Combined Chemotherapy and Immunotherapy Treatment Halts Growth of Metastatic Melanoma

A novel treatment for metastatic melanoma combines chemotherapy with the recently approved BRAF inhibitor vemurafenib, and immunotherapy with adoptive cell transfer therapy using lymphocytes genetically modified with a T-cell receptor (TCR) recognizing chicken ovalbumin (OVA).

The protein encoded by the BRAF gene plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene have been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small-cell lung carcinoma, and lung adenocarcinoma.

Vemurafenib (the name comes from V600E mutated BRAF inhibition) only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 50% of melanomas have this mutation. Melanoma cells without this mutation are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases. About 50% of patients with metastatic melanoma have the BRAF mutation and can be treated with vemurafenib. More than 50% of those treated respond well to the drug, but the responses usually last only a few months.

Investigators at the University of California, Los Angeles (USA) sought to combine the powerful, but often relatively short-term response to vemurafenib with the less potent but longer lasting effect of immunotherapy.

Using a fully immunocompetent mouse model of metastatic melanoma, the investigators combined treatment with vemurafenib with adoptive cell transfer therapy with lymphocytes genetically modified with a T-cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors or pmel-1 TCR transgenic lymphocytes.

They reported in the August 15, 2012, issue of the journal Cancer Research that the combined therapy resulted in superior antitumor responses compared with either therapy alone. The mice that received the combination therapy lived more than twice as long as those getting the BRAF inhibitor or immunotherapy alone. T-cell analysis showed that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells.

“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,” said senior author Dr. Antoni Ribas, professor of hematology and oncology at the University of California, Los Angeles (UCLA). “Combined therapy with the BRAF-specific inhibitor vemurafenib and T cell receptor engineered adoptive cell transfer resulted in superior antitumor effects. Although the absolute number of T cells infiltrating the tumor was not increased by vemurafenib, 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.”

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