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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Research Article

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 4

Serum cell binding and ADCC assay.

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Serum cell binding and ADCC assay. (A) Sera from high-dose cohort patien...
(A) Sera from high-dose cohort patient AVX701-0121 were incubated with CEA-expressing colon tumor cell line SW1463 (CEA+) and non-CEA–expressing colon tumor line COLO320 (CEA–). Results are represented as histograms of MFI for 1:50, 1:100, and 1:200 dilutions. Binding of prevaccination serum antibodies is represented by white peaks, and the postvaccination serum is represented by the gray peaks. The top row of histograms binds against SW1463 (CEA+) cell line and the lower row COLO320 cell line. The ELISA titer for patient AVX701-0121 was 1:200. (B) Serial dilutions of pre- and postimmunization sera from high-dose cohort patient AVX701-0109 were incubated with CEA-expressing colon tumor cell line SW1463 (CEA+) in an ADCC assay. The percentage of specific lysis is presented as mean ± SD. *P < 0.01 for prevaccination versus week 9 serum at 1:20 ratio. The ELISA titer for patient AVX701-0109 was 1:1,600.