Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
previously annotated by The Cancer Genome Atlas lung ACA dataset and all
hypermorphic mutations identified were located in the highly conserved
kinase domain. The majority of mutations have been known to enhance
kinase activity in melanoma in a fashion analogous to the well-known
BRAF V600E mutation. In line with these findings, we showed that kinase
domain mutations were hypermorphic as measured by MEK and ERK1/2
phosphorylation. We also showed that exposure of wild type BRAF cells to
radiation results only in a transient activation of MEK and ERK1/2. The MEK
inhibitor selumetinib selectively decreased the growth of cells with kinase
domain BRAF mutations and sensitized these cells to radiation. Conclusion:
BRAF mutations are associated with radiation resistance in lung ACA. Our
data nominates MEK inhibitors, a drug class currently in clinical use, as a
targeted therapeutic in select BRAF-mutant lung ACA. Further investigation
has the potential to yield an additional genotype-directed therapy that could
impact up to 4-6% of patients with lung ACA, a frequency comparable to that
of ALK rearrangements (4%) or EGFR mutations (10%).
Keywords: MEK inhibitors, precision medicine, radiogenomics, BRAF
MA13: MODERN TECHNOLOGIES AND BIOLOGICAL FACTORS IN RADIOTHERAPY
TUESDAY, DECEMBER 6, 2016 - 16:00-17:30
MA13.07 TUMOR-TARGETED RADIATION PROMOTES ABSCOPAL
EFFICACY OF REGIONALLY ADMINISTERED CAR T CELLS: A
RATIONALE FOR CLINICAL TRIAL
Masha Zeltsman 1 , Jonathan Villena-Vargas 1 , Andreas Rimner 2 , Marissa
Mayor 1 , David Jones 1 , Prasad Adusumilli 1
1 Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York/NY/United States of America, 2 Radiation Oncology, Memorial Sloan
Kettering Cancer Center, New York/NY/United States of America
Conclusion: Nivolumab has reasonable efficacy and good safety profile in the
real-life setting. ECOG PS ≥2 is associated with poor prognosis.
Keywords: Nivolumab, Anti-PD-1, ECOG PS, non-small cell lung cancer
MA13: MODERN TECHNOLOGIES AND BIOLOGICAL FACTORS IN RADIOTHERAPY
TUESDAY, DECEMBER 6, 2016 - 16:00-17:30
MA13.06 INTEGRATIVE GENOMIC PROFILING IDENTIFIES
BRAF MUTATIONS AS NOVEL RADIOTHERAPEUTIC TARGETS IN
ADENOCARCINOMAS OF THE LUNG
Eui Kyu Chie 1 , Priyanka Gopal 2 , Mohamed Abazeed 2
1 Radiation Oncology, Seoul National University College of Medicine, Seoul/Korea,
Republic of, 2 Translational Hematology Oncology Research, Cleveland Clinic,
Cleveland/OH/United States of America
Background: Patients with non-small cell lung cancer (NSCLC) display a
wide spectrum of oncologic outcomes, suggesting significant underlying
biologic diversity. However, current radiotherapeutic management is largely
homogeneous for a given stage, To advance genotype-directed radiotherapy
in NSCLC, we sought to identify genetic determinants of radioresistance by
leveraging cancer genomic data with a recently developed high-throughput
platform for measuring radiation survival. Methods: We used our recently
validated high-throughput proliferation assay to profile 104 lung cancer
cell lines, including 89 NSCLC and 15 small cell lung cancer (SCLC) lines, for
radiation survival. Survival curve analyses permitted quantitative assessment
of radiosensitivity. Genomic correlates of radiosensitivity were explored
by calculating the information-based similarity metric and correlating
genomic parameters by accessing Oncomap data from the Cancer Cell Line
Encyclopedia, the COSMIC database of the Cancer Genome Project, and The
Cancer Genome Atlas. Results: Radiation survival across lineages reflected
clinical experience regarding differential response to fractionated radiation
inasmuch as lung squamous cell carcinoma and adenocarcinoma (ACA) had
similar radiosensitivity, whereas SCLC and carcinoid were, respectively,
more and less radiosensitive. Importantly, radiosensitivity varied more
within a lineage than across lineages, with a 6-fold difference in integral
survival among ACA lines. Correlation with cancer genomic data revealed
BRAF mutations within the most resistant ACA lines (P = 0.0097, FDR =
0.957). A majority of the mutations identified by our analysis have been
Background: Our laboratory has demonstrated the augmented anti-tumor
efficacy of intrapleurally administered cancer-antigen mesothelin (MSLN)-
targeted chimeric antigen receptor (CAR) T cells (Sci Transl Med 2014), and
translated the approach to a clinical trial (NCT02414269) for thoracic
malignancies. We hypothesized that regionally administered MSLN CAR T
cells can circulate systemically to achieve abscopal anti-tumor efficacy in an
antigen-specific manner, and the abscopal efficacy can further be promoted
by tumor-targeted radiation therapy (RT). Methods: Using optimized
protocols that would permit non-necrotic, well-vascularized tumor growth in
pleura, chest wall, peritoneum and flank, tumors were established in
immunodeficient (NOD/SCID gamma) mice using mesothelioma or lung
adenocarcinoma (LAC) cells. Tumor burden progression, MSLN-targeted CAR
T-Cell accumulation at primary and distant tumors was monitored by
noninvasive bioluminescence imaging (BLI) and tumor volume measurements.
Results: A single dose of MSLN CAR T cells administered intrapleurally
proliferated (Figure 1A left panel), circulated extrapleurally and accumulated
at abscopal sites, including the lymph nodes, chest wall, peritoneum, and
flank within 3-5 days, with subsequent T-cell proliferation at abscopal sites
(Figure 1A right panel). Primary tumor-targeted, single-dose, thoracic RT prior
to T-cell administration augmented T-cell accumulation as demonstrated by
BLI (Figure 1B) and tumor T-cell quantification (p