Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Most cancer immunotherapies target mutated peptides (neoantigens) presented by human leukocyte antigen (HLA) molecules.
• Cancers with low mutational burden, like neuroblastoma, are poorly targeted by neoantigen-based therapies.
• Neuroblastoma is driven by epigenetic deregulation rather than mutations, presenting a challenge for current immunotherapies.

Purpose of the Study:

• To develop a novel immunotherapeutic strategy for neuroblastoma targeting intracellular oncoproteins.
• To engineer peptide-centric chimeric antigen receptors (CARs) capable of recognizing specific tumor-associated peptides.
• To overcome human leukocyte antigen (HLA) restriction in CAR T-cell therapy.

Main Methods:

• Identification of a neuroblastoma-specific peptide (QYNPIRTTF) derived from PHOX2B presented on HLA-A*24:02.
• Development of peptide-centric CARs using a counter-panning strategy.
• Computational modeling to predict cross-reactivity with other HLA allotypes.
• In vitro and in vivo validation of CAR T-cell efficacy against neuroblastoma cells.

Main Results:

• Peptide-centric CARs successfully targeted the PHOX2B-derived peptide QYNPIRTTF.
• CARs demonstrated cross-reactivity, recognizing the peptide presented by HLA-A*23:01 and HLA-B*14:02.
• Potent and specific killing of neuroblastoma cells expressing these HLAs was observed in vitro.
• Complete tumor regression was achieved in mouse models.

Conclusions:

• Peptide-centric CARs offer a promising approach to target intracellular oncoproteins previously inaccessible to immunotherapy.
• This strategy broadens the applicability of CAR T-cell therapy by overcoming conventional HLA restriction.
• The findings suggest a potential for wider patient benefit in neuroblastoma and other cancers with low mutational burden.