Researchers have identified potential new therapeutic strategies for patients with advanced melanoma who no longer respond to immunotherapy—an aim representing one of the most pressing clinical challenges in cancer care today.

The study, led by Mohammed Kashani-Sabet, M.D., medical director of CPMC’s Cancer Centre and an investigator at the CPMC Research Institute, builds on years of foundational work by the Cancer Avatar Programme team at CPMC to better understand the biological basis of resistance to immune checkpoint blockade (ICB) therapies.

The findings were published online in the Journal of Clinical Investigation and form the basis of a forthcoming investigator-initiated clinical trial at Sutter Health.

“Immunotherapy has transformed how we treat melanoma, but when it fails, our treatment options are extremely limited,” says Dr. Kashani-Sabet.

“We often need to resort to ineffective therapies developed decades ago. This study offers a new path forward.”

Using transcriptomic profiling and high-throughput drug screening made possible by the Cancer Avatar Programme, Dr. Kashani and team analysed tumours from 14 CPMC patients whose melanoma had progressed after PD-1-based immunotherapy compared with tumours from 15 treatment-naïve patients.

They identified several druggable genes and pathways, including those involved in mitogen activated protein kinase (MAPK) signalling, angiogenesis and apoptosis, and tested combinations of U.S. FDA-approved drugs targeting these pathways in patient-derived xenograft (PDX) models.

One combination, cobimetinib + regorafenib (Cobi+Reg), showed synergistic anti-tumour activity across multiple melanoma subtypes, including BRAF-, NRAS- and NF1-mutant tumours.

The regimen also reversed key resistance mechanisms, including restoring antigen presentation and increasing infiltration of activated CD8+ T cells.

“Cobi+Reg not only shrank tumours in preclinical models—it reactivated the immune system,” says Dr. Kashani-Sabet.

“This opens the door to combining targeted therapy with immunotherapy for even greater benefit.”

The study was conducted as part of the CPMC Cancer Avatar Programme, a precision oncology initiative that uses living tumour models to guide treatment decisions.

The project has already led to multiple clinical trials and is supported by the CPMC Foundation and philanthropic partners.

A CPMC led clinical trial testing the promising combinations identified in patients with immunotherapy-resistant melanoma is now in development and is anticipated to begin enrolling patients by late 2025.

“This is a prime example of how precision oncology at Sutter is helping transform care for patients who need new options beyond standard of care,” says Amanda Wheeler, M.D., chair of Sutter’s cancer service line.

Article: Combinatorial therapy regimens targeting preclinical models of melanoma resistant to immune checkpoint blockade

Source: Sutter Health