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P. Mitchell
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 15
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.01 - Integrating INDEL Mutations into Neoantigen Prediction in Lung Cancer: Developing Personalized Cancer Vaccines (ID 10150)
15:45 - 15:50 | Presenting Author(s): Yanyan Lou | Author(s): Y. Asmann, M. Thomas, K. Knutson
- Abstract
- Presentation
Background:
Mutant neoantigens generated from genetic alterations that are exclusively present in tumors represent highly promising cancer vaccine targets. However, publically available neoantigen prediction algorithms only identify and utilize single nucleotide mutations (SNVs) but not short insertion and deletions (INDELs). Short INDELs can lead to the generation of novel junctional or frameshift neoantigens which may be more immunogenic than neoantigens that result from single nucleotide missense mutations.
Method:
We developed a bioinformatics pipeline for neoantigen prediction using paired normal tissue and tumor exome sequencing, RNA sequencing and HLA binding prediction. 536 lung adenocarcinoma (LUAD) and 466 lung squamous cell carcinoma (LUSC) cases were analyzed using our bioinformatics pipeline. The non-synonymous somatic SNVs and short INDELs mutations were identified to generate a list of mutation neoantigen-derived and, when possible, their corresponding wild-type epitopes. Binding affinities of the paired wild-type and mutant peptides to HLA class I were then predicted and compared.
Result:
On average, 8.65 (range1-158) mutant neoantigen peptides per sample were identified in 395 out of 536 (73.6%) LUAD samples. Among them, 63.7% were SNVs and 36.3% were INDELs. On average, 8.54 (range 1-504) mutant neoantigen peptides per sample were identified in 360 out of 466 LUSC samples. Among those, 67% were SNVs and 33% were INDELs. Most neoantigen peptides are private in both LUAD and LUSC. The mutant neoantigen peptides identified from INDELs were predicted to have 3.9 (p = 2.42E-74) and 1.14 (p = 5.44E-67) fold higher HLA class I binding affinity than wild type peptide compared to those from SNVs in LUAD and LUSC respectively.
Conclusion:
Tumor INDELs may be a rich source of neoantigens with a higher predicted high HLA binding affinity in lung cancers that warrant consideration in development of a personalized cancer vaccine.
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MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)
15:50 - 15:55 | Presenting Author(s): Ferdinandos Skoulidis | Author(s): L.A. Albacker, M.D. Hellmann, M.M. Awad, Justin F Gainor, M.E. Goldberg, A.B. Schrock, L. Gay, J. Elvin, Jeffrey S. Ross, H. Rizvi, B. Carter, J. Erasmus, D.F. Halpenny, A. Plodkowski, N. Long, M. Nishino-Habatu, W.L. Denning, J. Rodriguez-Canales, P. Villalobos, E.R. Parra Cuentas, L.M. Sholl, J.L. Sauter, Y.Y. Elamin, Jianjun Zhang, G.C. Leonardi, Kwok-Kin Wong, P.J. Stephens, Vassiliki A Papadimitrakopoulou, Ignacio I. Wistuba, J.D. Wolchok, Alice Shaw, Pasi A Jänne, Charles M Rudin, V.A. Miller, John V Heymach
- Abstract
- Presentation
Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).
Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).
Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.
Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.
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MA 05.03 - The Early Monitoring of Derived Neutrophil-To Lymphocyte Ratio (dNLR) Could Be a Surrogate Marker of Benefit of Immunotherapy in NSCLC (ID 10147)
15:55 - 16:00 | Presenting Author(s): Laura Mezquita | Author(s): E. Auclin, M. Charrier, Roberto Ferrara, C. Caramella, David Planchard, S. Ponce, Luis Paz-Ares, C. Audigier-Valette, L. Tessonnier, G. Martinez, G. Zalcman, J. Lahmar, J. Remon, J. Adam, N. Chaput, J. Soria, Benjamin Besse
- Abstract
- Presentation
Background:
Baseline high derived NLR (dNLR>3, neutrophils/(leucocytes-neutrophils) ratio) has recently correlated with no benefit to immune checkpoint inhibitors (ICI) in advanced NSCLC, but the dynamic monitoring of dNLR has not been assessed in this population.
Method:
dNLR at baseline, at 2[nd] cycle and at progressive disease were retrospectively collected in advanced NSCLC patients treated with ICI from November 2012 to April 2017, in a multicentric cohort (N= 292) from 4 European centers. The primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), response rate (RR) and disease control rate (DCR).
