A high molecular weight melanoma-associated antigen - Specific chimeric antigen receptor redirects lymphocytes to target human melanomas

William R. Burns, Yangbing Zhao, Timothy L. Frankel, Christian S. Hinrichs, Zhili Zheng, Hui Xu, Steven A. Feldman, Soldano Ferrone, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Immunotherapy, particularly the adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL), is a very promising therapy for metastatic melanoma. Some patients unable to receive TIL have been successfully treated with autologous peripheral blood lymphocytes (PBL), genetically modified to express human leukocyte antigen (HLA) class I antigen-restricted, melanoma antigen-reactive T-cell receptors; however, substantial numbers of patients remain ineligible due to the lack of expression of the restricting HLA class I allele. We sought to overcome this limitation by designing a non-MHC-restricted, chimeric antigen receptor (CAR) targeting the high molecular weight melanoma-associated antigen (HMW-MAA), which is highly expressed on more than 90% of human melanomas but has a restricted distribution in normal tissues. HMW-MAA-specific CARs containing an antigen recognition domain based on variations of the HMW-MAA-specific monoclonal antibody 225.28S and a T-cell activation domain based on combinations of CD28, 4-1BB, and CD3ζ activation motifs were constructed within a retroviral vector to allow stable gene transfer into cells and their progeny. Following optimization of the HMW-MAA-specific CAR for expression and function in human PBL, these genemodified T cells secreted cytokines, were cytolytic, and proliferated in response to HMW-MAA-expressing cell lines. Furthermore, the receptor functioned in both CD4+ and CD8+ cells, was non-MHC restricted, and reacted against explanted human melanomas. To evaluate this HMW-MAA-specific CAR in patients with metastatic melanoma, we developed a clinical-grade retroviral packaging line. This may represent a novel means to treat the majority of patients with advanced melanoma, most notably those unable to receive current ACT therapies.

Original languageEnglish (US)
Pages (from-to)3027-3033
Number of pages7
JournalCancer Research
Volume70
Issue number8
DOIs
StatePublished - Apr 15 2010
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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