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Cancer immunotherapy drugs known as “checkpoint inhibitors” are powerful new tools for treating metastatic melanoma, but physicians struggle to predict which patients will benefit from a given drug and which may suffer unnecessary toxicity. Scientists at Dana-Farber Cancer Institute, however, have discovered genetic markers for resistance to ipilumumab, the first checkpoint inhibitor approved by the Food & Drug Administration for the disease, according to a new report in the Journal Cell.

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Checkpoint inhibitors target surface proteins on T cells that can act as switches preventing these immune-system cells from attacking tumors. Ipilimumab targets a protein known as CTLA-4 and was the first checkpoint inhibitor approved (on the basis of work from another Dana-Farber investigator and close collaborator on this project, F. Stephen Hodi, MD). Drugs from another class of checkpoint inhibitors that target a protein called PD-1 are also given for metastatic melanoma, sometimes in combination with ipilimumab.

Checkpoint inhibitors target surface proteins on T cells that can act as switches preventing these immune-system cells from attacking tumors. Ipilimumab targets a protein known as CTLA-4 and was the first checkpoint inhibitor approved (on the basis of work from another Dana-Farber investigator and close collaborator on this project, F. Stephen Hodi, MD). Drugs from another class of checkpoint inhibitors that target a protein called PD-1 are also given for metastatic melanoma, sometimes in combination with ipilimumab.

Dana-Farber computational biologist Sachet Shukla, PhD, and medical oncologist Pavan Bachireddy, MD, supervised by medical oncologist Catherine Wu, MD, studied RNA expression in tumors from 146 melanoma biopsies collected by four clinical studies of checkpoint inhibitors. They found a genetic signature for resistance to ipilimumab that was not present for nivolumab, a PD-1 inhibitor.

More surprisingly, the most highly expressed genes in patients that did not benefit from ipilimumab were from a sub-family of genes known as MAGE-A that has been targeted in numerous immunotherapy clinical trials. “Our work suggests that MAGE-A genes themselves actually can suppress critical factors needed to stimulate effective responses to therapy, and may be good targets for drug development efforts,” said Wu, who is senior author on a paper in Cell about the research.

MAGE-A Antigens and Cancer Immunotherapy


Abstract
MAGE-A antigens are expressed in a variety of cancers of diverse histological origin and germinal cells. Due to their relatively high tumor specificity, they represent attractive targets for active specific and adoptive cancer immunotherapies. Here, we (i) review past and ongoing clinical studies targeting these antigens, (ii) analyze advantages and disadvantages of different therapeutic approaches, and (iii) discuss possible improvements in MAGE-A-specific immunotherapies.


MAGE-A Tumor-Associated Antigens
MAGE-A were the first human tumor-associated antigens identified at the molecular level (1). They belong to the larger family of cancer/testis antigens (CTA), whose expression is consistently detected in cancers of different histological origin and germinal cells (2). The MAGE-A sub-family includes 12 highly homologous genes located on chromosome Xq28 (3, 4). Specific gene products have been identified by immunohistochemistry in cancers of different histological origin, including high percentages of non-small cell lung cancers (NSCLC), bladder cancers, esophageal and head and neck cancers, and sarcomas (5).



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340762/