Result:
Out of 292 patients (67%) were males, 264 (92%) smokers and 239 (83%) with PS ≤1, with median age 64 years; 153 (52%) had adenocarcinoma and 114 (30%) squamous; 44 (15%) were KRASmut, 11 (4%) EGFRmut and 3 (1%) ALK positive. PDL1 was ≥ 1% by immunohistochemistry in 67 (76%), negative in 21 (24%) and unknown in 204 patients. The median of prior lines was 1 (0-10). The median follow-up was 12 months (m) [11-14]. The median PFS and OS were 4m [3-5] and 11m [9-15]. Baseline dNLR was>3 in 106 patients (36%) and at 2[nd] cycle in 90 patients (32%). dNLR>3 at baseline and at 2[nd] cycle were associated with poor PFS (p<0.0001 and p=0.0008, respectively), poor OS (both p<0.0001) and progressive disease (p=0.002 and p=0.005, respectively). At 2[nd] cycle of ICI, the dNLR status (> high or ≤ 3 low) changed in 63 patients: in 38 (14%) dNLR decreased; in 25 (9%) dNLR increased. According to the dNLR monitoring (combining dNLR at baseline et at 2[nd] cycle), the median OS was 17m (95%CI 13-NA) when dNLR remained low (n=153), 10m (95%CI 7-NA) when dNLR changed (n=64) and 4m (95%CI 3-7) when dNLR remained high (dNLR>3, n=64, p<0.0001).The dNLR monitoring was also associated with PFS (p=0.002), RR and DCR (p=0.003 and p=0.013, respectively).
Conclusion:
Monitoring dNLR at baseline and at 2[nd] cycle could be a routinely tool to early assess benefit to ICI in NSCLC patients on treatment. The dNLR monitoring showed a strong correlation with OS and PFS. Modification of dNLR between baseline and 2[nd] cycle impacts outcomes in NSCLC patients treated with ICI.
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MA 05.04 - Distinct Immunosuppressive Microenvironment Determines Poor Prognosis of Nonsmokers with Adenocarcinoma of Non-Small Cell Lung Cancer (ID 7388)
16:00 - 16:05 | Presenting Author(s): Tomonari Kinoshita | Author(s): T. Fujita, Y. Hayashi, Takashi Ohtsuka, Tetsuya Mitsudomi, Hisao Asamura, Kazuhiro Yasufuku, Y. Kawakami
- Abstract
- Presentation
Background:
Recent clinical trials have demonstrated the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC). However, not all the patients receive survival benefit from these immunotherapies. In an attempt to refine the current strategy of cancer immunotherapy to treat NSCLC, we examined the influence of tumor-infiltrating lymphocytes (TILs) on postoperative survival.
Method:
We evaluated the prognostic significance of TILs (CD4[+], CD8[+], and FOXP3[+]) comprehensively by immunohistochemical (n = 234) and immune-related gene expression analysis (n = 58), and explored the relationship between immune features and clinical characteristics including histological types, smoking habit, epidermal growth factor receptor mutation, and postoperative survival.
Result:
Compared with non-adenocarcinoma (non-AD) patients, adenocarcinoma (AD) tumors had significantly higher number of tumor-infiltrating CD4[+] T cells (P < 0.05) but lower CD8[+] T cells and FOXP3[+] T cells (P < 0.01). We found higher accumulation of CD8[+] T cells in non-AD patients was correlated with longer survival, indicating it is a better prognostic factor (P < 0.02). On the contrary, high accumulation of CD8[+] T cells and FOXP3[+] T cells were identified as unfavorable prognostic factors (P < 0.05) in AD patients, particularly in AD nonsmokers (P < 0.02). The expression of activated T cell-related genes including interferon gamma and granzyme was associated with CD8[+] T-cell accumulation in non-AD patients, but not in AD patients, especially in AD nonsmokers. Infiltrating CD8[+] T cells were significantly less activated in immunosuppressive microenvironment with high expression of immunoregulation related genes including GATA3, IL13, CCR4 and CCL17 in AD nonsmokers (P < 0.05). In AD nonsmokers, there are possibly immunodysfunctional CD8[+] GATA3[+] T cells (P < 0.01) and immunoregulatory CD8[+] FOXP3[+] T cells (P < 0.01), accompanied by immunoregulatory CD4[+] FOXP3[+] CCR4[+] T cells (P < 0.01) that may be recruited by CCL17 produced by tumor-associated CD163[+] macrophages (P < 0.05) in IL13-associated tumor microenvironments (P < 0.05).
Conclusion:
In contrast to presence of activated CD8[+] T cells in non-AD, CD8[+] T cells are not activated, and may include dysfunctional and immunoregulatory T cells, accompanied by FOXP3[+] regulatory T cells and M2-like macrophages in IL13-associated tumor microenvironment of AD nonsmokers. Our study suggests that modulation of such immunosuppressive condition may be an attractive strategy for treatment of AD nonsmokers including immune-checkpoint blockade.
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MA 05.05 - Discussant - MA 05.01, MA 05.02, MA 05.03, MA 05.04 (ID 10821)
16:05 - 16:20 | Presenting Author(s): Laura Q Chow
- Abstract
- Presentation
Abstract not provided
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MA 05.06 - Comparison Study of PD-L1 Immunohistochemistry Assays with 22C3 and 28-8: Analysis on Surgical Specimens of NSCLC. (ID 8423)
16:20 - 16:25 | Presenting Author(s): Tomohito Saito | Author(s): K. Tsuta, M. Ishida, H. Ryota, Y. Takeyasu, K.J. Fukumoto, H. Matsui, Y. Taniguchi, H. Yanagimoto, T. Yokoi, T. Kurata, T. Murakawa
- Abstract
- Presentation
Background:
The checkpoint inhibitors programmed cell death and its ligand (PD-L1) antibodies are promising treatment agents for patients with advanced non-small cell lung cancer (NSCLC). Their clinical efficacy is predicted by drug-tailored PD-L1 immunohistochemistry (IHC) assays. We aimed to identify the similarity and distinction of 22C3 and 28-8 IHC tests.
