Project: Clinical Translation of an Exportin 1 (XPO1) Dependency in Select Pediatric Solid Tumors
Utilizing a novel tumor RNA analysis pipeline, we recently discovered that Wilms and rhabdoid tumors, two childhood kidney tumors, are unexpectedly dependent upon XPO1, a nuclear pore that pumps tumor suppressors out of the nucleus thereby inhibiting their function. We further showed that blocking XPO1, with a drug called Selinexor, was an effective strategy to shrink Wilms and rhabdoid tumors that we had established in mice. Selinexor had already completed a phase 1 study in children so we know the pediatric safety profile but a liquid formulation had not yet been available so younger children such as those with Wilms and rhabdoid tumors were not able to be evaluated. This project supports a phase 2 clinical trial in which we are evaluating how effective that the liquid suspension form of Selinexor is in patients with relapsed Wilms tumor, rhabdoid tumor, and other tumors for which XPO1 inhibition appears promising including a rare sarcoma called Malignant Peripheral Nerve Sheath Tumors (MPNST). We will enroll up to 9 young children as part of a safety assessment as well as up to 21 patients with Wilms tumor and up to 15 patients with other tumors as part of this study. Support from this grant will enable us to open the trial at 8 sites across the United States.
Project: Drug Delivery Program for Pediatric CNS Tumors: Blood Brain Barrier Disruption Using Novel Technologies
Columbia University’s program is developing two innovative methods—CED pumps and FUS sound waves—to deliver medicine directly to children’s brain tumors, aiming to improve treatment effectiveness while minimizing side effects.
Project: Defining the Spatial Architecture of Atypical Teratoid Rhabdoid Tumors
This project uses advanced mapping of ATRT tumors to understand how different cells function and interact, with the goal of developing safer, more precise treatments for young children.
Project: The Role of Neural Cell Adhesion Molecule (NCAM) in the Recognition and Killing of Tumor by CAR T Cells
This research tests whether the NCAM molecule can boost CAR T cell recognition and attack of solid pediatric tumors like neuroblastoma, aiming to make this therapy more effective for children.
Project: Infrastructure Support for Pediatric Graft-Versus-Host Disease Research at Mount Sinai
This funding request supports ongoing research using the MAP blood test to guide safer, more personalized steroid treatment for children with graft-versus-host disease after bone marrow transplants.
Project: Moving Closer to Establishing an Animal Model of Posterior Fossa A Ependymoma, a Childhood Brain Cancer
This study aims to create a better animal model of Posterior Fossa A ependymoma by testing whether the genes p73 and IGF2 drive tumor formation, with the goal of uncovering disease mechanisms and guiding new treatments.
Project: Peptide-Centric Chimeric Antigen Receptor (PC-CAR) T Cells for Therapy-Resistant Rhabdomyosarcoma
This project uses immunopeptidomics to identify unique tumor markers in therapy-resistant rhabdomyosarcoma and develop targeted CAR T cell therapies to improve treatment and overcome resistance.
Project: Early Immune Reconstitution in Pediatric and Young Adult Hematopoietic Cell Transplantation: Unraveling the Role of Dendritic Cells and Tregs in AGVHD
This study investigates how interactions between dendritic cells and regulatory T cells influence graft-versus-host disease after pediatric stem cell transplants, with the goal of improving personalized treatments and outcomes.
Project: Pediatric Early Phase Clinical Trials Program at Montefiore Medical Center
The Pediatric Early Phase Clinical Trials Program at Montefiore, expands access to innovative cancer therapies for underserved children by conducting early-phase studies, building trial capacity, and fostering research partnerships.
Project: The Role of Aneuploidy in Childhood B Acute Lymphoblastic Leukemia
This study develops lab models of hyperdiploid ALL to uncover how extra chromosomes influence cancer behavior and treatment response, aiming to guide better therapies for patients lacking these favorable traits.
Project: The Role of Aneuploidy in Childhood B Acute Lymphoblastic Leukemia
This study develops lab models of hyperdiploid ALL to uncover how extra chromosomes influence cancer behavior and treatment response, aiming to guide better therapies for patients lacking these favorable traits.
Project: Targeted Humoral and Cellular Therapy for Childhood, Adolescent and Yound Adult Classical Hodgkin Lymphoma
This project tests antibody-based therapies with reduced-toxicity chemotherapy and develops gene-edited immune cell treatments to improve outcomes and reduce long-term harm for children and young adults with classical Hodgkin Lymphoma.
Project: Columbia University PCF Developmental Therapeutics Program
The PCF Developmental Therapeutics Program at Columbia University develops and tests innovative treatments for children with incurable cancer through basic research, clinical trials, and personalized tumor profiling, and seeks continued support to sustain its staff and genomic technologies.
Project: Target Specific Delivery of Optimized RNA Therapeutics for the Treatment of Pediatric Sarcomas
This project develops a targeted delivery system to restore the cancer-fighting protein p53 by blocking MDM2, aiming to improve treatment and survival for children with aggressive rhabdomyosarcoma.
Project: Infrastructure Support for Pediatric Graft-Versus-Host Disease Research at Mount Sinai
This funding request supports ongoing research using the MAP blood test to guide safer, more personalized steroid treatment for children with graft-versus-host disease after bone marrow transplants.
Project: Investigating Mechanisms of Recurrence after Immune Gene Therapy in G34-Mutant Pediatric High-Grade Glioma
This study investigates why G34-mutant childhood brain tumors often recur after treatment, aiming to guide immune-based combination therapies that improve long-term survival.
