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D. Jones
Moderator of
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SC16 - Superior Sulcus Tumors (ID 340)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 4
- Moderators:D. Jones, W. Klepetko
- Coordinates: 12/06/2016, 14:30 - 15:45, Lehar 1-2
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SC16.01 - Imaging Techniques for Staging and Restaging of Superior Sulcus Tumors (ID 6663)
14:30 - 14:50 | Author(s): H. Prosch
- Abstract
Abstract not provided
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SC16.02 - Surgical Approaches in Superior Sulcus Tumors (ID 6664)
14:50 - 15:10 | Author(s): D. Grunenwald
- Abstract
- Presentation
Abstract not provided
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SC16.03 - Radiotherapy for Sulcus Superior Tumors (ID 6665)
15:10 - 15:30 | Author(s): M. Werner-Wasik
- Abstract
- Presentation
Abstract:
Superior sulcus tumors (SST) are unique among lung cancer in that they have a tendency for the invasion into the chest wall and a spread superiorly outside the lungs, namely into the brachial plexus and the sympathetic chain, therefore causing a well-defined constellation of symptoms and signs, such as chest wall/arm/shoulder pain, Horner’s syndrome, spinal cord compression, upper extremity edema etc. A primary surgical resection is rarely performed, and bi- or trimodality therapies are most often implemented, depending on tumor stage. A comprehensive evaluation of the tumor extent is mandatory before any intervention is undertaken. Following tumor biopsy to establish a diagnosis of non-small cell lung cancer, standard lung cancer staging studies need to be obtained, such as the chest and upper abdomen computerized tomography (CT) scan with intravenous contrast, a PET CT scan and contrast-enhanced brain imaging (CT or MRI). Routine blood work and pulmonary function testing are standard as well. However, there are two additional radiographic studies which are necessary for each superior sulcus tumors: (1) MRI scan of the brachial plexus; (2) MRI scan of the cervical and thoracic spine. The rationale for imaging of the brachial plexus is not to confirm that the plexus is invaded (which is evident based on the presenting symptoms and a physical examination), but rather to assess the degree of its vertical involvement, since only the lowest trunks of the brachial plexus can be safely resected without fear of causing paralysis of the upper extremity. The MRI of the vertebral column serves a double purpose: (1) to assess the degree (if any) of vertebral involvement and resulting resectability; (2) to image the proximity of the tumor to the spinal cord, which is crucial for radiation planning. SSTs can cause thecal sac or spinal cord compression by extending into the spinal canal through neural foramina, without apparent spine invasion, hence the need for the MRI, which provides a superior image quality than a chest CT scan. The overall treatment strategy depends on the nodal status (“N” stage). For those patients without nodal involvement (“N0”) or with involvement only of the ipsilateral hilar lymph nodes (“N1”), a common approach is to use concurrent induction chemo-radiotherapy, followed by the surgical resection. If obvious mediastinal nodal involvement is seen (“N2 or N3”), the recommendation is for definitive concurrent chemo-radiotherapy without subsequent surgery. Therefore, invasive staging of the mediastinum, either with mediastinoscopy or with EBUS, is mandatory, since it may result in avoiding surgery as part of management. General thoracic radiation therapy (RT) principles apply to the SSTs, such as: (1) use of the CT simulation for tumor and normal tissue imaging; (2) use of 6-10 MV photon energies (unless protons are applied); (3) careful definition of the GTV, Gross Tumor Volume, to include the visible tumor on lung windows and the abnormal lymph nodes on soft tissue windows; (4) adequate margins for the CTV, Clinical Target Volume, and the PTV, Planning Target Volume. In particular, a tendency to have very tight margins around the tumor which is in close proximity to the spinal cord should be avoided at all cost, since this may result in a marginal tumor failure. In comparison to lung cancers in other locations, local tumor progression of a SST can have devastating clinical consequences, resulting in unmanageable pain, limb paralysis and a low quality of life. The commonly used total RT doses are: 45-60 Gy in trimodality therapy (chemo-RT, then surgery) or 60-70 Gy in bimodality therapy (chemo-RT) in 2 Gy daily fractions. The dose-limiting normal structures are usually the spinal cord and brachial plexus. The maximum allowed dose to the spinal cord may need to be higher (54-55 Gy) in SSTs than in other lung cancers (50 Gy) in order not to compromise the minimum dose prescribed to the PTV by