JAK Mutations May Identify Patients Unlikely to Respond to Keytruda, Other PD-1 Blockers

JAK Mutations May Identify Patients Unlikely to Respond to Keytruda, Other PD-1 Blockers

The anti-PD-1 agent Keytruda (pembrolizumab) is unlikely to benefit patients whose cancers have mutations in the JAK1 or JAK2 genes, according to a recent UCLA study showing that such mutations lead to the loss of PD-L1, which is required for Keytruda to be effective.

The study, “Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations,” was published in Cancer Discovery. It sheds light onto why certain colon cancer and melanoma patients fail to respond to this promising immunotherapy.

In 2014, the U.S. Food and Drug Administration approved Keytruda for the treatment of advanced melanoma. Since then, Keytruda received approval for two other cancer indications, advanced non-small cell lung cancer and head and neck cancer, and helped thousands of patients live longer.

Keytruda and other PD-1 blockers have shown durable responses in advanced cancers, but studies have shown that nearly 25% of melanoma patients who first responded to Keytruda had disease progression within 21 months.

In an attempt to understand the mechanisms underlying this acquired resistance, Antoni Ribas, MD, director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, and colleagues already had conducted a study analyzing tumor samples before and after immunotherapy, and after tumor relapse. They had found that one tumor lost the B2M gene, leading to a malfunction of the JAK1 and JAK2 proteins, which affected how the immune cells recognized the cancer.

This time, Ribas and his team revealed that mutations in the JAK1 and JAK2 proteins induced the loss of reactive PD-L1 expression. Since Keytruda blocks the interaction between PD-1 and PD-L1, it is no longer effective in cancer cells lacking PD-L1.

The team analyzed samples from 23 melanoma patients and 16 colon cancer patients. Two patients (one with melanoma and one with colon cancer) had JAK1 or JAK2 inactivating mutations and did not respond to anti-PD-1 therapy.

Further analysis in 48 melanoma cell lines revealed that JAK mutations impaired the cells from responding to interferon gamma signaling, which led to a lack of PD-L1 expression.

The findings suggest that JAK mutations could be used to predict which patients are likely to respond to anti-PD-1 therapies like Keytruda or Opdivo (nivolumab).

“The recognition that JAK1/2 loss-of-function mutations would lead to lack of response to PD-1 blockade therapy could be incorporated in oncogenic sequencing panels used to select patients for precision cancer treatments,” the researchers wrote.

One comment

  1. Howard Schlauch says:

    I haven’t had the opportunity to read the published article – thank you for the summary.

    If the JAK mutation impairs responses to interferon gamma signaling and thus prevents upregulation of PD-L1, couldn’t you still theoretically observe responses assuming adequate activated CD8 TILs?

    If the checkpoint inhibitor doesn’t work on patients with the JAK mutation, then wouldn’t the line of thinking go that a robust immune response could still get you the desired result, owing to the lack of checkpoint? It seems as though perhaps the key to dealing with these JAK mutation patients is ensuring robust antigen specific CD8 TIL.

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