Innovative Strategies for Breast Cancer Immunotherapy
Abstract
We have previously reported the antitumor effects of anti-human endogenous retrovirus-K (HERV-K) monoclonal antibodies, as well as vaccines for breast cancer (BC) based on HERV-K envelope (env) protein as a tumor-associated antigen. Here, a chimeric antigen receptor (CAR) specific for HERV-K env protein (K-CAR) was generated using the Sleeping Beauty system. K-CARs from peripheral blood mononuclear cells of 9 BC patients and 12 normal female donors were able to inhibit growth of, and to exhibit significant cytotoxicity toward, BC cells but not MCF-10A normal breast cells. The antitumor effects were significantly reduced when the expression of HERV-K in BC cells was knocked down by a shRNA. Secretion of multiple cytokines, including IFN-, TNF-, and IL-2, was significantly enhanced in culture media of BC cells treated with K-CARs. Significantly reduced tumor growth and tumor weight was observed in xenograft models bearing MDA-MB-231 or MDA-MB-435.eB1 cells. Importantly, the K-CAR prevented tumor metastasis to other organs. Moreover, downregulation of HERV-K expression in tumors of mice treated with K-CAR correlated with upregulation of TP53 and downregulation of MDM2 and p-ERK. Our results indicate that CARs directed toward HERV-K may play an important role in immunotherapy of BC, and that K-CAR shows potential for use in clinical trials involving BC patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2014
- Accession Number
- AD1002216
Entities
People
- Feng Wang-johanning
Organizations
- SRI International