attempting to “spare” spinal cord. In patients presenting with severe pain, a simple field arrangement (such as anterior and posterior opposed fields) treating the tumor with wide margins is a good initial option allowing for a quick start, followed by a more advanced planning technique, such as 3-dimensional RT, intensity modulated RT (IMRT) or VMAT. The tolerance of brachial plexus was classically described as a maximum dose of 65 Gy, with recent publications suggesting that higher doses, up to 78 Gy result in 12% risk of Grade>3 radiation-related brachial plexopathy, and that brachial plexopathy is more common as a result of tumor progression than radiation damage. The most quoted prospective clinical trial reporting on treatment outcomes of SSTs is a landmark Phase II SWOG 9416 study, in which 95/110 enrolled patients without disease progression (86%) received thoracic RT to 45 Gy in 1.8 Gy fractions with concurrent cisplatin and etoposide chemotherapy, followed by surgery and further adjuvant chemotherapy. Eligible patients were those with T3-T4 primary tumors and N0 or N1 nodal status. The resection rate was 80% and 75% achieved a complete (R0) resection. The pathologic response rate (no tumor in the specimen or microscopic residual) was 56%; the overall 5 yr survival rate was 44% for all patients and 54% for those with a complete tumor resection. Since then, recognition in the surgical community that operating after RT doses higher than 45 Gy is safe, led to a more common use of the full RT dose, i.e. 60 Gy. If the patient initially planned for trimodality therapy is no longer a surgical candidate or refuses surgery, thoracic RT should continue to definitive dose without interruption. Therefore, it is crucial to perform re-imaging for response assessment in the last week of chemo-RT (if doses of <60 Gy are used) rather than schedule those several weeks later. References: Rusch, V.W., Giroux, D.J., Kraut et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus (initial results of Southwest Oncology Group trial 9416 (Intergroup trial 0160)) . J Thorac Cardiovasc Surg 121: 472–483, 2001. Kwong KF, Edelman MJ, Suntharalingam M et al. High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival. J Thoracic Cardiovasc Surg, 129:1250-57, 2005. Eblan MJ, Corradetti MN, Lukens JN et al. Brachial plexopathy in apical non-small cell lung cancer treated with definitive radiation: dosimetric analysis and clinical implications. Int J Radiat Oncol Biol Phys.85:175-81, 2013.
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SC16.04 - Individualized Extended Lung Cancer Surgery: The Chinese Experience (ID 7011)
15:30 - 15:45 | Author(s): Q. Zhou
- Abstract
Abstract:
Backgroud: Lung cancer is the leading cause of cancer deaths in the world. For patients with advanced non-small cell lung cancer (NSCLC), survival prognosis is very poor with chemotherapy and radiotherapy. However, the possibility of occult metastases may lead to discrepancy between clinical and pathologic staging and underestimation of the disease severity, and how to individualized choose the appropriate patients with locally advanced non-small cell lung cancer for surgery is controversies. In this study, we presented here the Chinese experience: individual precision surgery for locally advanced non-small cell lung cancer based on molecular staging.Methods: We developed several molecular biomarkers and molecular models from Circulation Tumor Cell (CTC ) detection, mi-RNA chip, Gene Chip from 1990. We used these Molecular biomarkers and molecular models for molecular staging, molecular typing, choosing indication of operation and neoadjuvant chemotherapy, predicting postoperative recurrence and prognosis of locally advanced non-small cell lung cancer.Results: We developed two molecular staging model for individualized surgical treatment for locally advanced non-small cell lung cancer involving heart, great vessels or both. 3308 patients with locally advanced non-small cell lung cancer were underwent completely resection of the cancer in the three medical center. The 1-, 3-, 5- and 10 year survival rate were 74.5%,62.3%,31.5% and 22.9%, respectively. We used our molecular staging model for neoadjuvant chemotherapy for 665 patients with locally advanced lung cancer. The 1-, 3-, 5- and 10-year survival rate were 79.35%, 51.46%, 27.39% and 20.34% of the patients, respectively. We used our molecular model to divide N2 lung cancer into invasive N2 and Non-invasive N2 group. We used our molecular models adenocarcinoma and squamous carcinoma to divide T4 lung cancer into high recurrence and low recurrence groups, and help postoperative adjuvant therapy.Conclusion: Our molecular staging and typing models can help us carry out individual precision surgery, predicting prognosis and cancer recurrence of the cancer for locally advancer no-small cell lung cancer.