Method:
Three hundred and ninety consecutive cases of completely resected NSCLC between January 2009 and September 2014 that had adequate tissue samples were investigated. From the archived samples, 5-μm thick sections were cut and stained with PD-L1 IHC 22C3 PharmDx and 28-8 PharmDx (Dako, Santa Clara, CA). The staining and evaluation in 22C3 and 28-8 test were performed by two separate laboratories. PD-L1 expression and high PD-L1 expression were defined as ≥1% and ≥50% of tumor cells stained, respectively. Statistical significance was defined as a p-value of <0.05.
Result:
The study population included 288 patients with adenocarcinomas, 70 with squamous cell carcinomas, 18 with large cell carcinomas, 9 with adenosquamous carcinoma and 5 with pleomorphic carcinoma. Two hundred and ninety-three patients had pStage I; 47, pStage II; and 46, p Stage IIIA tumors. Two hundred and twenty-nine specimens showed no PD-L1 expression with either 22C3 or 28-8. The detection rate of PD-L1 expression was 36.9% (144 cases) with 22C3 and 35.6% (139 cases) with 28-8, respectively (p= 0.710). The detection rate of high PD-L1 expression was 16.9% (66 cases) with 22C3 and 9.0% (35 cases) with 28-8 (p= 0.0013). The Spearman correlation coefficient was 0.866 (95% confidence interval, 0.838–0.890; p< 0.0001). Figure 1
Conclusion:
22C3 IHC assay may be more sensitive to detect high PD-L1 expression in NSCLC compard to 28-8 IHC assay, whereas 22C3 and 28-8 showed no significant difference to detect PD-L1 expression. Further investigation is necessary to reveal clinical, pathological and molecular background. This approach will help better interpretation of PD-L1 IHC results.
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MA 05.07 - Whole Body PD-1 and PD-L1 PET in Pts with NSCLC (ID 9219)
16:25 - 16:30 | Presenting Author(s): J. De Langen | Author(s): Anna-Larissa Nadia Niemeijer, Egbert F Smit, G.A. Van Dongen, A.D. Windhorst, M.C. Huisman, N. Hendrikse, I. Bahce, D.K. Lueng, R.A. Smith, W. Hayes, L.M. Wilson, S.J. Bonacorsi, D.J. Donnelly, P.E. Morin, A. Poot, D.J. Vugts, Erik Thunnissen
- Abstract
- Presentation
Background:
Tumor PD-L1 IHC relates moderately with treatment outcome following anti-PD1 therapy in pts with NSCLC and single biopsies do not account for tumor heterogeneity. Aim: 1. Assess safety of the PET procedures. 2. Quantify [89]Zirconium-labeled nivolumab ([89]Zr-nivo) and [18]F-labeled BMS-986192 ([18]F-PD-L1) uptake. 3. Assess tracer uptake heterogeneity. 4. Correlate tracer uptake with PD-1/PD-L1 IHC in tumor, stroma and with treatment outcome.
Method:
NSCLC pts eligible for treatment with nivolumab were included. Pts received whole body [18]F-PD-L1 and [89]Zr-nivo PET scans. Baseline tumor biopsy was required to assess PD-(L)1 IHC status (28.8 assay). SUV~peak~ was calculated for delineable lesions and correlated to PD-(L)1 IHC and response after 12 wks of nivolumab treatment.
Result:
10 pts (3 ≥50%, 5 ≥1%, 5 negative by PD-L1 IHC) were enrolled and 37 lesions analysed. No toxicity related to radiotracer was observed. Tumor uptake of both tracers was visualized in all pts, but not in all lesions. Tracer uptake varied among pts with mean [18]F-PD-L1 SUV~peak~ 4.6, range 0.5 - 14.4 and mean [89]Zr-nivo SUV~peak~ 5.0, range 1.6 – 11 (p=0.03) and within pts with mean SUV~peak~ difference 3.6-fold (±2.1) and 2.4-fold (±0.77) between lesions for [18]F-PD-L1 and [89]Zr-nivo, respectively. For lesions with ≥50% PD-L1 IHC, mean [18]F-PD-L1 SUV~peak~ was 8.0 (±4.7) as compared to 3.5 (±1.6) for lesions with <50% PD-L1 IHC (p=0.03). For tumors with high TIL/ stromal PD-1 expression, mean [89]Zr-nivo SUV~peak~ was 8.6 (±2.4) as compared to 6.1 (±2.1) for lesions with low PD-1 expression (p=0.1). Mean SUV~peak ~for [18]F-PD-L1 was 8.4 (±5.4) for pts with PR and 4.5 (±2.9) for pts with PD/SD (p=0.3). Mean SUV~peak~ for [89]Zr-nivo was 7.8 (±1.8) for pts with PR and 5.4 (±2.2) for pts with PD/SD (p=0.2).
