Recombinant Cancer Vaccines Offering Promise
Although currently there are no approved therapeutic cancer vaccines, the success of ongoing research in this area could very well change that within the next decade. One area of research that is proving particularly fruitful is the development of recombinant vaccines for use either alone or as an adjunct to existing cancer therapy. These vaccines have had promising results in early clinical studies, explained Dr. Jeffrey Schlom, chief of the Laboratory of Tumor Immunology and Biology, NCI Center for Cancer Research (CCR), during the first CCR Grand Rounds of 2004.
Much of the work to date on recombinant vaccines has focused on targeting several different tumor-associated antigens (TAAs), Dr. Schlom said. One specific TAA, carcinoembryonic antigen (CEA), has been used as a prototype for vaccine design and development because it is overexpressed in the vast majority of colorectal, pancreatic, and nonsmall cell lung cancers, as well as other carcinomas such as breast cancer.
Of the strategies that have been tested in early clinical trials to date, five have proven effective at boosting the body's immune response, Dr. Schlom said. Included among these strategies is the use of two types of poxvirus as vectors to deliver the CEA vaccine to the tumor site and injecting granulocyte macrophage-colony stimulating factor (GM-CSF) at the vaccination site as an adjuvant, to heighten the immune response to the CEA vaccine.
In a small, randomized clinical trial, researchers found that a "booster" approach - administering one CEA vaccine followed later by a second, different CEA vaccine - more effectively induced a CEA-specific T-cell response than use of either vaccine alone. "There was also a statistical correlation between the induction of these T-cell responses and prolonged survival," Dr. Schlom noted.
Following the positive results from early trials, recombinant vaccines were constructed containing both CEA genes and three costimulatory molecules, or TRICOM, and tested in preclinical trials.
"Compared to the vaccines devoid of costimulation or containing one or two costimulatory molecules, these vaccines were far superior in terms of antitumor effects and T-cell activation," Dr. Schlom said. Also, the cytokine, GM-CSF, he added, appeared to play a particularly important role in improving the strategy's efficacy. Researchers at NCI and major cancer centers across the country have continued to further enhance vaccines. For example, an agonist epitope has been added to CEA and CEATRICOM vaccines after it proved to further boost T-cell response compared to a CEA vaccine that relies on a native CEA epitope.
Clinical trials testing these various vaccine strategies are ongoing, Dr. Schlom said. In a collaborative clinical trial that has recently completed recruitment at Georgetown University, the CEA-TRICOM vaccines induced stable disease in 40 percent of advanced cancer patients four months after treatment. Increased survival was again seen in those patients who received a combination vaccine regimen along with a GM-CSF adjuvant. Meanwhile, several clinical trials using recombinant prostate-specific antigen (PSA)-based vaccines are ongoing in patients with various stages of prostate cancer, for instance, and a phase I trial has been launched using PSA-TRICOM vaccines.
These recombinant vaccines also are being tested in combination with other therapeutic regimens. In one preclinical model, Dr. Schlom said, the combined use of a TRICOM vaccine and local radiation demonstrated dramatic antitumor effects.
Looking forward to a time when therapeutic vaccines make their way into clinicians' armamentarium for cancer treatment, Dr. Schlom stressed that there indeed may be "fundamental differences" between the vaccines and conventional therapies.
"The immune response to a vaccine may indeed be a dynamic process that may or may not lead to the eradication of tumor," he said, "but may be sufficient to arrest tumor growth and induce a stable disease state leading to increased survival."