Targeting of intracellular oncoproteins with peptide-centric CARs

Mark Yarmarkovich (), Quinlen F. Marshall, John M. Warrington, Rasika Premaratne, Alvin Farrel, David Groff, Wei Li, Moreno Marco, Erin Runbeck, Hau Truong, Jugmohit S. Toor, Sarvind Tripathi, Son Nguyen, Helena Shen, Tiffany Noel, Nicole L. Church, Amber Weiner, Nathan Kendsersky, Dan Martinez, Rebecca Weisberg, Molly Christie, Laurence Eisenlohr, Kristopher R. Bosse, Dimiter S. Dimitrov, Stefan Stevanovic, Nikolaos G. Sgourakis, Ben R. Kiefel and John M. Maris ()
Additional contact information
Mark Yarmarkovich: New York University Grossman School of Medicine
Quinlen F. Marshall: Children’s Hospital of Philadelphia
John M. Warrington: Children’s Hospital of Philadelphia
Rasika Premaratne: Myrio Tx
Alvin Farrel: Children’s Hospital of Philadelphia
David Groff: Children’s Hospital of Philadelphia
Wei Li: University of Pittsburgh
Moreno Marco: University of Tubingen
Erin Runbeck: Children’s Hospital of Philadelphia
Hau Truong: Perelman School of Medicine at the University of Pennsylvania
Jugmohit S. Toor: University of California Santa Cruz
Sarvind Tripathi: University of California Santa Cruz
Son Nguyen: Massachusetts Institute of Technology
Helena Shen: Children’s Hospital of Philadelphia
Tiffany Noel: Children’s Hospital of Philadelphia
Nicole L. Church: Myrio Tx
Amber Weiner: Children’s Hospital of Philadelphia
Nathan Kendsersky: Children’s Hospital of Philadelphia
Dan Martinez: Children’s Hospital of Philadelphia
Rebecca Weisberg: Children’s Hospital of Philadelphia
Molly Christie: Children’s Hospital of Philadelphia
Laurence Eisenlohr: Children’s Hospital of Philadelphia
Kristopher R. Bosse: Children’s Hospital of Philadelphia
Dimiter S. Dimitrov: University of Pittsburgh
Stefan Stevanovic: University of Tubingen
Nikolaos G. Sgourakis: Perelman School of Medicine at the University of Pennsylvania
Ben R. Kiefel: Myrio Tx
John M. Maris: Children’s Hospital of Philadelphia

Nature, 2023, vol. 623, issue 7988, 820-827

Abstract: Abstract The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

Date: 2023
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DOI: 10.1038/s41586-023-06706-0

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