Tag: melanoma

For patients with advanced melanoma without BRAF mutation who no longer respond to immune checkpoint inhibitors, treatment options remain frustratingly limited. A new study from Vanderbilt researchers led by Professor Emerita of Pharmacology Ann Richmond outlines a promising therapeutic strategy that may re-sensitise these resistant tumours to immunotherapy.

The research introduces a three-drug combination that enhances immune activity and suppresses tumour-promoting immune cells by leveraging a low dose of the MEK inhibitor trametinib and multi-kinase inhibitor rigosertib alongside a CD40 agonist to shift the tumour microenvironment toward immune activation. Notably, all three agents have been either approved by the U.S. Food and Drug Administration or are currently in clinical trials, which may speed their path to patient testing.

“While agonist CD40 therapy can be helpful for treatment of melanoma, this therapy also induces the CD11b⁺ B regulatory cells that suppress the T cell response to tumours,” Richmond said. “We showed that combining CD40 therapy with trametinib and rigosertib prevents the induction of these B regulatory cells.”

Immune checkpoint inhibitors have become a mainstay of melanoma treatment, working by releasing the molecular “brakes” that prevent T cells from attacking cancer. But resistance to ICI is common in metastatic melanoma, especially in tumours that evolve immune-suppressive microenvironments. While CD40 agonists can activate immune cells, this therapy also unexpectedly expands CD11b⁺ regulatory B cells.

By combining CD40 activation with MEK and PI3K inhibition, the researchers blocked the expansion of suppressive B cells while retaining the benefits of CD40 stimulation. In preclinical mouse models of melanoma, the triple combination not only suppressed tumour growth but also restored responsiveness to checkpoint blockade.

Key findings

• B cells as a resistance mechanism: CD40 therapy alone induced regulatory B cells that dampen T cell–mediated tumor immunity.
• Triple combination prevents immune suppression: Co-treatment with trametinib and rigosertib blocked the agonist CD40 induction of regulatory B cells, allowing immune responses to proceed.
• ICIs regain effectiveness: The drug cocktail slowed tumor progression and re-sensitized resistant melanomas to anti-PD-1 therapy.

Translational promise

Because trametinib, rigosertib, and CD40 agonists are already in human trials or approved for other indications, this therapeutic strategy may advance more quickly than approaches requiring new drug development. Richmond’s team sees potential for testing the triple therapy in clinical trials for melanoma patients who have progressed on ICI.

“This approach provides a new route to enhance antitumor immunity in patients with tumors that no longer respond to immunotherapy,” Richmond said.

By Marissa Shapiro

Source: Vanderbilt University

Studying these craters could better assess immunotherapy’s success in treating solid tumours

Like the surface of the moon, new research published today in Cell finds the existence of craters on the surface of melanoma cells that serve as immune hubs, becoming major sites for tumour killing. These craters could serve as good markers for immunotherapy success.

This research provides insight into a key function of immune check-point blockade (ICB) cancer therapy that was previously unknown. ICB works by re-activating CD8+ T cells against tumours which shrinks and eventually kills the cancer cells. However, what facilitates local tumour killing by the infiltrating CD8+ T cells has remained a mystery.

Using a zebrafish model, researchers were able to monitor the infiltrating CD8+ T cells for up to 24 hours as they moved through the 3D architecture of endogenous melanoma tumours. Zebrafish provide the only tumour model where continuous live imaging over a 24 hour time period is feasible.  

“We found that rather than patrolling the entire tumour surface, CD8+ T cells aggregated in pockets on the melanoma border, forming prolonged interactions with melanoma cells,” says Leonard Zon, MD, Director of the Stem Cell Program at Boston Children’s Hospital and lead investigator of the study. “We termed these pockets Cancer Regions of Antigen presentation and T cell Engagement and Retention (CRATERs) and saw that, following immune stimulation, the CRATERs expanded and facilitated an effective immune response against the tumour.”

Zon, first author Aya Ludin, and the team also discovered CRATERs in human melanoma samples. Moreover, they saw similar structures in human lung cancer, indicating that CRATERs are likely not limited to melanoma and may form in other solid tumours.

To date, efficacy of therapeutic response to ICB therapy has been assessed mainly by estimating the degree of tumour necrosis and fibrosis. Indicators of CD8+ T cells infiltration has been associated with patient survival and treatment outcome, but direct evidence of effective immune cell-tumour cell interaction has been missing.

“Pending thorough clinical verification and taken together with other measurements, CRATERs may serve to more accurately assess the efficacy of an ongoing treatment and improve treatment outcomes,” said Zon.

The research team is now planning a prospective clinical trial to test if CRATERs are the best marker of ICB success.

Source: Boston Children’s Hospital via EurekAlert!

Increased activity in a specific biological pathway may explain why many patients with a deadly form of skin cancer do not respond to the latest cancer treatments, a new study shows.