Information from this presentation has been removed upon request of the author.
Author of
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.11 - Mechanistic Insights into CAR T-Cell Efficacy in the Treatment of Heterogenous Antigen Expressing Lung Adenocarcinoma (ID 6039)
17:12 - 17:18 | Author(s): D. Jones
- Abstract
- Presentation
Background:
Our laboratory has translated (NCT02414269, NCT02792114) mesothelin (MSLN), a cancer-antigen, targeted chimeric antigen receptor (CAR) T-cell therapy to solid tumors including for lung adenocarcinoma (ADC) patients. The goal of this study is to investigate the anti-tumor efficacy of MSLN CAR T cells against lung ADC with heterogenous MSLN expression, and further develop mechanistic insights to potentiate the therapy.
Methods:
Human CAR T cells transduced with M28z, MSLN CAR with CD28 costimulation, were tested in vitro (cytotoxicity by [51]Cr release assay, proliferation, cytokine secretion, LFA-1/ICAM-1 [lymphocyte function associated antigen-1/intercellular adhesion molecule 1] adhesion assay, and flow cytometry) and in vivo (tumor and T-cell bioluminescence imaging [BLI], survival) against low-, high- or a mixture (50:50 or 70:30) of MSLN-expressing A549 human lung ADC.
Results:
MSLN CAR T cells demonstrate antigen-intensity dependant cytotoxicity against both low- and high- MSLN-expressing A549 cells with additive bystander cytotoxicity against [51]Cr-labelled low-MSLN A549 cells in the mixture both in vitro (Figure Panel A) and in vivo (22 days delay in tumor progression by low-MSLN A549 cells). Flow cytometry demonstrated ICAM-1 overexpression on low-MSLN A549 cells when treated with effector cytokine-rich supernatant collected by exposure of CAR T cells to high-MSLN A549 cells (Panel B), LFA-1 expression by MSLN-activated CAR T cells (Panel B). Activated CAR T cells adherence to ICAM-Fc coated plates compared to controls (Panel C). LFA-1/ICAM-1 expression promoted adherence of antigen-activated CAR T cells to low antigen-expressing tumor cells (Panel D), which is inhibited in the presence of LFA-1 blocking antibody (Panel E). Figure 1
Conclusion:
We provide a mechanistic reason for the antigen-specific, bystander efficacy of CAR T cells against low-antigen expressing lung cancer cells. Strategies to augment LFA-ICAM interactions between CAR T cells and cancer cells can effectively translate mesothelin-targeted CAR T-cell therapy against heterogenous antigen-expressing solid tumor, lung cancer.
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MA12 - Miscellaneous Biology/Pathology (ID 476)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 4
- Moderators:B. Dome, W.D. Travis
- Coordinates: 12/06/2016, 14:20 - 15:50, Schubert 1
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MA12.05 - Can Tumor Spread through Air Spaces (STAS) in Lung Adenocarcinomas Be Predicted Pre- and Intraoperatively? (ID 6026)
14:50 - 14:56 | Author(s): D. Jones
- Abstract
- Presentation
Background:
We and others have reported the prognostic impact of tumor spread through air spaces (STAS) in lung adenocarcinomas. The goal of this study is to investigate preoperative predicting factors for STAS and to determine whether STAS can be detected by intraoperative frozen section analysis.
Methods:
In a cohort of 874 patients with small (≤2cm) stage I adenocarcinoma (1995-2012), we reviewed preoperative computed tomography (CT) and positron emission tomography (PET) scans. According to the 2016 Fleischner Society’s criteria, radiological whole tumor size, consolidation size, as well as C/T ratio (consolidation/whole tumor diameter) were determined using thin slice (<3mm) CT scans where available (n=174). Clinico-radiological prediction of STAS was evaluated by logistic regression model. Using the frozen section slides with adequate adjacent lung parenchyma surrounding tumor without artifact (n=48), the presence of STAS was evaluated by five pathologists who are unaware of the radiological findings or the pathological information on permanent slides. The kappa statistic was calculated to measure the agreement between two pathologists.
