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M. Sadelain
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MO19 - Lung Cancer Immunobiology (ID 91)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 2
- Moderators:Y. Sekido, J. Minna
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside 201 - 203, Level 2
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MO19.02 - The Tumor Immune Microenvironment in Octogenarians with Stage I Non-Small Cell Lung Cancer: Implications for Immunotherapy (ID 3155)
10:35 - 10:40 | Author(s): M. Sadelain
- Abstract
- Presentation
Background
The elderly have less-robust immune responses to infections, immunizations, and tumors, compared with younger people. Furthermore, preclinical studies have indicated that immunotherapeutic interventions are less effective in older animals. Considering the effects of age-associated changes in immune function, most clinical trials of cancer-related immunotherapy have been conducted in relatively young patients. With the increasing focus on immunotherapy for non-small cell lung cancer (NSCLC), we investigated the relationship between patient age and tumor immune parameters in stage I NSCLC.Methods
Tissue microarrays from patients with stage I NSCLC (n=1371; 1995-2009; median follow-up, 3.5 years) were constructed, and immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) were performed. Patients were categorized into 3 groups: (1) ≤65 years old, (2) 66-79 years old, and (3) ≥80 years old. Stains were analyzed for immune cell infiltration (low vs high) in the tumor nest. The Chi-Square test was used to analyze the association between immune parameters and age group. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS).Results
In total, 1116 patients with stage I lung adenocarcinoma and 255 patients with stage I squamous cell carcinoma were enrolled. Patients aged ≥80 years did not have a significantly poorer prognosis (n=155; 5-year RFS, 76.0%) than the patients in the two younger groups (p=0.65; Figure 1A). There were no statistically significant differences in numbers of tumor-infiltrating lymphocytes in the tumor nest between the three groups (Figure 1B), nor was there a statistically significant difference between the elderly group and the younger patients when effector regulatory immune response ratios were compared (FoxP3/CD3 ratio; high vs low, p=0.85). Figure 1Conclusion
In this large cohort of stage I NSCLC patients selected for surgical resection, the tumor microenvironment among elderly patients resembles other age groups. Our study provides important information while considering immunotherapy in elderly patients with lung cancer.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO19.12 - Prognostic Impact of Tumor-Infiltrating Immune Cells in Lung Squamous Cell Carcinoma (ID 2896)
11:35 - 11:55 | Author(s): M. Sadelain
- Abstract
- Presentation
Background
The prognostic significance of the tumor immune microenvironment in lung adenocarcinoma has been established by us (CCR 2011, JCO 2013, Oncoimmunology 2013) and others. Here, we investigate whether tumor-infiltrating immune cells correlate with prognosis, independent from TNM staging, in lung squamous cell carcinoma (SCC).Methods
All available tumor slides from therapy-naive, surgically resected solitary lung SCCs (n=485; 1999-2009) were reviewed. Tissue microarrays were constructed using 451 cases (stage I, 255; II, 131; III, 65) from 3 representative tumor areas. Immunostaining for CD3 (pan T cell marker), CD45RO (memory T cell), CD8 (cytotoxic T cell), CD4 (helper T cell), FoxP3 (regulatory T cell), CD20 (B cell), CD68 (macrophage), and CD10 (neutrophil) was performed. For each case, the average number of cells positive for T cell markers was recorded as the ratio to CD3+ lymphocytes, and classified as low or high by use of the median. CD20, CD68, and CD10 were classified as low or high by the number of positive cells (≥20, ≥50, and ≥10, respectively) as our recent publication (JCO 2013). Overall survival (OS) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.Results
Five-year OS was 59% for the entire cohort and 68% for stage I patients. Analysis of single immune cell infiltration revealed that high CD10+ neutrophil count was correlated with lower OS (5-year OS, 53%; n=160) than low CD10+ count (5-year OS, 61%; n=286; p=0.006). Analysis of biologically relevant immune cell combinations identified 2 significant factors of prognosis: (1) patients with high CD4+ and high FoxP3+ T cell ratios had worse prognosis (5-year OS, 52%; n=140) than the other groups (5-year OS, 62%; n=304; p=0.008), and (2) patients with high CD10+ neutrophil and low CD20+ B lymphocyte counts had worse prognosis (5-year OS, 43%; n=102) than the other groups (5-year OS, 63%; n=340; p<0.001). These results were confirmed in a subgroup analysis limited to stage I patients (p=0.020 for high CD4/high FoxP3+ ratios; p=0.007 for high CD10+/low CD20+ counts). In multivariate analysis, high CD4+/high FoxP3+ ratios (HR=1.58; p=0.001) and high CD10+/low CD20+ counts (HR=1.71; p<0.001) remained significantly associated with poorer survival (Table).Table. Multivariate analysis for overall survival
