoietic cell transplantation (HCT) field has seen major advancements over the past decade such as immune effector cell therapy (e.g., CD19-directed chimeric antigen receptor T cells [CAR T-cells] for B-cell malignancies) and hematopoietic stem cell gene therapy for hemoglobinopathies.1-3 As a result, many transplant programs, national organizations, and journals changed their names to be more inclusive of these emerging treatments. The former COG Stem Cell Transplant Committee was renamed the Cellular Therapy (CT) Committee to reflect this evolution in the field. Looking to the future, COG’s strong record of accomplishment in studying rare diseases is ideally suited to test emerging immune based cellular therapies for multiple hematologic and solid cancers in children and to treat post-HCT complications such as GVHD and refractory viral infections among others.
Most pediatric transplant and cellular therapy programs and smaller consortia treat small numbers of patients. International cooperative groups such as COG are necessary to conduct pivotal trials that require larger numbers of patients to move the field forward. The CT Committee’s three overarching goals are: 1) to improve the efficacy of CT (allogeneic, autologous and immune effector cells) in childhood cancer; 2) to improve the safety of CT; and 3) to optimize design, collaborate in the development, and assure timely completion of CT-related treatment and research protocols developed through COG disease and domain committees.