Abstract PR03: CD8+ T-cell distribution and immunomodulator expression in BRAF-mutant melanoma affect the response to BRAF inhibitor and chemotherapy
Authors: Wongchenko Matthew , Rabe Christina , Sosman Jeffrey , McArthur Grant , Xiao Yuanyuan , Gilbert Houston , Andries Luc , Kockx Mark , Koeppen Hartmut , Hegde Priti , Amler Lukas , Yan Yibing , Ribas Antoni 
Published: July 2015

Abstract
Although intense effort has been made in studying immune cell dynamics in tumors after treatment with targeted therapies and to recharacterize tumor stages based on their immune cell components, less is known about how baseline immune cell characteristics in tumors affect response to approved therapies. Here we describe baseline expression of immune regulators and CD8+ T-cell distribution in BRAF-mutated metastatic melanoma and their relationship with progression-free survival (PFS) on vemurafenib and chemotherapy. To our knowledge, we are the first to describe the baseline characteristics of tumor-infiltrating lymphocytes and their impact on outcomes in a large randomized, controlled trial in melanoma.
Archival or baseline samples were collected from patients in 2 clinical trials (BRIM2 and BRIM3) and analyzed. A total of 252 RNA samples were prepared from formalin-fixed, paraffin-embedded (FFPE) tissue samples and profiled for expression using a panel of 96 immune genes on the Fluidigm platform (Fluidigm Corp). Additionally, for 277 patients from the BRIM3 trial, CD8+ T cells were detected by immunohistochemistry (IHC) and quantified using Definiens (Definiens AG). Patients were defined as high or low expressers based on a median cutoff, and hazard ratios (HRs) were determined by cox proportional hazards modeling of PFS. HRs refer to the comparison of high and low expressing groups, where an HR&lt;1 is indicative of a better outcome for the high-expressing group.
A discovery (BRIM2) – validation (BRIM3) scheme was applied to assess the prognostic value of the expression of immune-related genes. Samples from the BRIM3 dacarbazine and vemurafenib arms were compared to assess the predictive value of the markers on the treatment effect of vemurafenib. Of the genes tested, 26 met our discovery criteria in the BRIM2 trial and 2, IL7 and IL12A, were validated in BRIM3. In the vemurafenib arm of BRIM3, patients with high expression of IL7 had improved PFS compared with patients with low IL7, with an HR of 0.63 (95% confidence interval [CI]: 0.41-0.97; P=0.03); high expression of IL12A had an HR of 0.58 (0.38-0.88; P=0.01). Neither gene was associated with PFS in the dacarbazine-treated arm; however, high and low expressers of both genes benefited from vemurafenib treatment.
Because immune contexture is known to be associated with outcomes, slides were stained for CD8+ T-cell content in 3 marker areas: center, peripheral, and invasive margin. In the dacarbazine arm, increased PFS was seen in patients with higher CD8+ T-cell content in the tumor center or periphery, with HRs of 0.58 (0.43-0.94; P=0.02) and 0.39 (0.25-0.59; P&lt;0.01), respectively. CD8+ T-cell content did not show a significant effect in vemurafenib-treated patients, and all groups benefited from vemurafenib treatment.
Based on these characterizations, tumor immune cell components seem to play important but varying roles in response to dacarbazine or vemurafenib treatment in BRAF-mutant melanoma.
This abstract is also being presented as Poster B22.
Citation Format: Matthew Wongchenko, Christina Rabe, Jeffrey Sosman, Grant McArthur, Yuanyuan Xiao, Houston Gilbert, Luc Andries, Mark Kockx, Hartmut Koeppen, Priti Hegde, Lukas Amler, Yibing Yan, Antoni Ribas. CD8+ T-cell distribution and immunomodulator expression in BRAF-mutant melanoma affect the response to BRAF inhibitor and chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr PR03.