Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule (original) (raw)

Abstract

The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC) constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses. Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an ALVAC-CEA-B7.1 vaccine (4.5 × 106, 4.5 × 107, and 4.5 × 108 plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA- B7.1 at doses up to 4.5 × 108 PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-γ enzyme-linked immunoassay spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses. This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1 to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with tolerable toxicity.

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1. Albert Einstein Cancer Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA Tel.: +1-718-430-3517 Fax: +1-718-430-3099, , , , , , US
   Heidi Hörig, David S. Lee, William Conkright, Joe Divito, Henry Hasson, Michelle LaMare, Audrey Rivera, David Park & Howard L. Kaufman
2. Virogenetics Corporation, Troy, NY, USA, , , , , , US
   John Tine
3. Pasteur Mérieux Connaught Laboratories, Swiftwater, Pa., USA, , , , , , US
   Ken Guito
4. Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Md., USA, , , , , , US
   Kwong Wong-Yok Tsang & Jeffrey Schlom

Authors

1. Heidi Hörig
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2. David S. Lee
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3. William Conkright
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4. Joe Divito
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5. Henry Hasson
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6. Michelle LaMare
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7. Audrey Rivera
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8. David Park
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9. John Tine
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10. Ken Guito
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11. Kwong Wong-Yok Tsang
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12. Jeffrey Schlom
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13. Howard L. Kaufman
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Received: 6 May 2000 / Accepted: 13 July 2000

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Hörig, H., Lee, D., Conkright, W. et al. Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule.Cancer Immunol Immunother 49, 504–514 (2000). https://doi.org/10.1007/s002620000146

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• Issue Date: October 2000
• DOI: https://doi.org/10.1007/s002620000146