PHOX2B PC-CAR T Enters Human Trials Following FDA IND Approval
Myrio's PHOX2B PC-CAR T therapy gains FDA approval for human trials, promising innovative treatment for patients with high-risk neuroblastoma.
US FDA
- Myrio's PHOX2B peptide-centric (PC)-CAR T therapy has received investigational new drug (IND) application approval from the FDA.
- A first-in-human trial for Myrio's "breaking HLA restriction" technology is planned to begin.
- Anticipated enrollment of the first patient is planned for mid-2025.
PHOX2B PC-CAR T has received IND application approval from the FDA, enabling its progression to human trials. This chimeric antigen receptor (CAR) T-cell therapy, co-developed with a leading children's hospital in Philadelphia, targets neuroblastoma.1
The therapeutic strategy centers on PHOX2B, a protein identified in neuroblastoma cells by John M. Maris, MD, whose team elucidated its peptide's potential as an immunotherapy target. Myrio developed a highly specific binder to the PHOX2B peptide-major histocompatibility complex (p-HLA) using its proprietary ReD™ technology.
Myrio's binder distinguishes itself from conventional binders by its ability to recognize the peptide in multiple HLA allotypes. This is referred to as "breaking HLA restriction,” and offers the potential to treat a broader population of patients using the same immunotherapy, addressing a key limitation in current CAR T approaches for solid tumors.
"Neuroblastoma is the most common tumor of the sympathetic nervous system [and] the most common malignancy of infancy and accounts for 15% of pediatric cancer-related deaths", said Maris, a pediatric oncologist at Children's Hospital of Philadelphia, co-head of the Pediatric Cancer Dream Team, and Giulio D'Angio Chair in Neuroblastoma Research, in a press release. “The current treatment options for patients with high-risk neuroblastoma are associated with low response rates and significant toxicities and the development of new treatment options is desperately needed. This investigational immunotherapy has the potential to be a major advance for patients suffering from this devastating disease".
This novel approach was detailed in a November 2023 Nature publication titled, "Targeting of intracellular oncoproteins with peptide-centric CARs.” The study highlights that while most oncogenic drivers are intracellular, their targeting is often limited to mutated peptides (neoantigens) presented by individual HLA allotypes. This poses a challenge for cancers like neuroblastoma, which have low mutational burdens.2
The research demonstrated that the neuroblastoma immunopeptidome is enriched with peptides from essential tumorigenesis proteins. Focusing on the unmutated peptide QYNPIRTTF, derived from the neuroblastoma-dependency gene PHOX2B and presented on HLA-A24:02, Myrio developed PC-CARs.
Researchers showed that the PC-CARs could also recognize QYNPIRTTF presented by other HLA allotypes, specifically HLA-A23:01, by recognizing a similar overall molecular surface. These data demonstrate potent and specific in vitro killing of neuroblastoma cells expressing these HLAs and complete tumor regression in mice, suggesting PC-CARs can expand immunotherapeutic targets to include nonimmunogenic intracellular oncoproteins across various HLA allotypes.
The IND approval represents the first human trial for a Myrio-developed binder, validating the company's technology. The phase 1 trial will be conducted under Maris's leadership, and the first patient enrollment is expected to be in mid-2025.1
“[T]his is a major step forward for Myrio. It is the culmination of many years of work at Myrio in developing bispecific binders to Human Leukocyte Antigens for the treatment of solid tumors, added Graeme Wald, chief executive officer of Myrio Therapeutics, in the press release.