Results:
In univariable model for predicting STAS, current smoker, larger consolidation tumor size, C/T ratio, and SUVmax were significant variables. In multivariable model, current smoker and C/T ratio were independent risk factors for the presence of STAS (p=0.027 and p<0.001, respectively; Table 1a). The sensitivity and the specificity of frozen section for prediction of STAS were 71% (95% confidence interval: 52-91%), 92.4% (81-100%) respectively, and the accuracy was 80% (71-89%). The kappa statistics were 0.40-0.74 (Table 1b) with 8/10 being moderate or substantial agreement.
Conclusion:
Smoking status and C/T ratio were independent predictors for the presence of STAS in patients with small lung adenocarcinomas. Frozen section prepared with adequate surrounding normal lung tissue may help identify STAS intraoperatively. Figure 1
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MA12.08 - Clinicopathological Significance of Increasing Percentage of High-Grade Histological Subtypes in Lung Adenocarcinomas (ID 6023)
15:14 - 15:20 | Author(s): D. Jones
- Abstract
- Presentation
Background:
In early-stage lung adenocarcinomas, high-grade micropapillary (MIP) and solid (SOL) predominant pathology is known to be associated with worse prognosis. The aim of this study is, in addition to predominant patterns, to investigate clinical impact of the presence of small amounts (≥5%) as well as increasing percentage of high-grade patterns.
Methods:
Invasive tumors from early-stage lung adenocarcinoma patients who underwent curative-intent resection with no induction therapy were investigated (N=2017; 1995-2012) (8[th] edition TNM pStage I=1390, II=357, III=270). In 388 cases, synchronous lymph node (LN) metastases were available. Histological subtype (lepidic [LEP], acinar [ACI], papillary [PAP], MIP, or SOL) percentages were stratified into 4 groups; 0-4%, 5-24%, 25-49%, and 50-100%. The association between increasing percentage of patterns of primary tumor and the incidence of lymphatic/vascular invasion, necrosis, tumor spread through air spaces (STAS) as well as estimated 5-year cumulative incidence of recurrence (CIR) were analyzed. The differences in distribution of each pathological variable between 4 groups was analyzed by Chi-square test. The percentages of histological pattern were compared between primary tumor and LN metastasis.
Results:
Increasing percentage of MIP pattern is associated with increasing incidence of lymphatic/vascular invasion, STAS, as well as 5-year CIR (Figure 1a, p<0.001). Increasing percentage of SOL pattern is associated with increasing incidence of necrosis and 5-year CIR (p<0.001). Presence (≥5%) of SOL pattern is associated with higher incidence of lymphatic/vascular invasion and STAS (p<0.001) compared to the absence (<5%) of SOL pattern, but no significant relationship between lymphatic/vascular invasion and proportion of SOL pattern. The percentage of SOL pattern in LN metastasis is higher than that in synchronous primary tumors (Figure 1b).
Conclusion:
In early-stage lung adenocarcinomas, presence (≥5%) of MIP or SOL patterns as well as increasing percentages is associated with poor prognostic clinicopathological variables and incidence of recurrence. Figure 1
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MA12.09 - Comparative Histological Subtype Analysis of Lung Adenocarcinoma Tumor and Metastatic Lymph Nodes and the Prognostic Impact (ID 6036)
15:38 - 15:44 | Author(s): D. Jones
- Abstract
- Presentation
Background:
The goal of this study is to investigate comprehensive comparative pathological analyses of both primary tumor and metastatic lymph node (LN) and correlate with lung cancer-specific death (LC-death) in patients with LN-positive lung adenocarcinoma.
Methods:
PN1/2 lung adenocarcinoma patients who underwent R0 resection without induction therapy (n=402, 2000-2012) were included in the study. In primary tumor, lymphatic/vascular/pleural invasion, necrosis, tumor spread through air spaces (STAS), as well as histologic subtypes according to 2015 WHO classification were evaluated. In metastatic LN, metastatic tumor size, extracapsular invasion, histologic subtypes were evaluated. Recurrence and LC-death were analyzed by Cox model.
Results:
Micropapillary and solid predominant subtypes were more frequent in LN metastases than in primary tumors (Figure). In multivariable analyses, adjuvant chemotherapy, pleural invasion, extracapsular invasion of LN metastasis, micropapillary predominant subtype in LN metastasis were independent factors for recurrence; adjuvant chemotherapy, pleural invasion, tumor STAS, and extracapsular invasion were for LC-death (Table).