Conclusion:
1. PET-imaging with both tracers is safe and feasible, with good tumor-to-normal tissue contrast. 2. Tumor uptake showed heterogeneity among pts and among tumors within pts. 3. Pts with ≥50% tumor PD-L1 expression showed higher [18]F-PD-L1 uptake. 4. Pts with high PD-1 expression showed higher [89]Zr-nivo uptake, and pts with PR demonstrated higher [18]F-PD-L1 and [89]Zr-nivo tracer uptake than pts with PD/SD, although these are without statistical significance which may be due to the small dataset.
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MA 05.08 - Very Early Response of Circulating Tumor Derived DNA Predict the Efficacy of Treatment by Nivolumab in Patients with Non-small Cell Lung Cancer (ID 8303)
16:30 - 16:35 | Presenting Author(s): Yuki Iijima | Author(s): T. Nakagomi, Y. Uchida, Y. Kobayashi, T. Tsutsui, Y. Kakizaki, Taichiro Goto, Y. Miyashita
- Abstract
- Presentation
Background:
Immunotherapy has become one of the options among the treatments of lung cancer. Nivolumab was first proven to have the utility as a second line treatment for non-small cell lung cancer. However, predictive factor of its efficacy is unknown. In recent years, studies have evolved on circulating tumor DNA (ctDNA). Clinical applications expanded and included prediction of prognosis, monitoring treatment effects and acquired resistance of driver genes, and assessment of residual tumor burden of resected cancer. In this study, we took cases in which tumor tissue was surgically resected or obtained by biopsy and the corresponding somatic mutations in plasma were studied. Then, we used these somatic mutations presumably derived from original tumor tissue as “tumor markers”. We took serial blood samples before and after starting nivolumab and examined to see whether early change of the level of ctDNA can predict long term treatment outcomes.
Method:
Fourteen patients who were treated by nivolumab from February 1st to September 30th in 2016 were studied. Peripheral blood samples were collected from the patients before, 1, 2, 4, 6 and 8 weeks after the initiation of nivolumab treatment. To identify somatic mutations in tissue and total plasma DNA, we performed targeted sequencing using “lung cancer panel” spanning whole exons of these 53 genes, and next generation sequencing was performed. Gene mutations detected in both tumor tissue and plasma were defined here as circulating tumor DNA (ctDNA). Early response of the level of ctDNA after starting nivolumab was evaluated to see whether it could predict treatment outcome.
Result:
Of 14 cases, 6 cases were Responders, and 8 Non-responders. ctDNA was detected more often in the serial plasma samples of patients carrying high tumor burden (p=0.02). In addition, basal and serial ctDNA analysis revealed that decrease of allelic frequency (AF) level within 2 weeks correlated with the good durable response, and on the contrary, the increase with no or poor response.
Conclusion:
In patients carrying high tumor burden, plasma analysis of ctDNA which was validated by tumor tissue, revealed the durable good response of nivolumab could be predicted within 2 weeks.
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MA 05.09 - Pre-Existing Immunity Measured by Teff Gene Expression in Tumor Tissue is Associated with Atezolizumad Efficacy in NSCLC (ID 10759)
16:35 - 16:40 | Presenting Author(s): Marcin Kowanetz | Author(s): W. Zou, M. McCleland, David R. Gandara, Shirish M Gadgeel, A. Rittmeyer, Fabrice Barlesi, Keunchil Park, D.S. Shames, H. Koeppen, M. Ballinger, A. Sandler, P. Hegde
- Abstract
- Presentation
Background:
Association between T-effector (Teff) gene expression (GE), a marker of pre-existing immunity, and OS benefit with atezolizumab (anti–PD-L1) was demonstrated in the Phase II study POPLAR of atezolizumab vs docetaxel in 2L+ NSCLC. We analyzed Teff GE association with atezolizumab efficacy in a larger Phase III study, OAK.
Method:
Patients with 2L+ NSCLC were randomized to receive atezolizumab or docetaxel. Teff signature was defined by 3 genes (PD-L1, CXCL9, and IFNγ), and Teff GE was measured by averaging the normalized expression of each gene. Teff GE subgroups were defined by quartiles. PD-L1 expression was assessed using the SP142 IHC assay; the TC1/2/3 or IC1/2/3 subgroup had ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).
