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A. Mansfield
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.08 - Discussant for MA08.05, MA08.06, MA08.07 (ID 6959)
11:00 - 12:30 | Author(s): A. Mansfield
- Abstract
- Presentation
Abstract not provided
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.02 - Anti-Tumor Immunity is a Key Determinant of SCLC Survivorship (ID 5759)
14:20 - 15:50 | Author(s): A. Mansfield
- Abstract
- Presentation
Background:
While the majority of small cell lung cancer (SCLC) patients succumb to their disease within a few months, there is a small group of patients who survive for many years after their diagnosis. Factors contributing to the SCLC long-term survivorship remain largely unknown. Herein, we compared tumors from exceptional survivors (EXS) and patients with the expected outcome (EOP) to determine genomic and immunological determinant of SCLC survivorship.
Methods:
In the Mayo Clinic tissue registry, we identified surgical blocks from 12 EXS who survived > 4 years after surgery and 14 EOP who died < 2 years of surgery. These cohorts were created to have no statistical differences in clinical TNM stage, curative versus non-curative intent surgery, age, gender, and smoking status between EXS and EOP. Tumor areas were macro-dissected for gene expression profiling by the Human Transcriptome Array (Affymetrix). Also, tissue sections were stained for key immunological markers, including CD8, CD4, CD3, CD279, FoxP3, CD138, CD20, CD21, CD14, CD68, and also LYZ. Concentrations of immune cells in intra-tumor areas (IE), stroma (ST), and tumor/non-tumor interface (IF) were assessed by an image processing program (Aperio). Staining patterns in each of the three zones in EXS and EOP tumors were compared.
Results:
More than 90% of differentially expressed genes were over-expressed in EXS compared with EOP. Furthermore, over 75% of the known over-expressed genes were either immunoglobulin or MHC related and a majority of the remaining genes were immune function related such as cytokines. We then performed IHC for key immunological markers and found significantly higher concentration of immune cells including CD8 and PD-1 positive cells in the tumor microenvironment, especially at the tumor stromal interface in EXS compared with EOP (p < 0.005 for both markers). Furthermore, the total number of infiltrating immune cells (T-cells, B-cells, Plasma cells, monocytes and macrophages was significantly higher in EXS in the interface region (p < 0.0005).
Conclusion:
Gene expression profiling revealed that anti-tumor immunity is an important factor for SCLC survival. Further studies by IHC suggested the presence of immune cells especially cytotoxic T-cells in the tumor microenvironment and particularly at the tumor-stromal interface to be major contributors to long term survivorship in SCLC. These findings suggest that immunotherapeutic strategies may be effective for patients with SCLC.
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OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
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OA13.07 - Intrapleural Modified Vaccine Strain Measles Virus Therapy for Patients with Malignant Pleural Mesothelioma (ID 5655)
14:20 - 15:50 | Author(s): A. Mansfield
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MM) remains an almost universally fatal disease with limited treatment options. Preclinical models indicate the preferential oncolytic activity of the modified vaccine strain measles virus carrying the gene for the human sodium-iodine symporter (NIS) – MV-NIS. Intraperitoneal and intravenous administration of MV-NIS was recently found to be potentially effective in patients with refractory ovarian cancer and multiple myeloma. However, whether MV-NIS is directly oncolytic or triggers an anti-tumor immune response remains unclear.
Methods:
We conducted a phase I dose escalation study with 3+3 design and ongoing maximal tolerated dose (MTD) expansion cohort. MV-NIS was administered as first or second line therapy via a tunneled intrapleural catheter to patients with MM. MV-NIS dose ranged from 10[8] TICID~50~ to 9 x 10[9] TICID~50~. In the absence of dose limiting toxicity and disease progression, patients received up to 6 cycles of MV-NIS therapy (Phase I). Currently additional patients are being randomized between a single and multiple cycles. MV-NIS infection and replication are monitored by Iodine[123] SPECT/CT (Phase I only) as well as by RT-PCR and/or plaque-assay. Anti-tumor immunity is monitored in the blood and pleural fluid and patients are followed clinically by chest CT using the modified RECIST criteria.
Results:
Twelve patients (3/dose level) received MV-NIS therapy. There were no dose limiting adverse events and therapy was well tolerated. The best therapeutic response was stable disease, which was achieved at 1 month by 8/12 evaluable patients (67%). Median overall survival was 449 days (95%CI: 221, 484) (~15 months) (4/12 patients remain alive), and median progression free survival was 63 days (95% CI: 33, 174) (~2 months). MV infection and replication were detectable by RT-PCR and plaque assay in the pleural fluid between 24-72 hours after treatment. I[123] SPECT-CT demonstrated only marginal viral gene expression in a single patient treated with the highest dose level. MV-NIS therapy effectively boosted pre-existing anti-MV neutralizing antibody responses in the plasma and pleural fluid of most patients. We observed a transient inflammatory response in the pleural space after MV-NIS administration. In addition, induction or boosting of anti-tumor antibody responses was observed.
