An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer
Michael A. Morse, … , Jonathan Smith, H. Kim Lyerly
Michael A. Morse, … , Jonathan Smith, H. Kim Lyerly
Published August 2, 2010
Citation Information: J Clin Invest. 2010;120(9):3234-3241. https://doi.org/10.1172/JCI42672.
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An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer

Abstract

Therapeutic anticancer vaccines are designed to boost patients’ immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.

Authors

Michael A. Morse, Amy C. Hobeika, Takuya Osada, Peter Berglund, Bolyn Hubby, Sarah Negri, Donna Niedzwiecki, Gayathri R. Devi, Bruce K. Burnett, Timothy M. Clay, Jonathan Smith, H. Kim Lyerly

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Figure 1

Treg analysis for patients and healthy volunteers.

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Treg analysis for patients and healthy volunteers. Patient blood was ana...
Patient blood was analyzed prevaccination and at week 12 (3 weeks following the fourth and final vaccination) by flow cytometry staining for CD4+CD25+ and intracellular FoxP3 to determine percentage of Tregs. (A) The percentage of CD4+CD25+FoxP3+ cells and the (B) number of CD4+CD25+FoxP3+ cells per μl whole blood are represented for each patient by a square for cohort 1, triangle for cohort 2, and circle for cohort 3 (maximal tolerated dose [MTD]) at prevaccination week 0 and postvaccination week 12. (A) The percentage of CD4+CD25+FoxP3+ cells of normal donors (ND) was determined and analyzed using the same methods and is presented as a comparison (diamonds). The mean (bar) is also represented for ND, before vaccination, and after vaccination. Statistical significance is noted by Student’s t test between percentage of Tregs of normal donors and cancer patients in the study (P = 0.03). The differences in the percentage of Tregs before and after vaccination are not statistically significant for any of the vaccine doses (P > 0.2).