Conclusion:
In lung adenocarcinoma lymph node metastases, predominant micropapillary pattern and extracapsular invasion indicate high risk for recurrence and lung cancer-specific death. Figure 1 Figure 2
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MA12.10 - Histological Subtyping of Matched Primary and Metastases Sites in Lung Adenocarcinoma: Significance of Solid Predominance (ID 5767)
15:20 - 15:26 | Author(s): D. Jones
- Abstract
- Presentation
Background:
Clinical significance of 2015 WHO classification histological subtype of early-stage lung adenocarcinoma (LADC) has been well documented; the incidence and significance of histological subtypes in autologous metastatic tumors is unknown.
Methods:
Histological subtyping was performed on paired primary and metastatic LADC tumor samples from patients who underwent resection of metastases (N=203, 1996-2012). 57 cases with inadequate tumor specimen and 4 cases diagnosed as local recurrence were excluded.
Results:
Location of metastatic sites were – brain 51 (35.9%), lung 48 (33.8%), lymph node 14 (9.9%), pleura 10 (7.0%), and adrenal gland 5 (3.5%). Metastatic tumors demonstrated more frequent solid histological pattern than primary tumors (first predominance: 51% vs. 24%; second predominance 29% vs. 17%, Figure 1). Among all histological subtypes, solid subtype showed the highest concordance between primary and metastatic tumors (Figure 2). In addition, analysis of all available clinicopathological factors showed significantly higher percentage of solid subtype in both primary and metastatic tumors was observed in patients with smoking history (p=0.003 and p=0.004, respectively).
Conclusion:
Analysis of a large cohort of primary and autologous metastatic LADC tumors demonstrated a higher percentage of solid histological pattern metastases, even in cancers with a low solid component in the primary site of disease. Figure 1Figure 2
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MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:M. Thomas, P. Mitchell
- Coordinates: 12/06/2016, 16:00 - 17:30, Stolz 1
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MA13.07 - Tumor-Targeted Radiation Promotes Abscopal Efficacy of Regionally Administered CAR T Cells: A Rationale for Clinical Trial (ID 5456)
17:24 - 17:30 | Author(s): D. Jones
- Abstract
- Presentation
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<0.01). In a mouse model of primary pleural, abscopal antigen-expressing and non-expressing flank tumors (Figure 1C), a single, low-dose, non-cytotoxic thoracic RT enhanced abscopal site CAR T-cell accumulation that resulted in tumor regression (p=0.01; Figure 1D). Figure 1
Conclusion:
Regionally administered mesothelin-targeted CAR T cells proliferate and eradicate the primary tumor, accumulate and demonstrate anti-tumor efficacy at abscopal sites prior to eradication of the primary tumor in an antigen-specific manner. A single low-dose primary tumor-targeted radiation therapy promotes scopal and abscopal anti-tumor efficacy. These results provide rationale to initiate a clinical trial of combination regional therapies with radiation therapy and CAR T cells.
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OA01 - Risk Assessment and Follow up in Surgical Patients (ID 371)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
- Moderators:W. Zhong, E. Lim
- Coordinates: 12/05/2016, 11:00 - 12:30, Schubert 2
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OA01.03 - Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Stage I NSCLC Patients: A Competing Risk Analysis (ID 4952)
11:20 - 11:30 | Author(s): D. Jones
- Abstract
- Presentation
Background:
At the time of diagnosis, two-thirds of patients with lung cancer are ≥65 years of age with significant comorbidities. We sought to determine the short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who underwent resection for stage I non-small cell lung cancer (NSCLC).
Methods:
Of 5371 consecutive patients who had undergone curative-intent resection of primary lung cancer (2000–2011), 2186 patients with pStage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were considered, including, Charlson comorbidity index, predicted postoperative (ppo) diffusion capacity of the lung for carbon monoxide (DLCO), and ppo–forced expiratory volume in 1 second (FEV1). Association between factors and cause-specific mortality was performed using competing risks approach.
Results:
Of 2186 patients, 1532 patients (70.1%) were ≥65 years of age, including 638 patients (29.2%) ≥75 years of age. In patients ≥65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer–specific CID, the higher noncancer-specific early-phase mortality was enhanced in patients ≥75 years of age compared with 65-74 years of age (Figure 1a). Multivariable analyses adjusted by age, sex, smoking status, comorbidities, tumor size, and surgical procedures showed that low ppoDLCO was an independent predictor for severe morbidity (p<0.001), 1-year mortality (p<0.001), and noncancer-specific mortality (p<0.001), whereas low ppoFEV1 for lung cancer–specific mortality (p=0.002). PpoDLCO can be used for estimation of 5-year cumulative incidence of noncancer death (Figure 1b, right, red curve) because of its linear relation, whereas ppoFEV1 for lung cancer-specific death (Figure 1b, left, black curve).
