B Schilling1, W Sondermann2, F Zhao2, K G Griewank2, E Livingstone2, A Sucker2, H Zelba3, B Weide4, U Trefzer5, T Wilhelm5, C Loquai6, C Berking7, J Hassel8, K C Kähler9, J Utikal10, P Al Ghazal11, R Gutzmer11, S M Goldinger12, L Zimmer2, A Paschen2, U Hillen2, D Schadendorf2. 1. Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK). Electronic address: bastian.schilling@uk-essen.de. 2. Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK). 3. University Medical Center, University of Tübingen, Tübingen. 4. German Cancer Consortium (DKTK); University Medical Center, University of Tübingen, Tübingen. 5. German Cancer Consortium (DKTK); Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin. 6. German Cancer Consortium (DKTK); Department of Dermatology, University of Mainz, Mainz. 7. German Cancer Consortium (DKTK); Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich. 8. German Cancer Consortium (DKTK); Department of Dermatology, Heidelberg University Hospital, Heidelberg. 9. Department of Dermatology, Venerology and Allergology, University of Schleswig-Holstein Hospital, Campus Kiel. 10. German Cancer Consortium (DKTK); Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg; Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim. 11. Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany. 12. Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Abstract
BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.
BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanomapatients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.
Entities:
Keywords:
T cells; dabrafenib; lymphocytes; melanoma; treatment; vemurafenib
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