Project: FLT3 Killer T Cell Immunotherapy for High-Risk Pediatric Leukemias
PCF is excited to announce that our grant will help to fund a planned first-in-human phase 1 clinical trial led by Sarah K. Tasian, MD, which will use a new immunotherapy to target the FLT3 receptor protein in high-risk pediatric leukemias.
Chemotherapy fails many patients with high-risk leukemias, particularly infants with acute lymphoblastic leukemia (ALL) and children with acute myeloid leukemia (AML) with high-risk genetic alterations who have poor long-term survival. Recent CAR T-cell therapies targeting the CD19 protein on ALL cells have been very effective in overcoming chemotherapy resistance and can now cure many children with relapsed ALL. However, some leukemias have learned to outsmart these therapies in various ways. One problem is that infant and childhood ALL with KMT2A genetic rearrangements are more likely to change into AML after CD19 CAR T-cell immunotherapy, which usually makes them incurable.
To date, it has been challenging to develop successful immunotherapies for pediatric AML. To address this problem, CHOP’s collaborative research team, led by Dr. Tasian and her colleague Dr. Terry Fry at Children’s Hospital Colorado, developed and tested a new CAR T-cell immunotherapy targeting an alternative protein called FLT3 that occurs at high levels in a type of AML and in infant ALL. In the laboratory, FLT3 CAR T cells were very effective at attacking and killing both AML and ALL cells in both in vitro and in vivo models of the disease. Remarkably, FLT3 CAR T cells eradicated both KMT2A-rearragned ALL and ALL that had turned into fatal AML after CD19 CAR T-cell treatment of the patient.
“Based upon our promising lab results, we aim to test FLT3 CAR T cells in pediatric patients through a first-in-human/child phase 1 clinical trial,” said Sarah K. Tasian, MD, a pediatric oncologist and Chief of the Hematologic Malignancies Program at CHOP. “Our research team has a strong track record of bench-to-bedside translation of CAR T cells for high-risk pediatric leukemias and is uniquely poised to undertake this challenge. Because of the funding provided by Pediatric Cancer Foundation, we can now work to translate our FLT3 CAR T-cell immunotherapy from promising results in the laboratory to the clinic. We hope that this clinical trial will have significant potential to credential a promising new immunotherapy against a shared target in two major types of high-risk childhood leukemias.”
The Cancer Immunotherapy Program at CHOP has revolutionized the care and the cure of children with relapsed/refractory B-cell ALL via its pioneering investigation of CD19-targeted killer T cells (CART19) that led to first-in-child FDA approval of the tisagenlecleucel cell therapy product in 2017. The program has continued to change and set new paradigms through investigation of additional CAR T cell therapies for children with B-cell ALL or lymphoma, AML, T-ALL, and neuroblastoma.
To find out more information visit: chop.edu/centers-programs/cancer-immunotherapy-program.
Project: Enhancing CAR T Cell Persistence Through Memory Reprogramming
Dr. Weber’s research is focused on developing methods to enhance human CAR-T cell therapies for pediatric cancer by endowing T cells with improved durability and exhaustion resistance. His laboratory specializes in modeling and interrogating CAR-T cell exhaustion, a biological process that limits CAR-T cell efficacy in patients. Dr. Weber’s research will uncover molecular programs that drive human CAR-T cell dysfunction, identify targets for therapeutic intervention, and inform universal strategies that improve CAR-T cell efficacy in cancer patients. Poor CAR-T cell persistence is a major barrier to progress for CAR-T Cell therapy and limits clinical responses in children. The overall goals of his research are to identify the molecular mechanisms that govern CAR-T cell behavior – both good and bad – and leverage those insights to enhance T cell fitness for CAR-T cell therapy targeting pediatric malignancies.
Project: Strengthening bench-to-bedside research initiatives at the Comprehensive Neurofibromatosis Center at Columbia University
Phase 0/1 study examining the use of non-invasive focused ultrasound (FUS) with oral selumetinib administration in children with progressive inoperable plexiform neurofibroma
Neurofibromatosis type 1 (NF1) is a rare and under-researched cancer predisposition syndrome that affects 1 in 3,000 people worldwide. Patients with NF1 require monitoring for the development of skin, peripheral, and central nervous system tumors. Plexiform neurofibroma (PNF) is a benign tumor that can grow within a nerve anywhere in the body and seen in about 30-50% of NF1 patients with an approximately 10-15% chance to develop into a malignant peripheral nerve sheath tumor (MPNST), a type of sarcoma. Selumetinib, a MEK-inhibitor is FDA-approved for patients with progressively growing PNFs which can’t be safely removed by surgery. Focused Ultrasound (FUS) has been successfully used to open the blood-brain barrier allowing drugs entering the brain in higher concentrations. We plan to combine FUS with selumetinib to achieve better drug penetration into the PNF which could decrease the systemic side effects of selumetinib and improve quality of life by alleviating the need for surgery.
Project: ALPHA-PARTICLE RADIO-IMMUNOTHERAPY FOR PEDIATRIC GLIOBLASTOMA
Researchers created a low-dose radiation treatment that boosts immune response against tumors, and after success in mice, they plan to test it in pet dogs with brain tumors as a step toward human trials.
Interested in becoming one of Pediatric Cancer Foundation’s partners? Fill out our grant application and we will be in touch.