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Process to better understand how advanced melanoma adapts to immunotherapy

Date:
May 9, 2017
Source:
University of California, Los Angeles (UCLA), Health Sciences
Summary:
A new study could be a significant step toward understanding how certain cases of advanced melanoma shield themselves from pembrolizumab, the FDA-approved treatment that harnesses the immune system to attack the disease.
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A new study by scientists at the UCLA Jonsson Comprehensive Cancer Center could be a significant step toward understanding how certain cases of advanced melanoma shield themselves from pembrolizumab, the FDA-approved treatment that harnesses the immune system to attack the disease.

The researchers, led by UCLA's Dr. Antoni Ribas, studied how melanoma cancer cells react to the interferon gamma pathway, which guides cell signaling and can affect the way cancer cells react to pembrolizumab. The team then discovered and mapped out the molecules involved in this signaling pathway. The findings lay the groundwork for developing new and improved combination therapies for patients who are resistant to stand-alone immunotherapy treatments.

Pembrolizumab (marketed as Keytruda) works by signaling the patient's immune system to recognize and attack cancer cells, with minimal side effects. It was approved in 2014 by the U.S. Food and Drug Administration to treat advanced melanoma, and approved recently to treat people with advanced non-small cell lung cancer. The medication is currently being tested as a treatment for other types of cancer.

In February, a study published by Ribas and colleagues in Cancer Discovery showed that people with cancers containing genetic mutations JAK1 or JAK2 (which are known to prevent tumors from recognizing or receiving signals from T cells to stop growing), will receive little or no benefit from pembrolizumab. This discovery enabled the scientists to determine why some people with advanced melanoma or colon cancer will not respond to the drug.

That built on 2016 research by Ribas and colleagues, published in the New England Journal of Medicine, in which they analyzed pairs of tumors both before a patient had undergone immunotherapy treatment and after relapse. The results showed that one of the tumors lost a gene called B2M, which resulted in a change in how the cancer is recognized by the immune system. The disruption caused JAK1 and JAK2 to function improperly and prevented the immune system from attacking the cancer.

The new study was conducted over a two-year period; the scientists analyzed dozens of melanoma cell lines and several tumor samples from patients. In the laboratory, researchers also used an advanced technology called a lentivirus shRNA screen to locate which molecules were involved in the interferon receptor pathway signaling process.

The research allows further investigations into how the immune systems of patients with advanced cancers can resist anti-PD-1 immunotherapy treatments, the class of treatments that includes pembrolizumab.

The study is published in the journal Cell Reports.


Story Source:

Materials provided by University of California, Los Angeles (UCLA), Health Sciences. Note: Content may be edited for style and length.


Journal Reference:

  1. Angel Garcia-Diaz, Daniel Sanghoon Shin, Blanca Homet Moreno, Justin Saco, Helena Escuin-Ordinas, Gabriel Abril Rodriguez, Jesse M. Zaretsky, Lu Sun, Willy Hugo, Xiaoyan Wang, Giulia Parisi, Cristina Puig Saus, Davis Y. Torrejon, Thomas G. Graeber, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Robert Damoiseaux, Roger S. Lo, Antoni Ribas. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Reports, 2017; 19 (6): 1189 DOI: 10.1016/j.celrep.2017.04.031

Cite This Page:

University of California, Los Angeles (UCLA), Health Sciences. "Process to better understand how advanced melanoma adapts to immunotherapy." ScienceDaily. ScienceDaily, 9 May 2017. <www.sciencedaily.com/releases/2017/05/170509133051.htm>.
University of California, Los Angeles (UCLA), Health Sciences. (2017, May 9). Process to better understand how advanced melanoma adapts to immunotherapy. ScienceDaily. Retrieved May 29, 2017 from www.sciencedaily.com/releases/2017/05/170509133051.htm
University of California, Los Angeles (UCLA), Health Sciences. "Process to better understand how advanced melanoma adapts to immunotherapy." ScienceDaily. www.sciencedaily.com/releases/2017/05/170509133051.htm (accessed May 29, 2017).

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