Publishing in the journal Cancer Research, the study featured data generated from experiments with human tissues and cells from patients with advanced melanoma that were implanted into mice. Results uncovered therapeutic targets that could limit melanoma growth in patients whose cancer failed to respond to initial treatment with immune checkpoint inhibitors.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the study focused on a subgroup of melanoma patients with mutations in the neurofibromin 1 (NF1) gene. NF1 mutations are just one type among several mutations, including those in the BRAF, NRAS, and PARP genes, that are linked to many cases of cancer, particularly melanoma. As many as 27% of melanoma patients are estimated to have NF1 mutations.

While immunotherapy, which stimulates the immune system to attack cancer cells as it would an invading virus, has proved to be a successful treatment, it does not work well for more than half of NF1-mutant melanoma patients.

“There is a pressing need for new drug therapies for melanoma patients with neurofibromin 1 mutations that do not respond to the latest immunotherapy, and for which there are no subsequent effective treatment options,” said study lead investigator Milad Ibrahim, PhD. Ibrahim is a postdoctoral fellow in the Dr Iman Osman Laboratory in the Ronald O. Perelman Department of Dermatology at the NYU Grossman School of Medicine.

To investigate why these patients were treatment resistant, investigators examined tumour cells from 30 melanoma patients who did not respond to immunotherapy. NF1 mutations were found in 40% of these melanoma samples. The samples came from NYU Langone’s extensive repository from more than 6000 melanoma patients.

Molecular testing showed that the signalling pathway built around a protein called epidermal growth factor receptor (EGFR) was more active in NF1 mutant melanoma cells than in cells with other melanoma-gene mutations. Increased EGFR activity has long been linked to abnormal cell growth in tumours and shorter survival with various cancers. The researchers also found that NF1 mutant melanoma cells depended on increased EGFR activity for survival, regardless of the presence of other mutations.

Because EGFR-inhibiting drugs are already used to treat some head and neck cancers, as well as colorectal and lung cancers, researchers then tested two drugs in the class, cetuximab and afatinib, in both NF1 mutant cell cultures and cancer cell lines without NF1 mutations. After transplanting both tumour cell types into mice and treating them with these drugs, results showed that both EGFR inhibitors were effective against cells and transplanted tumours with NF1 mutations, and they had no effect on melanomas without NF1 mutations.

“Our study results reveal a unique vulnerability in melanoma patients with neurofibromin 1 mutations, that an overexpression of the epidermal growth factor receptor pathway is essential for their survival and growth,” said the study’s senior investigator, Professor Iman Osman, MD.

“While further tests are needed, our results support a novel approach of deploying EGFR inhibitors either alone or in combination with other immunotherapies for treatment of melanoma patients whose tumours harbour NF1 mutation,” said the study’s co-senior investigator, Associate Professor Markus Schober, PhD.

However, Schober says this requires further testing in a clinical trial, which the research team plans to develop. He adds that if trial findings prove successful, the team’s research could provide a lifeline for many of these melanoma patients.

Source: NYU Langone Health

Mitochondrial pathways help melanoma cells become aggressive, and some currently available drugs target these pathways.

Researchers have discovered that the most aggressive melanomas, the deadliest form of skin cancer, overactivate two key processes in mitochondria. Blocking these pathways with currently available drugs effectively killed melanoma cells. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

By mapping the proteins expressed in 151 tumour and normal skin samples, investigators found that the most aggressive melanomas hyper-activate the machinery that builds mitochondrial proteins and the mitochondrial system that turns nutrients into energy.

Remarkably, blocking these pathways effectively halted or killed melanoma cells cultured in lab dishes. Two types of drugs accomplished this: antibiotics, originally designed to block bacterial protein synthesis machinery, which closely resembles the machinery found in mitochondria, and specialised energy-production inhibitors. Importantly, non-cancerous skin cells remained mostly unaffected, highlighting the safety and specificity of these treatment approaches.

“This discovery identifies melanoma’s excessive reliance on mitochondrial energy as its Achilles’ heel, revealing a therapeutic vulnerability that we can exploit with existing drugs,” said senior author Jeovanis Gil, PhD, of Lund University in Sweden. “By pairing mitochondrial blockers with today’s standards of care, we may cut off a major escape route that cancers use to resist therapy and come back.”

Dr Gil added that the mitochondrial-protein signature his team discovered can be measured in routine biopsy material and could serve as a biomarker to identify patients most likely to benefit from mitochondrial-targeted add-on therapies. By enabling clinicians to match treatments to each patient’s tumour biology, these findings mark a step forward for precision medicine in melanoma. Moreover, because mitochondrial rewiring fuels resistance across many cancers, success in melanoma could open the door to similar personalised combination strategies in other hard-to-treat cancers. 

Source: Wiley