Variable HR 95% CI p High CD4+/high FoxP3+ ratios 1.58 1.21–2.06 0.001 High CD10+/low CD20+ counts 1.71 1.28–2.27 <0.001 Age (>65 years old) 1.51 1.09–2.09 0.014 Sex (male vs. female) 1.31 1.01–1.69 0.043 Smoking pack years (>90) 1.01 1.00–1.01 0.003 Stage (II and III vs. I) 1.53 1.16–2.02 0.002 Lymphovascular invasion 1.38 1.02–1.88 0.040 Conclusion
High CD4+/high FoxP3+ ratios and high CD10+/low CD20+ counts are significant factors of prognosis for lung SCC, independent of TNM staging. Targeting regulatory T cells or enhancing tumor-specific B-cell responses may thus have applicability for the treatment of lung SCC.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O08 - Preclinical Therapeutic Models I (ID 92)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Biology
- Presentations: 2
- Moderators:C. Mascaux, R. Natale
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium A, Level 1
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O08.02 - Critical Role of CD28 Costimulation in Tumor-Targeted T-cell Therapy Clinical Trial for Pleural Malignancies (ID 2995)
16:25 - 16:35 | Author(s): M. Sadelain
- Abstract
- Presentation
Background
Successful translation of adoptive T-cell therapy for solid cancers is predicated on the ability to generate a potent antitumor immune response and establish T-cell persistence. Thoracic malignancies typically lack expression of costimulatory ligands but do express negative regulators of T- cell function—factors that may impede T-cell therapy. We hypothesized that cancer antigen–targeted T cells engineered with activating CD28 costimulatory signaling would eradicate tumor and establish long-term functional persistence.Methods
Mesothelin-specific chimeric antigen receptors (CARs) were engineered without (Mz) or with (M28z) a CD28 costimulatory domain. CAR-transduced human T cells were evaluated in vitro for cytotoxicity ([51]Cr-release assay), cytokine release (Luminex cytokine-release assay), and proliferation (cell-counting assay). In vivo assessment included monitoring of tumor progression by bioluminescence imaging (BLI), flow cytometric analysis of splenic/peripheral blood T-cell phenotypes, and Kaplan-Meier analysis of median survival, in NOD-scid IL-2Rγ-null mice bearing orthotopically implanted mesothelin-expressing mesothelioma cells (MSTO-211H: CD80/86-, TGF-β+, PD-L1+) and treated with human T cells transduced to express either Mz, M28z, or a control vector.Results
In vitro, M28z CAR–transduced T cells exhibited equivalent cytotoxicity but enhanced Th1 cytokine secretion and antigen-specific proliferation, compared with Mz transduced T cells. In vivo, mice treated with a single low dose of M28z CAR–transduced T cells achieved tumor eradication and prolonged survival (median survival not reached; p=0.01), compared with mice treated with an equal dose of Mz-transduced (median survival, 63 days; tumor eradication in 20% of mice) or control CAR–transduced (median survival, 36 days) T cells (Figure 1A, 1B). Furthermore, CD28 costimulation enhanced CD62L[-]CD45RA[-] effector memory T-cell persistence (Figure 1C), leading to a robust T-cell proliferative response and superior control of tumor burden on tumor rechallenge 87 days after T-cell administration (Figure 1D, 1E). Figure 1Conclusion
CD28 costimulation plays an important role in achieving long-term antitumor efficacy and functional persistence in mesothelin-targeted T-cell therapy. These data provide the scientific rationale for our upcoming clinical trial for pleural malignancies.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O08.03 - T-cell Imaging to Noninvasively Monitor Adoptive T-cell Therapy for Thoracic Malignancies (ID 2994)
16:35 - 16:45 | Author(s): M. Sadelain
- Abstract
- Presentation
Background
Noninvasive T-cell imaging technology allows monitoring of adoptive T-cell responses without the need for invasive biopsies. Herein, we report dynamic imaging of tumor-targeted T cells in preclinical models by use of luminescent-enhanced firefly luciferase vector, and we further demonstrate the successful use of a clinical-grade herpes simplex virus type 1 thymidine kinase (HSV1-tk)–incorporated vector for monitoring of T-cell trafficking, antigen-specific proliferation, and biodistribution.Methods