Conclusion:
In patients undergoing curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with increasing impact as patient age increases. Figure 1
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OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
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OA02.06 - Converting Tumor-Mediated PD-L1 Inhibition into CAR T-Cell Costimulation to Potentiate Thoracic Cancers Immunotherapy (ID 6058)
11:55 - 12:05 | Author(s): D. Jones
- Abstract
- Presentation
Background:
To overcome tumor-mediated inhibition of chimeric antigen receptor (CAR) T cells, we herein investigated the impact of tumor PD-L1 upregulation on CAR T-cell exhaustion and anti-tumor efficacy, and further developed clinically translatable T-cell extrinsic as well as intrinsic strategies to overcome PD-L1 inhibition in models of lung cancer (LC) and malignant pleural mesothelioma (MPM).
Methods:
Human T cells were transduced with MSLN-specific CAR with CD28 and CD3zeta domains (M28z) were tested in vitro and in clinically-relevant LC and MPM mouse models by bioluminescence imaging, BLI of tumor burden progression. To counteract PD-1/PD-L1 inhibition in vivo, we evaluated the efficacy of PD-1 blocking antibody or cell-intrinsic genetic-engineering strategies by cotranducing M28z CAR T cells with a PD-1 dominant negative receptor (PD1-DNR) or with PD-1/4-1BB fusion protein.
Results:
A single, low-dose of M28z CAR T cells is able to resist the progression of established tumor for 40 days, but mice eventually died with progressing tumor. Tumor harvest analysis demonstrated the PD-1 and PD-L1 upregulation on CAR T cells and tumor cells (Figure panel A). We then confirmed in vitro that PD-L1 inhibits M28z T-cell effector functions (proliferation, cytotoxicity and cytokine secretion). The addition of PD-1 blocking potentiates CAR T-cell therapy in vivo but its efficacy requires multiple injections (Panel B). In contrast, a single dose of M28z T cells coexpressing PD1-DNR restore effector functions, enhance tumor burden control (Panel C) and prolong median survival (56 vs 82 days, p=0.001). Converting PD-L1 inhibition into a positive costimulatory signal by PD-1/4-1BB construct cotransduction into M28z CAR T cells enhanced cytokine secretion and T-cell accumulation (Panel D). Figure 1
Conclusion:
Our results demonstrate the therapeutic benefit of providing optimal costimulation and coinhibitory blockade to counteract PD-L1/PD-1 immunosuppression, thus potentiate CAR T-cell therapy for lung cancer and mesothelioma.
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OA07 - Lymph Node Metastases and Other Prognostic Factors for Local Spread (ID 376)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
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OA07.06 - In Early-Stage Lung Adenocarcinomas, Survival by Tumor Size (T) is Further Stratified by Tumor Spread through Air Spaces (ID 5905)
15:15 - 15:25 | Author(s): D. Jones
- Abstract
- Presentation
Background:
We investigated whether tumor spread through air spaces (STAS) further stratifies survival beyond tumor size, T-descriptor independent of resection type (lobectomy or limited resection) and surgical margin.
Methods:
In patients with pT1a-T2bN0M0 lung adenocarcinomas (LADC, n=1399), tumor size, distance of STAS from the tumor, type of resection, surgical margin were evaluated. The patients with small (≤2cm) tumors were divided into STAS(-) (n=561) and STAS(+) (n=307) and their cumulative incidence of recurrence (CIR), and lung cancer-specific death (CID) were compared with patients with larger tumors (2-3cm, n=299) by use of competing risk analysis.
Results:
Of 1399 tumors, 521 (37%) were STAS(+). Compared to STAS(-), recurrence rates were higher with STAS(+) tumors even when the margin is ≥tumor size (Figure 1). In patients with ≤2cm STAS(+) tumors, CIR and CID are higher than in patients with larger (2-3cm) tumors (Figure 2). The poor prognostic influence of STAS(+) was evident even when analyzed by the procedure or recurrence pattern (Figure 2 table).
