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EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

Publication ,  Journal Article
Sampson, JH; Choi, BD; Sanchez-Perez, L; Suryadevara, CM; Snyder, DJ; Flores, CT; Schmittling, RJ; Nair, SK; Reap, EA; Norberg, PK; Herndon, JE ...
Published in: Clin Cancer Res
February 15, 2014

PURPOSE: Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. EXPERIMENTAL DESIGN: We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. RESULTS: At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. CONCLUSION: All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

February 15, 2014

Volume

20

Issue

4

Start / End Page

972 / 984

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Single-Chain Antibodies
  • Receptors, Antigen, T-Cell
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice
  • Humans
  • ErbB Receptors
  • Cell Line, Tumor
  • Brain Neoplasms
 

Citation

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Sampson, J. H., Choi, B. D., Sanchez-Perez, L., Suryadevara, C. M., Snyder, D. J., Flores, C. T., … Johnson, L. A. (2014). EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res, 20(4), 972–984. https://doi.org/10.1158/1078-0432.CCR-13-0709
Sampson, John H., Bryan D. Choi, Luis Sanchez-Perez, Carter M. Suryadevara, David J. Snyder, Catherine T. Flores, Robert J. Schmittling, et al. “EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.Clin Cancer Res 20, no. 4 (February 15, 2014): 972–84. https://doi.org/10.1158/1078-0432.CCR-13-0709.
Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, et al. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res. 2014 Feb 15;20(4):972–84.
Sampson, John H., et al. “EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.Clin Cancer Res, vol. 20, no. 4, Feb. 2014, pp. 972–84. Pubmed, doi:10.1158/1078-0432.CCR-13-0709.
Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, Schmittling RJ, Nair SK, Reap EA, Norberg PK, Herndon JE, Kuan C-T, Morgan RA, Rosenberg SA, Johnson LA. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res. 2014 Feb 15;20(4):972–984.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

February 15, 2014

Volume

20

Issue

4

Start / End Page

972 / 984

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Single-Chain Antibodies
  • Receptors, Antigen, T-Cell
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice
  • Humans
  • ErbB Receptors
  • Cell Line, Tumor
  • Brain Neoplasms