Result:
753 of 850 patients from the OAK primary analysis constituted the biomarker evaluable population (BEP) for Teff GE. Expression of the Teff signature was associated with PD-L1 expression by IHC (P = 7.3×10[−45]). Although no significant PFS benefit with atezolizumab vs docetaxel was observed in the BEP (HR, 0.94 [95% CI: 0.81, 1.10]) or the TC1/2/3 or IC1/2/3 subgroup (HR, 0.93 [95% CI: 0.76, 1.15]), a gradient of improved PFS benefit with atezolizumab was observed with increasing Teff GE. Significant PFS benefit occurred with ≥ median Teff GE cutoff (HR, 0.73 [95% CI: 0.58, 0.91]; Table). Teff GE also enriched for improved OS; however, a trend toward OS benefit was still observed in patients with low Teff GE (Table).Table. PFS and OS with atezolizumab vs docetaxel by PD-L1 IHC and Teff GE subgroups PFS, HR (95% CI) OS, HR (95% CI) OAK primary population (N = 850)[a] ITT[a] 0.95 (0.82, 1.10) 0.73 (0.62, 0.87) TC1/2/3 or IC1/2/3[a ](n = 463) 0.91 (0.74, 1.12) 0.74 (0.58, 0.93) TC2/3 or IC2/3[a] (n = 265) 0.76 (0.58, 0.99) 0.67 (0.49, 0.90) OAK BEP for Teff GE (N = 753) BEP 0.94 (0.81, 1.10) 0.71 (0.59, 0.85) TC1/2/3 or IC1/2/3 (n = 420) 0.93 (0.76, 1.15) 0.74 (0.58, 0.95) Teff GE subgroups ≥ 25% (n = 570) 0.91 (0.76, 1.09) 0.67 (0.54, 0.83) < 25% (n = 183) 1.11 (0.82, 1.49) 0.87 (0.63, 1.21) ≥ 50% (n = 379) 0.73 (0.58, 0.91) 0.59 (0.46, 0.76) < 50% (n = 374) 1.30 (1.05, 1.61) 0.87 (0.68, 1.11) ≥ 75% (n = 190) 0.66 (0.48, 0.91) 0.60 (0.42, 0.87) < 75% (n = 563) 1.10 (0.92, 1.31) 0.76 (0.62, 0.92) [a]Rittmeyer A. et al. Lancet, 2017;389:255-265. NCT02008227.
Conclusion:
This is the first demonstration of the association between markers of Teff biology and clinical outcomes with cancer immunotherapy in a randomized Phase III trial. Teff GE may reflect pre-existing immunity and be a more sensitive biomarker compared with PD-L1 IHC, identifying more patients (50% prevalence) likely to experience PFS benefit with atezolizumab.
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MA 05.10 - Discussant - MA 05.06, MA 05.07, MA 05.08, MA 05.09 (ID 10822)
16:40 - 16:55 | Presenting Author(s): David Rimm
- Abstract
- Presentation
Abstract not provided
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MA 05.11 - Endothelial Adhesion Molecule Overexpression Correlates to Decreased CD8 T Cells and Increased B/Treg Cells in Lung Cancer (ID 8609)
16:55 - 17:00 | Presenting Author(s): Young Kwang Chae | Author(s): Wooyoung Monica Choi, W.H. Bae, J. Anker, A.A. Davis, Wade Thomas Iams, M. Cruz, M. Matsangou, F.J. Giles
- Abstract
- Presentation
Background:
Immunotherapy has become a promising recourse for lung cancer therapy. The endothelium separates circulating immune cells and the tumor microenvironment, and it is necessary for immune cells to penetrate this barrier to accost the tumor. This requires cell-matrix interactions via endothelial adhesion molecules(EAM) such as selectin and integrin. While it is expected that higher expression of EAM is linked to greater immune cell infiltration in general, little is known as to its actual effect on various types of immune cells in human lung cancer.
Method:
Based on the TCGA database, mRNA-seq values of genes related to the leukocyte recruitment cascade were analyzed in 504 patient samples with lung squamous cell carcinoma(SCC) and 522 patient samples with lung adenocarcinoma. The genes were divided into 3 sets: rolling, firm adhesion, and transmigration. Immune cell infiltration of each set was analyzed using Gene Set Enrichment Analysis(GSEA), and p values were derived from Fisher’s exact and Chi-squared tests.
Result:
In lung SCC, overexpression(z score>2.0) of the above genes was statistically significantly correlated with decreased infiltration of activated CD4/CD8 T cells, but increased infiltration of activated B/Treg cells (Figure1). Similar trend was also observed in lung adenocarcinoma. Macrophage, dendritic cells, and natural killer cells showed increased infiltration in the EAM overexpression groups of both SCC and adenocarcinoma. Overall survival showed no significant difference in all three EAM gene overexpression groups in both types of lung cancer.Figure 1
Conclusion:
We demonstrate for the first time that overexpression of EAM genes is linked to differential infiltration of various immune cells (including decreased CD4/CD8 T cells and increased activated B/Treg cells) in human lung cancer tissue. Recruitment of B/Treg cells by EAM may have an impact on inactivation of infiltrated T cells in the tumor microenvironment. This suggests that EAM status may serve as a predictive biomarker for T cell-mediated immunotherapy.
