Selective BRAF inhibitors induce marked T cell infiltration into human metastatic melanoma
Menée sur 37 échantillons tumoraux prélevés sur 15 patients atteints d'un mélanome non opérable de stade III ou IV, immédiatement avant et environ 7 jours après le début d'un traitement à l'aide d'un inhibiteur de BRAF (vemurafenib ou GSK2118436), cette étude évalue les effets du traitement sur la réponse immunitaire
Purpose: To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK 2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment. Patients and Methods: Thirty-seven tumor biopsies were collected from fifteen unresectable American Joint Committee on Cancer stage III or IV melanoma patients immediately before and approximately seven days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was performed on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B. Results: Tumor infiltration by CD4+ and CD8+ lymphocytes increased markedly following BRAF inhibitor treatment (both ρ=0•015). There was a correlation between the degree of tumor infiltration by CD8+ and Granzyme B expressing lymphocytes in post BRAF inhibitor treated biopsies (r=0•690, ρ=0•013). Increased intratumoral CD8+ lymphocyte expression correlated with a reduction in tumor size and an increase in necrosis in post treatment biopsies (r= -0•793, ρ=0•011 and r=0•761, ρ=0•004, respectively). Conclusion: The increase in tumor infiltrating lymphocytes (TILS) induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses.