In recent years, immune checkpoint inhibitors (ICIs) have emerged as an effective treatment against melanoma. But despite their success helping patients, clinical trials have found that over half of melanoma patients either do not benefit at all or become resistant to these forms of immunotherapy.
These patients have limited options for second-line treatment, but this may soon change thanks to a new finding by TFRI-funded researchers from the Montreal Cancer Consortium (MCC).
According to a study published in Clinical Cancer Research (June 2021), a subset of ICI-resistant melanoma patients who display mutations in a specific pathway known as the interferon (IFN)γ-JAK-STAT pathway could benefit from a second-line treatment using a different type of immunotherapy altogether: oncolytic viruses.
This could provide new hope for a group of melanoma patients who are ICI-resistant.
“Our study provides functional evidence to support the use of oncolytic viruses as a precision-medicine strategy to treat ICI resistant and treatment-naïve melanomas with defects in this specific pathway,” says Dr. Ian Watson, a melanoma researcher at McGill University's Goodman Cancer Research Centre and a co-leader of the MCC.
To make this finding, the team drew on a growing field of research that is trying to answer why some melanoma patients respond favourably to ICIs while other don’t. While it still isn’t clear why this occurs, scientists agree that mutations in the IFNγ signaling pathway genes are one of the best-established mechanisms of ICI resistance. These mutations may be present in melanomas prior to treatment, but also arise during treatment.
With this in mind, Dr. Watson and his team began searching for alternative ways to treat patients with mutations in this specific pathway. Because the IFNγ signaling pathway plays a role in the immune response, they hypothesized that a different type of immunotherapy could be effective at treating these patients: oncolytic viruses (OVs).
OVs are a form of immunotherapy that makes use of natural or genetically altered viral strains to preferentially target cancer cells. They work in two ways: by entering and replicating inside of cancer cells, leading to cell death, and by stimulating the immune system to target the tumour.
The team used patient derived cell lines to test the efficacy of different OVs in treating melanomas with mutations in the IFNγ-JAK-STAT pathway. Their results were impressive: when compared to other melanomas, melanomas with mutations in IFNγ pathway that conferred resistance to ICI were 22-fold more sensitive to a modified form of the vesicular stomatitis virus (VSV).
This opens the door for a precision-medicine strategy to use OVs as a second-line therapy for these patients.
But that’s not all. The team also found that inhibiting a component of the IFNγ pathway, known as the Janus kinases, using drugs already approved to treat inflammation in combination with VSV leads to increased sensitivity even in melanomas without any mutations in IFNγ pathway.
“This demonstrates the potential clinical utility of JAK inhibitors-OV combination as a first-line melanoma therapy,” according to Dr. Watson
Immune checkpoint inhibitor-resistance mutations in the IFNγJAK-STAT pathway increase melanoma sensitivity to oncolytic virus treatment
Tan-Trieu Nguyen, LeeAnn Ramsay, Mozhdeh Ahanfeshar-Adams, Mathieu Lajoie, Dirk Schadendorf, Tommy Alain, Ian R. Watson
This study was partially funded by a Terry Fox Research Institute grant to the Montreal Cancer Consortium Pilot for the Marathon of Hope Cancer Centres