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MA 05.12 - Oncogenic Drivers Induce Production of CCL5 to Recruit Regulatory T-Cells Early in Lung Cancer Progression (ID 10289)
17:00 - 17:05 | Presenting Author(s): William W Lockwood | Author(s): E. Franks, E. Halvorsen, E. Melesse, A. Unni, J. Collier, M.H. Oh, V. Lam, G. Krystal, J.C. English, W.L. Lam, Stephen Lam, N. Abraham, K.L. Bennewith
- Abstract
- Presentation
Background:
Lung cancer development is driven by the expression of mutant oncogenes, with EGFR and KRAS the most frequent in lung adenocarcinoma. However, these mutations alone are not sufficient for tumorigenesis suggesting additional factors influence tumour development and progression, including the balance of anti-tumour immune effector cells and pro-tumorigenic immune suppressor cells. Tumour cells can evade immune surveillance by producing cytokines to recruit immune modulatory cells that promote an immune suppressive environment, such as regulatory T cells (Tregs). We hypothesized that oncogene signaling regulates the production of cytokines by tumour cells in order to recruit immune suppressive cells and promote lung tumour development.
Method:
We used CIBERSORT to quantify 22 immune cell types in over 300 human lung adenocarcinoma and 100 matched normal lung tissues, and validated findings with immunohistochemistry. Cells expressing doxycycline inducible EGFR[L858R] and KRAS[G12V]were analyzed for cytokine production using a multiplex assay (LUMINEX). EGFR (Afatinib) and MEK (Trametinib) inhibitors were used in lung cancer cell lines harbouring EGFR or KRAS mutations and cytokine production was quantified using ELISA. Conditioned media from EGFR[L858R] and KRAS[G12V] expressing cells were used in a trans-well assay to determine if secreted cytokines could induce Treg migration. Transgenic mouse models of lung adenocarcinoma and bronchoalveolar lavage (BAL) from patients with and without lung cancer were used to assess CCL5 and Tregs in vivo.
Result:
Treg cells were significantly enriched in lung tumours and not normal tissue. CCL5 production is increased rapidly upon oncogene induction and subsequent transformation of normal cells and is dependent on sustained ERK signaling for continued expression. Conditioned medium from EGFR[L858R] expressing cells increased Treg migration, which was mitigated by an anti-CCL5 antibody. Transgenic mice expressing EGFR[L858R ]or KRAS[G12D] in the lung epithelium recruited Tregs to the lung upon tumor induction. Assessment of CCL5 in BAL from patients with and without lung cancer is currently in progress.
Conclusion:
Oncogene driven ERK signaling may regulate expression of CCL5 from lung tumour cells, and oncogene induced CCL5 production stimulates Treg migration ex vivo. These data suggest CCL5-mediated Treg recruitment to lung tumours may occur in early stages of lung tumour development and that targeted inhibition of CCL5 or ERK signaling may represent therapeutic strategies to block recruitment of immunosuppressive Tregs by lung tumours.
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MA 05.13 - Scavenger Receptor MARCO Defines a Targetable Tumor-Associated Macrophage Subset in Lung Cancer (ID 8641)
17:05 - 17:10 | Presenting Author(s): Linnea La Fleur | Author(s): V. Boura, A. Berglund, Johanna Sofia Margareta Mattsson, Dijana Djureinovic, J. Persson, H. Brunnström, J. Isaksson, E. Branden, H. Koyi, Patrick Micke, M. Karlsson, J. Botling
- Abstract
- Presentation
Background:
Tumor-associated macrophages (TAMs) with immunosuppressive and tumor promoting features are attractive targets for immunotherapy. MARCO is a scavenger receptor expressed on a subpopulation of macrophages in secondary lymphoid organs. A recent study performed in animal models concluded that treatment with an anti-MARCO antibody results in reprogramming of the TAMs and inhibition of tumor growth and metastatic spread. The expression and function of MARCO in lung cancer TAMs is not known.
Method:
The infiltration of TAMs expressing MARCO, CD68, CD163 and MSR1, in the tumor and stromal compartments, was analyzed by immunohistochemistry in a non-small cell lung cancer (NSCLC) cohort (n=352). In addition, PD-L1 expression was assessed on tumor cells. Immunofluorescence was performed on selected cases to evaluate marker co-expression. Associations to immune cells and regulatory inflammatory pathways were studied in a subset of cases (n=174) with available RNA-seq data.
Result:
A large variance in TAM density could be observed between cases as well as a strong correlation between CD68 and CD163, indicating a pro-tumor phenotype of infiltrating macrophages. Correlation to clinical data showed a trend towards worse survival for patients with high macrophage infiltration. TAM expression of MARCO was seen on a subpopulation of pro-tumor macrophages. The majority of MARCO expressing TAMs were found to be located within tumor cell nests. Interestingly, stromal macrophages expressing MARCO tended to aggregate in close proximity to the tumor nests. On the transcriptomic level, increased MARCO gene expression correlated to genes linked to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules like PD-L1 and CTLA-4. The association between macrophage infiltration and tumor cell PD-L1 expression was confirmed by immunohistochemistry. Also, co-expression of PD-L1 and MARCO could be detected on certain macrophages within the tumor cell nests.
