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A Nonviral Approach to Generate Transient Chimeric Antigen Receptor T Cells Using mRNA for Cancer Immunotherapy
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Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target

Kamal Mandal1, Gianina Wicaksono1, Clinton Yu2

  • 1Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.

Nature Cancer
|October 31, 2023
PubMed

Insights

Researchers discovered a novel approach to target cancer cells by identifying unique protein structures on their surface. This method successfully targeted acute myeloid leukemia (AML) cells, offering a promising new avenue for cancer immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Biochemistry

Background:

  • Expanding cellular therapies is limited by the lack of cancer-specific surface markers.
  • Current target discovery methods often miss unique protein conformations on tumor cells.

Purpose of the Study:

  • To explore cancer-specific surface protein conformations as immunotherapeutic targets.
  • To develop a novel strategy called 'structural surfaceomics' for identifying these targets.
  • To validate this approach in acute myeloid leukemia (AML).

Main Methods:

  • Utilized structural surfaceomics, integrating cross-linking mass spectrometry and glycoprotein surface capture.
  • Applied the technology to acute myeloid leukemia (AML) samples.
  • Developed and characterized recombinant antibodies against the identified target.

Main Results:

  • Identified the activated conformation of integrin β2 as a specific target for AML.
  • Demonstrated that chimeric antigen receptor T cells targeting this conformation eliminate AML cells and patient-derived xenografts.
  • Showed no significant toxicity to normal hematopoietic cells.

Conclusions:

  • Validated a novel AML-specific target antigen based on protein conformation.
  • Structural surfaceomics provides a powerful toolkit for discovering and targeting conformation-specific antigens.
  • This strategy holds potential for broader applications in cancer immunotherapy.

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