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Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors.

Publication ,  Journal Article
Martin, AL; Anadon, CM; Biswas, S; Mine, JA; Handley, KF; Payne, KK; Mandal, G; Chaurio, RA; Powers, JJ; Sprenger, KB; Rigolizzo, KE; Mehta, S ...
Published in: Mol Cancer Ther
July 5, 2022

Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non-small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 5, 2022

Volume

21

Issue

7

Start / End Page

1184 / 1194

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Receptors, Odorant
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasms, Glandular and Epithelial
  • Lung Neoplasms
  • Immunotherapy, Adoptive
  • Humans
  • Female
  • Cell Line, Tumor
 

Citation

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Martin, A. L., Anadon, C. M., Biswas, S., Mine, J. A., Handley, K. F., Payne, K. K., … Conejo-Garcia, J. R. (2022). Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors. Mol Cancer Ther, 21(7), 1184–1194. https://doi.org/10.1158/1535-7163.MCT-21-0872
Martin, Alexandra L., Carmen M. Anadon, Subir Biswas, Jessica A. Mine, Katelyn F. Handley, Kyle K. Payne, Gunjan Mandal, et al. “Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors.Mol Cancer Ther 21, no. 7 (July 5, 2022): 1184–94. https://doi.org/10.1158/1535-7163.MCT-21-0872.
Martin AL, Anadon CM, Biswas S, Mine JA, Handley KF, Payne KK, et al. Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors. Mol Cancer Ther. 2022 Jul 5;21(7):1184–94.
Martin, Alexandra L., et al. “Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors.Mol Cancer Ther, vol. 21, no. 7, July 2022, pp. 1184–94. Pubmed, doi:10.1158/1535-7163.MCT-21-0872.
Martin AL, Anadon CM, Biswas S, Mine JA, Handley KF, Payne KK, Mandal G, Chaurio RA, Powers JJ, Sprenger KB, Rigolizzo KE, Innamarato P, Harro CM, Mehta S, Perez BA, Wenham RM, Conejo-Garcia JR. Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors. Mol Cancer Ther. 2022 Jul 5;21(7):1184–1194.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 5, 2022

Volume

21

Issue

7

Start / End Page

1184 / 1194

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Receptors, Odorant
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasms, Glandular and Epithelial
  • Lung Neoplasms
  • Immunotherapy, Adoptive
  • Humans
  • Female
  • Cell Line, Tumor