Conclusion:
MARCO expression characterizes a specific subpopulation of pro-tumor macrophages that are enriched in PD-L1 positive NSCLC cases. Patients with significant infiltration of MARCO positive TAMs could benefit from treatment with anti-MARCO antibodies, possibly in combination with available immune checkpoint inhibitors.
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MA 05.14 - Differential Expression of IFN-Stimulating DNA Sensors STING and cGAS in Lung Cancer Subtypes (ID 9578)
17:10 - 17:15 | Presenting Author(s): Charles Caldwell Jr | Author(s): Hui Yu, K. Ellison, L. Rozeboom, C.J. Rivard, Fred R. Hirsch
- Abstract
- Presentation
Background:
STING is a protein that promotes type I IFN production (IFNα/β) essential for activation of dendritic cells and antigen presentation and priming of T-cells. The cytoplasmic DNA sensor cGAS (cGAMP Synthase) is able to detect tumor DNA, and in response will synthesize cGAMP. cGAMP binds STING specifically, resulting in production of type I IFN. STING is therefore referred to as an adaptor protein essential for immune signaling following detection of tumor DNA. Analysis of the TCGA database indicates decreased survival in lung adenocarcinoma patients lacking STING expression. STING expression is decreased in tumor tissues and can be lost as the tumor progresses. One reported mechanism of loss of STING or cGAS in tumors is due to hypermethylation, a common occurrence in lung cancer. Agonists of STING show potent immune response and are currently in clinical trials. Importantly, recent studies show that expression of STING and cGAS proteins are essential for response to PD-1:PD-L1 blockade.
Method:
Section not applicable
Result:
We analyzed 55 NSCLC and 39 SCLC cell lines, and 317 NSCLC and 78 SCLC tissues for STING and cGAS expression using immunohistochemistry. 14/55 (25.45%) NSCLC cell lines and 25/39 (64.10%) SCLC cell lines showed no STING expression. Separated in to adenocarcinoma (AC) and squamous cell carcinoma (SCC) subsets, STING expression in AC shows loss of STING as tumor stage increases (Positive: 70% Stage I, 65% Stage II, 52% Stage III, 40% Stage IV, 71% total; n=156) while STING expression is low at all stages of SCC (Positive: 29% Stage I, 18% Stage II, 36% Stage III, 13% Stage IV, 27% total; n=161). SCLC tissues stained showed widespread loss of STING (Positive: 40% Stage I, 27% Stage II, 31% Stage III, 100% Stage IV, 37.18% total, n=78). Expression of cGAS was higher in AC (94%) than SCC (75%) and showed no correlation with stage. TCGA analysis of STING methylation shows hypermethylation in AC (0.15- ± 0.13 tumor vs 0.05 ± 0.02 normal, n=422) and SCC (0.23 ± 0.16 tumor vs 0.04 ± 0.03 normal, n=359). cGAS shows slight methylation in AC (0.05 ± 0.07 tumor vs 0.05 ± 0.01 normal, n=422) but a large increase in SCC (0.19 ± 0.24 tumor vs 0.04 ± 0.01 normal, n=359).
Conclusion:
This study indicates drastic differences in STING and cGAS expression in AC, SCC, and SCLC. Differential expression of these proteins could impact the efficacy of STING agonists, radiation therapy, and immunotherapy in lung cancer.
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MA 05.15 - Discussant - MA 05.11, MA 05.12, MA 05.13, MA 05.14 (ID 10823)
17:15 - 17:30 | Presenting Author(s): Hiroyuki Suzuki
- Abstract
- Presentation
Abstract not provided
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Author of
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-039 - Spatial Heterogeneity of Immunological Markers Between Cores and Complete NSCLC Sections Using Multispectral Fluorescent IHC (ID 9728)
09:30 - 09:30 | Author(s): P. Mitchell
- Abstract
Background:
Immunotherapy with immune checkpoint inhibitors have revolutionised the management of solid organ malignancy including melanoma and NSCLC. Direction has turned to the tumour immune microenvironment (TIM) to explore predictive biomarkers. The spatial arrangement of immune infiltrative cells has the potential to better explain the TIM. Vectra multispectral immunohistochemistry (IHC) allows accurate definition of the TIM and may help detect mechanisms of immune evasion.
Method:
Multispectral fluorescent immunohistochemistry with a panel including CKAE1/3, CD8, FOXP3 and PD-L1 (clone E1L3N, Cell Signalling Technology) was used to analyse the TIM in six patients (pts) with resected NSCLC (full face section from block). Respective tissue microarrays were collected in triplicate from each specimen and underwent conventional IHC scoring for PD-L1, tumour infiltrating lymphocytes (TILs), CD8, FOXP3 and scored (0,1,2,3). The spatial arrangement of lymphocytes relative to tumour cells, stroma and PD-L1 expression was examined.