Conclusion:
STAS further stratifies survival beyond tumor size, T-descriptor in early-stage (pT1a-2b) lung adenocarcinoma based on the higher prognostic potential for recurrence and lung cancer-specific death independent of the type of resection or margin. Figure 1 Figure 2
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.03 - Tumoral IL-7 Receptor is a Potential Target for Lung Adenocarcinoma Immunotherapy (ID 5800)
12:20 - 12:30 | Author(s): D. Jones
- Abstract
- Presentation
Background:
IL-7/IL-7 receptor (IL-7R) interactions have been shown to prevent apoptosis in lung cancer cells and promote stromal pro-tumor immune cell homing and differentiation. The aim of this study is to investigate the correlation between tumoral IL-7R expression and stromal pro-tumor immune cells (FoxP3+ Tregs and CD163+ M2 macrophages) and to determine prognostic impact of the combination of these markers in lung adenocarcinomas.
Methods:
In resected stage I lung adenocarcinoma (n=913; 1995-2009), antigen expression of IL-7R, FoxP3 and CD163 was evaluated by immunohistochemistry (IHC) using tissue microarrays and mRNA expression was quantified by RT-PCR. Prognosis was analyzed by both recurrence free probability (RFP) and lung cancer-specific survival (LCSS).
Results:
In IHC analysis, high tumoral IL-7R, stromal FoxP3, and stromal CD163 expression were individually associated with lymphatic/vascular invasion, and increasing percentage of solid histological patten. A correlation was seen between IL-7R, FoxP3 and CD163 expression by mRNA and IHC analyses (Figure1). The co-existence of high expression of these 3 markers was found in 16% of patients and was associated with worse outcomes (Figure2). In multivariable analysis, triple marker co-existence was an independent risk factor for RFP (p=0.004) and LCSS (p=0.008).
Conclusion:
Tumoral IL-7 receptor is a potential target for lung adenocarcinoma immunotherapy. Figure 1 Figure 2
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-084 - Implications of 8th Edition TNM Proposal: Invasive vs. Total Size for T Descriptor in pT1a-2bN0M0 Lung Adenocarcinoma (ID 5788)
14:30 - 14:30 | Author(s): D. Jones
- Abstract
Background:
The aim of this study was to conduct a clinicopathological comparative analysis of total tumor versus invasive tumor size in pT1a-2bN0M0 nonmucinous lung adenocarcinomas.
Methods:
Resected pT1a-2bN0M0 lung adenocarcinomas (1995-2012) based on 8th edition of TNM classification using total (N=1475) and invasive tumor size (N=1482) were included. Recurrence free probability [RFP] and lung cancer-specific survival [LCSS]) were compared between both pT-staging systems using Kaplan-Meier method.
Results:
Use of invasive size for the T descriptor increased the number of pT1a tumors by 2 fold compared to use of total tumor size (316 vs. 161), with no difference in RFP and LCSS (RFP, 82% vs. 80%; LCSS, 94% vs. 93%). Use of invasive rather than total size also showed better stratification of lymphatic/vascular invasion and high-grade histological subtypes according to increasing pT stage. RFP and LCSS in invasive-size-based pT2b were lower than those in total-size-based pT2b (RFP, 44% vs. 60%; LCSS, 69% vs. 77%).
Conclusion:
In pT1a-2bN0M0 nonmucinous lung adenocarcinoma, the 8th edition TNM proposal to use invasive rather than total size for the pT descriptor gives better prognostic discrimination by capturing a larger number of patients with favorable prognosis (pT1a) and providing better stratification for pT2b. Figure 1 Figure 2
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P1.08 - Poster Session with Presenters Present (ID 460)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.08-047 - Decreasing Use of Epidural Analgesia with Increasing Minimally Invasive Lobectomy: Impact on Postoperative Morbidity (ID 4941)
14:30 - 14:30 | Author(s): D. Jones
- Abstract
Background:
The goal of this study is to assess the impact of the decreasing use of epidural analgesia (infusion ≥24 hours) on the incidence of postoperative morbidity following minimally invasive surgical (MIS; includes VATS and robotic-assisted) lobectomy in patients with non-small cell lung cancer (NSCLC).
