John Maris, MD

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.

“We have a vision of future peptide-centric CARs where the eligibility to receive the therapy is just the HLA type and not the specific cancer type. It expands the patient population.”