Conclusion:
The intrapleural administration of MV-NIS is safe, resulted in stable disease for 67% of patients and may be associated with favorable overall survival in MM. While there was only transient infection and viral replication, we observed the induction of anti-tumor immune responses supportive of potential long-term therapeutic impact. The study continues with the MTD expansion cohort.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-060 - EGFR Mediates Activation of RET in Lung Adenocarcinoma with Neuroendocrine Differentiation Characterized by ASCL1 Expression (ID 5804)
14:30 - 15:45 | Author(s): A. Mansfield
- Abstract
Background:
Achaete-scute homolog 1 (ASCL1) is a neuroendocrine transcription factor expressed in 10-20 % of lung adenocarcinomas (AD) with neuroendocrine (NE) differentiation. Previously, we demonstrated that ASCL1 functions as an upstream regulator of the RET oncogene in AD with high ASCL1 expression (A[+]AD). In this study, we examined the potential role of wild type RET in influencing the oncogenic properties of A[+]AD. We also screened for drugs that could selectively target RET signaling and examined the role of the two RET isoform separately.
Methods:
The association of the mRNA expression for the long (RET51) and short (RET9) RET isoforms with overall survival (OS) were assessed in a case-control study of stage-1 A[+]AD patients surgically resected at the Mayo Clinic (1994-2007). Cases and controls were defined as patients who survived < 3.5 years after surgery (n= 29) and > 5 years after surgery (n=38), respectively. mRNA was isolated from FFPE tissue and analyzed by a nanostring assay. Associations of each isoform mRNA with the OS was determined by the area under the receiver operative characteristics (AUC). For drug screening, HCC1833 lung AD cells with endogenously high expression of ASCL1 were stably transfected with either empty vector or an ASCL1-shRNA. Differential sensitivities of tyrosine kinase inhibitors (TKIs) in the pair of syngeneic cell lines were measured by Cell-Titer Glo (Promega). Interactions between EGFR and RET was examined by co-immunoprecipitation.
Results:
Expression of RET51 mRNA was associated with poor OS (p=0.005, AUC 0.71). We detected modestly increased sensitivity to sunitinib and vandetanib in A[+]AD compared with A[-]AD cells. However, the EGFR inhibitors gefitinib and the dual EGFR and HER2 inhibitor lapatinib resulted in ≥ 10 fold higher cytotoxicity in A[+]AD cells than in A[-]AD cells. Subsequent experiments demonstrated that EGF stimulation of EGFR mediates the phosphorylation of RET in multiple A[+]AD cells. RET and EGFR were found to interact only in presence of EGF and predominantly through the long RET isoform (RET51).
Conclusion:
Herein we demonstrate that wild type EGFR predominantly interacts with the long isoform of RET (RET51) in A[+]AD cells. In the presence of EGF this results in activation of RET. High RET51 is associated with worse OS. Furthermore, compared to A[-]AD cells, A[+]AD cells appear to be more sensitivity to EGFR inhibitors. In summary, our results suggest that A[+]AD patients may benefit from treatment with EGFR inhibitors even in the absence of an EGFR mutation.
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-064 - Global Practice Patterns of Multifocal Lung Cancer (ID 4398)
14:30 - 15:45 | Author(s): A. Mansfield
- Abstract
Background:
Multifocal lung cancer (MFLC) is a clinical scenario that is more frequently diagnosed with the increased utilization of computed tomography of the chest. The management of MFLC is limited by the difficulties in accurately staging a patient and understanding whether lesions represent separate primaries or metastatic disease. We sought to understand the global practice patterns of MFLC.
Methods:
A questionnaire was developed and sent to members of the International Association for the Study of Lung Cancer through REDCap electronic data capture tools to assess how a hypothetical patient with synchronous MFLC would be evaluated and treated. Responses were compared by specialty using the χ[2] test.
Results:
We received 221 responses from multiple specialists (74 Thoracic Surgeons, 68 Medical Oncologists, 32 Pulmonologists, 22 Radiation Oncologists and 25 others) primarily from Europe (n=76) and North America (n=62). Over 87 respondents reported 20 or more years of experience in the field. Most respondents recommended surgery (n=140, 63%), but many others did not (n=39, 18%) or were uncertain (42, 19%). Surgeons (n=60/74, 81%) were significantly more likely to recommend surgery than medical oncologists (n=37/68, 54%), pulmonologists (n=21/32, 66%) or radiation oncologists (n=10/22, 45%; p=0.01). Lobectomy of the primarily involved lobe (n=42, 30%) and various combinations of segmentectomies (n=48, 34%) were the most commonly recommended surgical approaches. Of those who recommended surgery, most would obtain a PET/CT to rule out distant metastasis (n=135, 97%) and an MRI to rule out brain metastases (n=76, 55%) but in the absence of radiographic lymph node involvement most would not stage the mediastinum by bronchoscopy or mediastinoscopy prior to resection (n=90, 65%). Many preferred obtaining multiple biopsies of separate lesions (n=139, 63%) and genetic testing of these lesions (n=146, 66%) to assess their histologic and genetic agreement. In the case that surgery was not offered or declined, more respondents recommended radiation (n=114, 52%) than those who did not (n=50, 23%) or were uncertain (56, 26%). Similarly, in the absence of surgery or radiotherapy, slightly more respondents recommended systemic chemotherapy (n=83, 38%) than those who did not (n=79, 36%) or those who were uncertain (n=59, 27%).
Conclusion:
Although most respondents favored surgery when feasible for MFLC, many were uncertain as to the optimal approach for this disease. Optimal management of MFLC requires greater evidence from studies which is currently lacking, and current strategies are strongly influenced by specialty bias.