T cells transduced with mesothelin-targeted chimeric antigen receptors (M28z) were either cotransduced with an enhanced firefly luciferase vector (effLuc-M28z) or singly transduced with HSV1-tk-M28z (TK-M28z). To simultaneously visualize tumor during T-cell PET imaging, cancer-cell imaging was performed using MSTO-GFP/ffLuc+ (MSTO-211H cells transduced to express mesothelin and the green fluorescent protein/firefly luciferase fusion protein). In vitro, uptake of [18]F-FEAU radiotracer by T cells was measured by [3]H channel counting. In vivo studies used either SCID-beige or NSG mice bearing pleural or flank tumors. Bioluminescence imaging (BLI) quantification was determined by the mean number of photons per second in the region of interest. PET imaging with [18]F-FEAU was performed in a 3-dimensional microPET scanner. T-cell imaging results were validated by flow cytometric and immunohistochemical analysis of harvested tissue.Results
Quantification studies showed a linear relationship between photon emission and T-cell number both in vitro and in vivo. In vivo, evaluation of T-cell biodistribution kinetics, by intravenous administration of effLuc-M28z T cells into mice bearing flank tumors, demonstrated initial accumulation of T cells in the lungs, liver, and spleen and progressive accumulation in the tumor (Figure 1A). Pleurally administered effLuc-M28z+ T cells displayed an increasing BLI signal (5-fold; p<0.01) in response to antigen 72 hours after administration, compared with pleurally administered effLuc+ T cells alone (control) (Figure 1B). T-cell accumulation in pleural tumor and extrathoracic sites (spleen) was confirmed by flow cytometric analysis of tissues harvested at serial time points (Figure 1C). These results were reproduced with clinical-grade vector TK-M28z+ T cells administered intrapleurally in mice bearing pleural tumor. Serial [18]F-FEAU PET imaging showed antigen-specific T-cell accumulation with decreasing tumor burden, as seen by corresponding tumor BLI (Figure 1D). Figure 1Conclusion
We provide an optimized method for monitoring of T-cell trafficking, localization and proliferation in thoracic malignancies. Our findings—derived using a clinical-grade imaging construct and substrate—provide convincing evidence for the use of noninvasive T-cell monitoring in our upcoming adoptive T-cell therapy clinical trial.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O22 - Mesothelioma III (ID 122)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Mesothelioma
- Presentations: 1
- Moderators:P. Baas, R. Gaafar
- Coordinates: 10/29/2013, 16:15 - 17:45, Bayside Gallery A, Level 1
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O22.02 - CD8 T-cell Infiltration and Tumor IL-7R Expression are Independent Prognostic Factors in Epithelioid Malignant Pleural Mesothelioma (ID 2935)
16:25 - 16:35 | Author(s): M. Sadelain
- Abstract
- Presentation
Background
Following our publication (Cancer Immunol Immunother 2011) demonstrating the prognostic importance of chronic inflammatory cell infiltration in epithelioid malignant pleural mesothelioma (MPM), we investigated the prognostic significance of the immune microenvironment in the tumor nest and the tumor-associated stroma in epithelioid MPM.Methods
A tissue microarray (TMA) was constructed from 170 epithelioid MPM cases, with 6 representative tumor cores and 3 representative stromal areas. Immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) and interleukin receptors (IL-7R and IL-12Rβ2) were performed. TMA slides were analyzed for immune cell infiltration of tumor and stroma (low vs high, divided by use of the median), as well as for immune marker expression (sum of intensity and distribution). Overall survival (OS) was estimated using Kaplan-Meier analysis, and log-rank tests and Cox proportional hazards models were used to analyze the association between each marker and OS.Results
Analysis of single immune cell infiltration for all patients revealed that high tumor CD8+ T-cell infiltration, high CD20+ B-cell infiltration, and low tumor IL-7R expression correlated with higher OS (Figure). Combined tumor CD8+ and CD4+ cell infiltration significantly correlated with better OS (5-year OS, 36% [n=61] vs. 20% [n=96]; p=0.008). In a multivariate analysis including age, stage, lymph node metastases, lymphatic invasion, and vascular invasion, high CD8+ T-cell infiltration and low tumor IL-7R expression were independent predictors of OS (Table). Figure 1Figure 2Conclusion
Tumor CD8+ T-cell infiltration and tumor IL-7R expression are independently associated with survival, which highlights the biologic and prognostic significance of the immune microenvironment for patients with epithelioid MPM.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
