Year First Funded: 2024

ACGT – Barbara Netter Collaboration Award, 2024

A major barrier impeding progressing cancer cellular therapy is the lack of highly tumor-specific targets with negligible normal tissue expression. Ideally, CAR T-cell targets will not only be highly differentially expressed, but also essential oncoproteins required for tumor sustenance and so less prone to downregulation as a mechanism of immune escape.

While chemoradiotherapy can cure 4 out of 5 children with cancer, 1 of 5 dying is unacceptable and survivors often have lifelong therapy-related morbidities including secondary cancers. CAR T-cell therapy has revolutionized the approach to pediatric acute lymphoblastic leukemia, and there are clear recent signs of efficacy in pediatric solid tumors, credentialling perhaps that CAR T cells can navigate the immunosuppressive tumor microenvironment of childhood cancers.

Pediatric malignancies arise due to misappropriation of normal fetal developmental pathways, typically due to epigenetic deregulation of lineage-restricted proteins that can be dramatically overexpressed in cancer cells. The research collaborators recently showed non-mutated peptides derived from these oncofetal proteins are recurrently presented on common HLA alleles and are targetable with CARs (Yarmarkovich, Nature 2021). By discovering scFvs that are highly specific for the peptide in the MHC groove, peptide-centric CAR (PC-CAR) T cells cured mice of highly aggressive patient-derived xenografts of human neuroblastoma in published and ongoing IND-enabling studies. PHOX2B is master regulator of sympathetic nervous system development (cell of origin) and a familial neuroblastoma gene, and a 9mer peptide is recurrently presented on each HLA-A*24:02 allele studied to date. Because of the peptide-centric nature of the scFv, we also showed that nine other HLA-A alleles present this same peptide in similar enough fashion to be recognized by our lead PHOX2B PC-CAR, including HLA-A*23:01, a common allele in individuals of African descent.

The vision of the research team is to develop a suite of PC-CARs for pediatric cancer indications that covers the entire population. They recently solved the crystal structure of their first PC-CAR in complex with the PHOX2B peptide-HLA-A*24:02 complex which provided significant insights into design principals allowing for therapeutic expansion across HLA allotypes and mitigation of toxicity liabilities through molecular mimicry of the peptide-MHC complex (manuscript in review). In this collaboration, they propose the next step in their vision which is to accelerate the first PC-CAR to the clinic and perform a first-in-human first-in-child Phase 1/1b clinical trial. In parallel, they will perform the IND enabling studies for the second PC-CAR trial that focuses on a peptide derived from IGFBPL1 recurrently presented on HLA-A*02:01.

Highly specific and potent scFv binders have been developed in collaboration with our industry partner Myrio Therapeutics and potent cytotoxicity demonstrated in vitro.

The ultimate goal is curative therapy with minimal toxicity.

ACGT – Barbara Netter Collaboration Award, 2024

The long-term vision of this collaboration is to develop T cell-based immunotherapies for pediatric brain tumors with the potential to become standards of care.

Globally, there are more than 400,000 children that are diagnosed with cancer each year, and in developed countries cancer remains the most common cause of death by disease for children. While cure rates for pediatric patients with leukemias and lymphomas have improved significantly, outcomes for pediatric patients with malignant brain tumors lag behind with an overall 5-year survival rate of approximately 65% in developed countries. However, depending on brain tumor type, survival rates can be much lower, including for group 3 and 4 medulloblastoma (MB) and ependymoma (EPN). 

Pediatric brain tumors are in desperate need of a transformative therapeutic approach since current approaches are often not curative and are associated with significant acute and long-term associated toxicities. Radiation, one of the cornerstones of current treatment approaches, has significant long-term side effects to the developing brain leading to “pyrrhic victories” in which long-term survivors suffer from learning disabilities, behavioral issues, and an inability to fully integrate into our society and fast-paced social networks. 

The bold vision of this ACGT-funded collaboration is to develop a curative Synthetic T-cell Therapy for pediatric brain tumors. The high specificity of such T-cell therapies would make them less toxic than current standard-of-care therapies, reducing acute and long-term adverse effects and the risk of late recurrences.

Several pieces of evidence suggest that researcers are at a propitious time for success in delivering novel Synthetic T cell-based therapies for pediatric brain tumors, and in this collaborative research proposal the focus is on chimeric antigen receptor (CAR) T-cell therapy. First, CAR T-cell targets for pediatric brain tumors have already been identified by the research collaborators (B7-H3, GD2, GPC2) and data is already available to credential them as safe for early phase clinical trials. Second, locoregional and/or intravenous delivery of CAR T cells has demonstrated significant antitumor activity in children with diffuse midline gliomas and glioblastoma and in adults with glioblastoma multiforme. Third, the research group has deep expertise in developing next-generation CAR therapeutics with enhanced potency compared to first-generation CAR immune cells created a decade ago. This expertise will be fully leveraged by our team to enhance the potency and durability of effect. Fourth, the group brings experts in syngeneic murine models and patient-derived orthotopic xenografts that allow interrogation of the tumor microenvironment of brain tumors and to use these models to develop evidence-based CAR T-cell products for future clinical testing.