ORLANDO-A promising approach in vector vaccine development is the use of a combination of vaccination strategies that enhance T-cell responses for specific tumor-associated antigens, said Jeffrey Schlom, PhD, chief of the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institutes, Bethesda, Maryland.
ORLANDOA promising approach in vector vaccine development is the use of a combination of vaccination strategies that enhance T-cell responses for specific tumor-associated antigens, said Jeffrey Schlom, PhD, chief of the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institutes, Bethesda, Maryland.
Dr. Schlom spoke at a symposium on cancer vaccines held in conjunction with the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO) and sponsored by Antigenics Inc. and the University of Connecticut School of Medicine.
"Because tumor-associated antigens are, by definition, either weakly immunogenic or functionally nonimmuno-genic, vaccine strategies must be developed in which the presentation of the antigens to the immune system results in far greater activation of T cells than is being achieved naturally in the host," Dr. Schlom said.
He described a number of vaccine strategies that have been used to enhance T-cell responses to specific antigens. Vectors have been used to provide more efficient delivery of tumor-associated antigens to antigen-presenting cells. A DNA vaccine may be created through the insertion of single or multiple genes of interest, such as genes for known antigens, into a viral vector such as a poxvirus.
The pox vectors vaccinia and avipoxfowlpox and/or canarypox (ALVAC, Aventis Pasteur)have been used successfully in this regard. These vectors allow for insertion of multiple genes, do not integrate into host DNA, and efficiently infect antigen-presenting cells, including dendritic cells.
According to Dr. Schlom, the use of two different recombinant vectors, known as a prime-and-boost strategy, induces a more potent T-cell response compared with the use of a single vector. Multiple vaccinations with recombinant vaccinia vectors cannot be used because of induction of host immunity to the virus, he said. However, primary vaccination with a recombinant vaccinia vector followed by booster vaccinations with a recombinant avipox vector can optimally induce T-cell responses.
Vaccine responses can also be enhanced by the use of T-cell costimulatory molecules, such as B7-1, ICAM-1, or LFA-3. These costimulatory molecules are essential for vigorous T-cell activation. With poxvirus vector vaccines, it is possible to insert the genes for these costimulatory molecules directly into the vaccine vector.
Other strategies to increase immune responsiveness include "epitope enhancement," a procedure in which the amino acid sequence of the tumor antigen is altered to enhance its immunogenicity, and the administration of cytokines as biologic adjuvants to stimulate the immune system.
Dr. Schlom explained how several of these strategies have been incorporated into the development of CEA/TRICOM, a recombinant poxvirus-based vaccine directed against the carcinoembryonic antigen (CEA) that also incorporates a triad of costimulatory molecules (TRICOM): B7-1, ICAM-1, and LFA-3. These studies are being conducted in collaboration with Therion Biologics, Cambridge, Massachusetts.
Overexpression of CEA occurs in a wide range of human carcinomas including colorectal, pancreatic, breast, and non-small-cell lung cancerand, to some degree, in normal colon epithelium. According to Dr. Schlom, several clinical studies have demonstrated that CEA-based vaccines can elicit CEA-specific T-cell responses, and studies have also shown that CEA-specific T cells are capable of attacking cancer cells that express CEA.
In preclinical studies, Dr. Schlom said that recombinant fowlpox (rF)-CEA/TRICOM was more effective at inducing CEA-specific T-cell responses than rF-CEA or rF-CEA/B7-1 vaccines.
Also, a diversified prime/boost strategy involving recombinant vaccinia (rV)-CEA/TRICOM and rF-CEA/TRICOM was more potent than rF-CEA/TRICOM alone. In addition, the simultaneous administration of GM-CSF as an adjuvant further enhanced CEA-specific T-cell responses.
At ASCO, John Marshall, MD, of Georgetown University Medical Center, presented the results of an ongoing phase I dose-escalation study of sequential vaccination with the two TRICOM vaccines (abstract 24). Patients received rF-CEA/TRICOM alone, rV-CEA/TRICOM followed by booster vaccinations with rF-CEA/TRICOM, or rV-CEA/TRICOM followed by rF-CEA/TRICOM and GM-CSF adjuvant.
Dr. Marshall reported significant CEA-specific T-cell responses in the majority of patients. In addition, he described a durable complete response in one patient after only two injections of rF-CEA/TRICOM lasting 15 months before death from another cause and some cases of significant stable disease.
Dr. Schlom said that clinical evaluation of CEA/TRICOM is now underway in a collaborative effort involving the National Cancer Institute and eight other cancer centers throughout the United States. Phase I and II studies are now ongoing at these centers.
The studies will assess the safety and immunologic effects of the CEA/TRICOM vaccination strategies in patients with advanced metastatic colorectal cancer and other CEA-expressing carcinomas. They will evaluate prime-and-boost strategies involving rV-CEA/TRICOM and rF-CEA/TRICOM and assess the effect of adjuvant GM-CSF.