Methods:
We reviewed 1206 patients who underwent MIS lobectomy for pathological stage I-III NSCLC in 2009-10 (n=506) and 2014-15 (n=700) at our institution. Clinical data was obtained from a prospectively maintained database and by review of individual patient medical records. Patients with induction therapy (n=225) or conversion from MIS to thoracotomy (n=99) were excluded. Postoperative morbidity (≤30 days) was graded based on the Common Terminology Criteria for Adverse Events (CTCAE). Statistical comparison was performed using Chi-squared analysis and Fisher’s exact test.
Results:
A total of 884 patients were included in this study (2009-10, n=401; 2014-15, n=483). The rate of MIS lobectomy significantly increased in 2014-15 compared to 2009-10 (74% vs. 53%, p<0.001) with a simultaneous decrease in the use of epidural analgesia (92.9% vs. 53.6%, p<0.001; Figure 1A and 1B). In the MIS group, there was no difference in age, sex, or pathological stage between the 2009-10 and 2014-15 cohorts. There was no significant change in the incidence of any, severe respiratory or cardiovascular morbidity (CTCAE grade ≥3) following MIS lobectomy between the two time periods evaluated (Figure 1C). However, the incidence of CTCAE grade ≥2 respiratory morbidity in 2014-15 was higher than that in 2009-10 (7.1% vs. 12.6%, p=0.047).Figure 1
Conclusion:
In our study cohort, the observed decrease in use of epidural analgesia with the increasing rate of MIS lobectomy did not affect the incidence of severe postoperative morbidity.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-029 - Cases Demonstrating Spread Through Air Spaces (STAS) Reflects Invasive Growth and Not an Artifact (ID 6059)
14:30 - 14:30 | Author(s): D. Jones
- Abstract
Background:
STAS is defined as a pattern of tumor cell spread in the lung parenchyma beyond the edge of a lung cancer. It has been postulated that this is an ex vivo artifact due to the force of knife with the premise that STAS is clinically unimportant and it should be ignored like true artifacts.
Methods:
We present three cases providing evidence that STAS is not an artifact and is clinically relevant.
Results:
Case 1: 68F underwent wedge resection of a left upper lobe (LUL) lung adenocarcinoma. During the surgical procedure the surgeon did not cut across the tumor, but sent a separate wedge biopsy as an additional margin. The latter wedge contained an 8 mm focus of adenocarcinoma consisting almost entirely of a STAS pattern with a 1mm area of acinar growth. Case 2: 66M underwent RUL wedge resection in August 2013 for a 1.3 cm lung adenocarcinoma. The resection margin was positive with only STAS in the margin. In the absence of any clinical sign of recurrence or metastases, a completion right upper lobectomy was performed revealing three separate foci of residual adenocarcinoma including 1.5 and 1.0 mm acinar areas and a 0.5 mm focus of STAS with N1 and N2 lymph node metastases. Adjuvant chemotherapy and radiation were given. In 2014, the patient developed multiple bilateral nodules and in November underwent LUL wedge resection that showed three foci of adenocarcinoma with a STAS predominant pattern. In July 2016, the patient remains on chemotherapy with slowly growing bilateral nodules. Case 3: A 77M presented with pneumonia and bilateral ground glass opacities with focal consolidation. A biopsy, originally interpreted as benign, showed diffuse involvement by adenocarcinoma with a STAS predominant pattern. The morphology does not explain the consolidation seen on CT indicating the surgeon did not cut across the main tumor area.
Conclusion:
We present three cases which provide evidence that STAS is not an artifact that should be ignored. In two cases the extensive STAS predominant pattern was not a knife cutting artifact because the main tumor was not cut either by the surgeon or pathologist. In the third case, STAS was the only pattern of tumor identified at a wedge resection margin. If this had been ignored, the residual and metastatic tumor would not have been identified delaying introduction of chemotherapy. These findings support the concept that STAS is a clinically important invasive pattern and not an artifact.
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SC25 - The Role of Surgeons in Multimodality Clinical Trials (ID 349)
- Event: WCLC 2016
- Type: Science Session
- Track: Surgery
- Presentations: 1
- Moderators:N. Ikeda, G. Stamatis
- Coordinates: 12/07/2016, 11:00 - 12:30, Strauss 2
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SC25.01 - Trial Design for Multimodality Treatment of NSCLC (ID 6705)
11:00 - 11:20 | Author(s): D. Jones
- Abstract
- Presentation
Abstract not provided
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