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Updated: Sep 16, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Combinatorial therapy regimens targeting preclinical models of melanoma resistant to immune checkpoint blockade
Imran Khan1,2, Aida Rodriguez-Brotons1, Anukana Bhattacharjee3
1California Pacific Medical Center (CPMC) Research Institute, San Francisco, California, USA.
Abstract:
Few effective therapeutic options exist after progression on immune checkpoint blockade (ICB) for melanoma. Here, we utilized a platform incorporating transcriptomic profiling, high-throughput drug screening, and murine models to demonstrate the preclinical efficacy of several combinatorial regimens against ICB-resistant melanoma. Transcriptomic analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. High-throughput drug screening targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft models. The combination of cobimetinib and regorafenib (termed Cobi+Reg) emerged as a particularly promising regimen, with efficacy against distinct molecular melanoma subtypes and after progression on ICB in immunocompetent models. Transcriptomic and spatial analysis of Cobi+Reg-treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either modality in vivo. This analytical platform exploits the biology of ICB-resistant melanoma to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.
Insights
New drug combinations show promise for melanoma patients resistant to immune checkpoint blockade (ICB). Cobimetinib and regorafenib (Cobi+Reg) effectively treated ICB-resistant melanoma in preclinical models, suggesting new therapeutic strategies.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Limited effective treatments are available for melanoma patients who progress on immune checkpoint blockade (ICB).
- Understanding the molecular mechanisms of ICB resistance is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To identify effective combinatorial regimens against ICB-resistant melanoma using a multi-platform approach.
- To evaluate the preclinical efficacy of identified combinations in patient-derived xenograft and immunocompetent models.
Main Methods:
- Transcriptomic profiling of ICB-resistant melanomas to identify targetable pathways.
- High-throughput drug screening (HTDS) to discover effective drug combinations.
- Preclinical testing of promising combinations, including cobimetinib and regorafenib (Cobi+Reg), in murine models.
Main Results:
- Transcriptomic analysis revealed activated pathways in ICB-resistant melanoma.
- HTDS identified several effective combinations, with Cobi+Reg showing broad efficacy across subtypes and post-ICB progression.
- Cobi+Reg treatment upregulated antigen presentation machinery and increased T cell infiltration.
- Combination of Cobi+Reg with ICB demonstrated superior efficacy compared to monotherapy in vivo.
Conclusions:
- A multi-platform approach successfully identified therapeutic vulnerabilities in ICB-resistant melanoma.
- Cobimetinib and regorafenib (Cobi+Reg) represent a promising combination for advanced melanoma resistant to ICB.
- These findings provide a basis for designing clinical trials in ICB-resistant melanoma.
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