BRAF Inhibition Is Associated With Enhanced Melanoma Antigen Expression

BRAF Inhibition Is Associated With Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients With Metastatic Melanoma

Clin Cancer Res. 2013 Jan 10;[Epub Ahead of Print], DT Frederick, A Piris, AP Cogdill, ZA Cooper, et al

BRAF Inhibition Is Associated With Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients With Metastatic Melanoma

Clin Cancer Res. 2013 Jan 10;[Epub Ahead of Print], DT Frederick, A Piris, AP Cogdill, ZA Cooper, et al

SUMMARY

OncologySTAT Editorial Team

BRAF inhibitors have produced impressive response rates in patients with metastatic melanoma, but early relapse is common. Immunotherapy agents have also been successful, and there is preclinical evidence of synergy between the two therapeutic approaches. Frederick et al evaluated the immune response to BRAF inhibition, alone or combined with MEK inhibition, in patients with metastatic melanoma.

A total of 16 patients with metastatic melanoma containing BRAF^V600E received a BRAF inhibitor (vemurafenib) alone or a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib). Tumor biopsies were performed before treatment, after 10 to 14 days of treatment, and at the time of progression.

BRAF inhibition was associated with increased melanoma antigen expression, with increases of 4.9-, 16.4-, 13.3-, and 14.1-fold in MART, TYRP-1, TYRP-2, and GP100, respectively. Melanoma antigen expression did not differ in biopsies from patients receiving a BRAF inhibitor alone or combined BRAF/MEK inhibition, except for TYRP-2, which was higher in the combination treatment patients. BRAF inhibition was also associated with significant increases in CD8+ T-cell infiltrate.

BRAF inhibition had significant effects on the tumor microenvironment. Immunosuppressive cytokines IL-6 and IL-8 decreased with BRAF inhibition, whereas markers of T-cell cytotoxicity increased. Of interest, markers of T-cell exhaustion (TIM3 and PD1) were also significantly increased with BRAF inhibition, as was expression of the immunosuppressive ligand PDL1.

Patients who progressed on therapy showed an increase in melanoma antigen expression and CD8+ T-cell infiltrate at the time of progression. Of the patients who progressed on BRAF monotherapy, 1 later received combined BRAF/MEK inhibitors. Tumor biopsy after treatment showed restoration of melanoma antigen expression and CD8+ T-cell infiltrate.

The study supports the hypothesis that combined BRAF-targeted therapy and immunotherapy may improve responses in patients with metastatic melanoma. BRAF inhibition enhanced the tumor microenvironment by increasing melanoma antigen expression and markers of T-cell cytotoxicity, while decreasing expression of immunosuppressive cytokines.

The immune response to BRAF inhibition may be limited, however, due to the paradoxical increases in exhaustion markers on T cells and in PDL1 seen in the current study. Further, melanoma antigen expression and CD8+ T-cell infiltrate were suppressed at the time of progression, suggesting reactivation of the MAPK pathway.

These findings suggest that successful combination therapy may require use of pro-immune cytokines, such as IL-2, and immune checkpoint blockade with agents that target CTLA-4, PD1, or PDL1 to augment the immune response to BRAF inhibition. Studies combining BRAF-targeted therapy and immunotherapy are currently underway.

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This does not sound like good news.  But aren't people on this forum getting some good results with the braf inhibition?