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New understanding of immunology in cancer patients has identified a number of targets for designing effective immunotherapy. Strategies for inhibiting regulatory checkpoints that subvert T-cell responses or to favorably modulate the local tumor microenvironment are among the approaches under investigation.
"Research toward creating a vaccine for melanoma has yielded disappointing results to date. Recently, however, a number of immune-suppressive mechanisms have been identified that may explain these results, and new approaches designed to block the involved inhibitory pathways and stimulate T-cell activation appear promising," Dr. Kaufman tells Dermatology Times.
The finding that regulatory checkpoints acting to subvert the immune system response are upregulated in patients with melanoma and most other types of cancer has directed researchers to develop strategies for disabling them. Brakes on a car provide a good analogy for the role of these regulatory checkpoints, says Dr. Kaufman, vice chairman of surgical oncology, Columbia University Medical Center.
Various molecular mediators in this pathway have been identified. Among those, CLTA4 appears to be one of the "master brakes," and research with anti-CLTA4 antibodies is the farthest along in clinical development. Two companies are developing different versions of an anti-CLTA4 antibody. Both have already progressed into phase 3 trials, and results are anticipated within the year.
"Research completed to date shows that when CLTA4 is turned off with this antibody, T cells stay active, and injection with the antiCLTA4 antibody also seems to be demonstrating therapeutic benefit in clinical trials of melanoma patients completed so far," Dr. Kaufman says.
In one phase 2 study involving several hundred patients with metastatic disease, there was an overall response rate of 15 percent, including some patients with brain metastasis.
The response rate was about 35 percent among patients who developed autoimmune breakthrough events, which is the major side effect of the treatment.
"More recently we have learned how to control this problem using low doses of steroids or TNF blockade without adversely altering the antitumor effect," Dr. Kaufman says.
In addition to CLTA4, a host of other pathways appear to act as regulatory checkpoints, and a number of other drugs are in various phases of development targeting those.
"Data so far suggest some may be more potent than others, but I think this is a very exciting area that may allow us to release the brakes on the immune system response to vaccination. Then, we can re-evaluate the potential of vaccines," he says.
Research in the area of tumor immunology has also led to a realization of the importance of addressing the immune response in the local tumor microenvironment, rather than systemically.
"Prior studies with vaccines showed they were effective at priming T-cell responses based on assays performed using peripheral blood, but it appears the active T cells are shut down at the site of the tumor. The mechanism may involve the regulatory checkpoints or a host of alternative pathways that may be mediated by interleukin-10 or other molecules," Dr. Kaufman explains.
These findings have led to the design of strategies for altering the local tumor microenvironment, so the balance favors tumor rejection versus growth.
One approach involves intratumoral injection of virus-based vaccines. Dr. Kaufman and colleagues have been working on that strategy with administration of poxvirus vaccines, and others are using a herpesvirus vaccine.
Other researchers are looking at the use of topical immune response modifiers, such as imiquimod or newer derivatives that act by binding to toll-like receptors on immunologic cells.
"Whereas 10 years ago, it was believed that cancer patients were generally immunosuppressed, the fact that they are not more prone to infections and do not manifest other signs of immunosuppression point to the fallacy of that thinking. Current concepts hold there is local immunosuppression at the tumor site and not elsewhere in the body," he says.
"The host immune system does eradicate melanoma in a small percentage of patients, and that is a very important observation as we try to develop treatments," Dr. Kaufman says.
Disclosure: Dr. Kaufman has no financial interest in the subject matter he discussed.