Result:
All six pts had adenocarcinoma histology, with the following level of PD-L1 expression: low(0-5%;n=2), intermediate(5-50%;n=2) and high(>50%;n=2)Figure1. In PD-L1[hi] pts Vectra staining showed uniform staining of PD-L1 across the full face. CD8 lymphocytes were present mainly in tertiary lymphoid structures without evidence of clustering. In PD-L1[lo] pts, one had heterogenous staining of TILs with dense stromal clustering (3:1 ratio of stroma to intratumoural). Neither patient (PD-L1[lo]) demonstrated significant PD-L1 uptake on full section assessment. Of the PD-L1[int] pts, although heterogeneity in PD-L1 expression was evident across the full face, the majority of tumour rich areas stained positively and TILs were uniform in the stroma. FOXP3 had low expression across all 6 patients <1% almost uniformly in the stroma.Figure 1
Conclusion:
Although PD-L1 staining heterogeneity was limited in this small dataset, clear differences in immune-cell infiltrate were seen between full-face sections and limited cores. Multiplex Immunofluorescent IHC provides accurate quantification of immune infiltrates and spatial alterations within the TIM and may facilitate predictive biomarkers.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-038 - Diagnosis of Leptomeningeal Disease and Clonal Heterogeneity with Digital Droplet PCR (ddPCR) in EGFR Mutated NSCLC (ID 8929)
09:30 - 09:30 | Author(s): P. Mitchell
- Abstract
Background:
Non-small cell lung cancer (NSCLC) spread to the central nervous system (CNS) is associated with universally poor outcomes. Diagnosis of leptomeningeal (LM) disease is particularly challenging, with radiological and cytological assessment of CSF often negative. Examination of cell-free DNA (cfDNA) is promising method for the assessment of tumour mutation status and disease monitoring. We examine its utility in the diagnosis and management of LM disease.
Method:
Patients with EGFR mutated NSCLC with symptoms suggestive of LM disease underwent cerebrospinal fluid (CSF) sampling and ddPCR assessment. Matched plasma and/or tumour biopsy samples were obtained. Clinical data was collected retrospectively. Genomic DNA was extracted from 1 mL of CSF and 4 mL of plasma using the Qiagen QIAamp Circulating Nucleic Acid kit and T790M and L858R mutations were assessed by using the QX200 ddPCR assays. Survival was calculated from diagnosis and diagnosis of LM disease.
Result:
Seven patients (pts) were included in the analysis. Most pts, 6/7 (86%) developed LM either during or after EGFR tyrosine kinase inhibitor (TKI) therapy. EGFR mutations were demonstrated in CSF in 6 (86%) pts, but only 2 (29%) demonstrated the same mutation profile in both CSF and plasma. Causes of discrepancy were between CSF and plasma/tissue were: two cases were CSF positive but had no extrathoracic disease to biopsy, 1 case was negative in the CSF for T790M but positive in plasma and on biopsy and one case was wild type in CSF but positive on plasma and biopsy for G719A+T790M mutation. Six pts (86%) received therapy after diagnosis of LM disease and OS from LM diagnosis ranged from 1.0 -15.8 months.Sex/ Age Therapy at diagnosis of CNS disease Duration of response to prior TKI (months) Therapy after diagnosis of CNS disease OS from diagnosis (months) OS from diagnosis of LM (months) Baseline EGFR mutation Tissue biopsy mutation profile CSF EGFR mutation profile (ddPCR) Plasma EGFR mutation profile (ddPCR) CSF cytology M/64 Nivolumab Erlotinib: 12.4 Gefitinib: 2.5 AZD3759 WBRT Osimertinib 52.7* 15.8* L858R L858R L858R + T790M L858R + T790M Positive - carcinoma F/68 Osimertinib Erlotinib: 18.2 Osimertinib: 7.2 Nil 28.6 1.7 L858R L858R + T790M Sample 1: L858R Sample 2: L858R + T790M N/A Sample 1 - negative Sample 2 - positive F/50 Osimertinib Erlotinib: 6.4 Osimertinib: 6.1 Erlotinib (1500mg weekly) 15.7 1.0 L858R L858R + T790M L858R L858R + T790M + C797S Positive - carcinoma F/79 Nil N/A Erlotinib (1500mg weekly) 74.5* 9.5* Exon 19 deletion No site for biopsy Exon 19 deletion Wild type Positive - carcinoma M/64 Erlotinib Erlotinib: 10.5 Erlotinib (1500mg weekly) 15.0 9.1 L858R No site for biopsy L858R Wild type Not performed F/63 Erlotinib Erlotinib: 5.9 Osimertinib 7.8* 1.3* G719A G719A + T790M WT G719A Not performed M/60 Erlotinib Erlotinib: 22.0 Erlotinib (1500mg weekly) 31.0* 7.4* Exon 19 deletion No site for biopsy Exon 19 deletion Exon 19 deletion Negative
Conclusion:
ddPCR is able to detect cfDNA in CSF, where other diagnostic modalities may be negative, and demonstrates both initial and resistance mutations. Heterogeneous mutation status may guide therapy when LM disease remains sensitive to targeted therapy.
