Combination therapy delivers one-two punch to skin cancer, boosting anti-tumor activity

August 16, 2012

(Medical Xpress) -- Treating metastatic melanoma by combining immunotherapy with a drug that inhibits the cancer-spreading activity of a common gene mutation significantly increased survival times in an animal model, according to a study by researchers at UCLA's Jonsson Comprehensive Cancer Center.

In the study, animals that received a combination of the recently approved BRAF inhibitor Zelboraf and an engineered T-cell immunotherapy had better tumor responses and lived more than twice as long as those getting the BRAF inhibitor or immunotherapy alone. The findings provide strong support for testing the combination therapy in human clinical trials, which Jonsson Cancer Center researchers hope to launch within two years.

About 50 percent of patients with metastatic melanoma — some 4,000 people a year — have the BRAF mutation and can be treated with Zelboraf. More than 50 percent of them respond well to the drug, but the responses usually last only a few months. With immunotherapy, fewer patients respond, but the responses are more durable.

By pairing these therapies in a one–two punch, researchers hope to maintain the high response rates associated with Zelboraf and combine them with the longer disease-free progression times seen with immunotherapy, said the study's first author, Dr. Richard Koya, a Jonsson Cancer Center scientist and an assistant professor of surgical oncology at UCLA.

"The idea was to target two different aspects of anti-cancer biology, hitting the tumor cells themselves with the BRAF inhibitor and adding in T cells educated to induce a specific anti-tumor immune response," Koya said. "The results we saw in this study were very promising."

The findings of the two-year study were published Aug. 15 in the peer-reviewed journal Cancer Research.

The researchers also found that the BRAF inhibitor helped boost the power of the immunotherapy, creating a greater combination effect, said senior study author Dr. Antoni Ribas, a Jonsson Cancer Center scientist and UCLA professor of hematology–oncology.

"We found that both treatments were more effective when administered together, and we were surprised to see that a drug that should only be targeting the BRAF-mutant cancer cells was also having a beneficial effect on the T cells," Ribas said.

In the immunotherapy technique, called adoptive T-cell transfer (ACT), lymphocytes are genetically engineered to express a receptor that recognizes melanoma cells, creating an army of immune cells that attack the cancer. The lymphocytes are modified genetically to become specific to the melanoma cells and are injected into the body.

The study was done using a model based on unique cell lines developed at UCLA. Previously, no implantable BRAF mutation–driven melanoma model that was able to grow progressively in mice with fully competent immune systems was available.

It is vital to develop new drugs to treat metastatic melanoma, as few options are available for patients, the researchers said. Zelboraf works well, but most patients eventually relapse.

"This is a patient population that we are not able to cure," Koya said. "With what we have now, we are just prolonging their lives. We need to have more options, and we hope this combination therapy proves to be an effective alternative."

About 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease.

"In conclusion, combined therapy with the BRAF-specific inhibitor Zelboraf and T cell receptor engineered adoptive cell transfer resulted in superior anti-tumor effects," the study states. "Although the absolute number of T cells infiltrating the tumor was not increased by Zelboraf, the combination increased the functionality of antigen-specific T lymphocytes. Therefore, our studies support the clinical testing of combinations of BRAF targeted therapy and immunotherapy for patients with advanced melanoma."

Explore further: Second mutation in BRAF-mutated melanoma doesn't contribute to resistance

Related Stories

Second mutation in BRAF-mutated melanoma doesn't contribute to resistance

April 1, 2012
A second mutation found in the tumors of patients with BRAF-mutated metastatic melanoma does not contribute to resistance to BRAF inhibitor drugs, a finding that runs counter to what scientists expected to be true.

Scientists uncover mechanism for melanoma drug resistance

March 6, 2012
Cancer is tough to kill and has many ways of evading the drugs used by oncologists to try and eliminate it.

New drug, Vemurafenib, doubles survival of metastatic melanoma patients

March 1, 2012
A report published this week in the New England Journal of Medicine shows that the 50 percent of metastatic melanoma patients with a specific genetic mutation benefit from the drug Vemurafenib – increasing median survival ...

Study uncovers mechanism by which melanoma drug accelerates secondary skin cancers

January 18, 2012
Patients with metastatic melanoma taking the recently approved drug vemurafenib (Zelboraf) responded well to the twice daily pill, but some of them developed a different, secondary skin cancer. Now, researchers at UCLA's ...

Uncommon BRAF mutation in melanoma sensitive to MEK inhibitor drug therapy

July 16, 2012
An uncommon mutation of the BRAF gene in melanoma patients has been found to respond to MEK inhibitor drugs, providing a rationale for routine screening and therapy in melanoma patients who harbor the BRAF L597 mutation.

New melanoma drug Zelboraf nearly doubles survival in majority of patients

February 22, 2012
Investigators from Vanderbilt-Ingram Cancer Center (VICC) and 12 other centers in the United States and Australia have found that a new drug for patients with metastatic melanoma nearly doubled median overall survival.

Recommended for you

Researchers release first draft of a genome-wide cancer 'dependency map'

July 27, 2017
In one of the largest efforts to build a comprehensive catalog of genetic vulnerabilities in cancer, researchers from the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute have identified more than 760 genes ...

Cancer-death button gets jammed by gut bacterium

July 27, 2017
Researchers at Michigan Medicine and in China showed that a type of bacterium is associated with the recurrence of colorectal cancer and poor outcomes. They found that Fusobacterium nucleatum in the gut can stop chemotherapy ...

Long-sought mechanism of metastasis is discovered in pancreatic cancer

July 27, 2017
Cells, just like people, have memories. They retain molecular markers that at the beginning of their existence helped guide their development. Cells that become cancerous may be making use of these early memories to power ...

Manmade peptides reduce breast cancer's spread

July 27, 2017
Manmade peptides that directly disrupt the inner workings of a gene known to support cancer's spread significantly reduce metastasis in a mouse model of breast cancer, scientists say.

Blocking the back-door that cancer cells use to escape death by radiotherapy

July 27, 2017
A natural healing mechanism of the body may be reducing the efficiency of radiotherapy in breast cancer patients, according to a new study.

Glowing tumor technology helps surgeons remove hidden cancer cells

July 27, 2017
Surgeons were able to identify and remove a greater number of cancerous nodules from lung cancer patients when combining intraoperative molecular imaging (IMI) - through the use of a contrast agent that makes tumor cells ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.