Checkpoint Blockade In Lung Cancer Research Articles

Macrophage xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer

Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor microenvironment (TME), which promotes tumor growth, immunosuppression and angiogenesis. Because of the high plasticity of macrophages and the extremely complex tumor microenvironment, the mechanism of TAMs in cancer progression is still largely unknown. In this study, we found that xCT (SLC7A11) was overexpressed in lung cancer-associated macrophages. Higher xCT in TAMs was associated with poor prognosis and was an independent predictive factor in lung cancer. In addition, lung cancer growth and progression was inhibited in xCT knockout mice, especially macrophage-specific xCT knockout mice. We also found that the deletion of macrophage xCT inhibited AKT/STAT6 signaling activation and reduced M2-type polarization of TAMs. Macrophage xCT deletion recruited more CD8+ T cells and activated the lung cancer cell-mediated and IFN-γ-induced JAK/STAT1 axis and increased the expression of its target genes, including CXCL10 and CD274. The combination of macrophage xCT deletion and anti-PDL1 antibody achieved better tumor inhibition. Finally, combining the xCT inhibitor erastin with an anti-PDL1 antibody was more potent in inhibiting lung cancer progression. Therefore, suppression of xCT may overcome resistance to cancer immunotherapy.

EP05.02-020 IL-9Stimulates Anti-tumor Immune Response and Facilitates Checkpoint Blockade in Lung Cancer

Lung cancer continues to be the most common cause of cancer-related mortality. There was mounting evidence that interleukin-9 (IL-9) was associated with cancer. Its function in lung cancer, however, is still debatable. The goal of this study was to elucidate the role of IL-9 in lung cancer and the mechanisms involved using murine lung carcinoma models.

MO4-4 Safety of immune checkpoint blockade in lung cancer and pre-existing autoimmune diseases: NEJ047 multi-center study

The safety and efficacy of immune checkpoint blockade (ICB) in patients with non-small cell lung cancer (NSCLC) and pre-existing autoimmune disease (AID) remain unclear since clinical trials have excluded these populations.

Bmi1 Resistance Pathway and Immune Checkpoint Blockade in Lung Cancer

Combined chemotherapy and radiation is a standard therapy for locally advanced lung cancers. However, the resistance mechanisms to these therapies and how they affect further adjuvant immunotherapy are not well understood. Our previous studies have shown that radiation led to the activation of Bmi1 as a mechanism of radiation resistance, which in turn upregulated the inhibitory immune checkpoint ligand PD-L1. Our hypothesis is that inhibition of Bmi1, a target for chemoradiotherapy resistance, with concurrent PD-L1 checkpoint blockade would have a synergistic enhanced immune response after chemoradiation therapy in a preclinical model of lung cancer.A small molecule inhibitor, PTC-596 (PTC Therapeutics, NJ), has been shown to inhibit the expression of Bmi1. For in vitro studies, we tested the effects of PTC-596 on the expression of both Bmi1 and PD-L1 in several lung tumor cell lines. To create a mouse model that simulates the PACIFIC trial treatment regimen, Lewis lung carcinoma cells (LLC1; 1 x 106 unsorted cells in 100 ul) derived in C57BL/6J strain were injected subcutaneously into the flank of immunocompetent C67BL/6J mice. When average tumor volume reached 100 mm3, the mice were treated with phase 1 treatment of radiation (dose 30 Gy in 10 fractions daily) delivered through SAARP platform and cisplatin (2mg/kg, every 3rd day for 10 days) and then randomized to receive phase 2 treatments: 1). Vehicle control every day; 2). Inhibitory anti-PD-L1 antibody every other day (200mg/kg, every 3 days for 4 cycles); 3). PTC-596 once a day (12.5 mg/kg, once a day); 4). Combined inhibitory anti-PD-1 antibody and PTC-596. Each treatment group had 10 mice.In both human and mouse lung tumor cell lines, fractionated radiation treatments upregulated Bmi1 expression and also increase the frequency of Bmi1-high, PD-L1-high expressing cells. Treatment with PTC-596 downregulated expression of Bmi1 and PD-L1 in these cells. In the PACIFIC study mouse model, cisplatin chemotherapy with fractionated radiation resulted significant growth delay than compared to no treatment. In the phase 2 of adjuvant treatment, the anti-PD-L1 antibody plus PTC-596 combination group, but not in groups receiving either treatment alone, had continued significant tumor size reduction. Immunological markers are being analyzed to determine if the immune response is enhanced.These results suggest that chemoradiation therapy leads to the activation of Bmi1 as a resistance mechanism, which in turn results in the activation of inhibitory immune checkpoint PD-L1 leading to immune escape and acquired resistance to immunotherapy. Treatment with PTC-596 demonstrated synergistic benefits to anti-PD-L1 immunotherapy after pre-chemoradiation treatment of preclinical mouse lung tumor model.

Radiation-activated secretory proteins of Scgb1a1+ club cells increase the efficacy of immune checkpoint blockade in lung cancer.

Radiation therapy (RT) in combination with immune checkpoint inhibitor (ICI) represents a promising regimen for non-small cell lung cancer (NSCLC), however, the underlying mechanisms are poorly characterized. We identified a specific dose of RT that conferred tumor regression and improved survival in NSCLC models when combined with ICI. The immune-modulating functions of RT was ascribed to activated lung-resident Scgb1a1+ club cells. Importantly, mice with club cell-specific knockout of synaptosome-associated protein 23 failed to benefit from the combination treatment, indicating a pivotal role of club cell secretome. We identified 8 club cells secretory proteins, which inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation, and enhanced anti-tumor immunity. Notably, CC10, a member of club cell secretome was increased in plasma of NSCLC patients responding to the combination therapy. By revealing an immune-regulatory role of club cells, our studies have the potential to guide future clinical trials of ICI in NSCLC.

Abstract 5902: Integrative genomic analysis of checkpoint blockade in lung cancer: A multi-institution SU2C collaborative

Abstract PD-1/PD-L1 checkpoint blockade has been a landmark advance for many patients suffering from advanced non-small cell lung cancer (NSCLC). However, detailed biomarkers of response beyond tumor mutational burden (TMB) are still poorly understood. As part of the effort to elucidate these additional signatures, we describe our progress on the Stand Up to Cancer Lung (SU2C-Lung) cohort. Initial characterization of exomes recapitulates mutational and copy number profiles seen in The Cancer Genome Atlas (TCGA) project. To better define expression subtypes using RNA sequencing, we performed non-negative matrix factorization (NMF) across an aggregated set of publicly available NSCLC expression data (including adenocarcinoma, squamous cell carcinoma, and large cell neuroendocrine histologies), and demonstrate good concordance in the SU2C-Lung cohort between this expression-based classifier and clinically annotated histology. To gain further insight into how immune cell infiltrates vary across our cohort, we additionally tested two common deconvolution algorithms, EPIC and CIBERSORT. While these two methods agree for some prominent cell types, such as B cells and CD4 T cells, discrepancies in minor infiltrating components such as NK cells may suggest a limit to the inference of rare subpopulations from bulk sequencing data.Finally, we describe a novel approach for determining single-gene predictors of response. Using the method, which is based on comparison of top single transcriptional features identified from random bootstraps of the full cohort as compared to a set of background shuffles, we are able to show that we remain powered for discovery of RNA response biomarkers despite the typically burdensome toll of multiple hypothesis correction at genome wide scale. Acknowledgment: Supported by Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant SU2C-AACR-DT17-15. Citation Format: Monica Arniella, Arvind Ravi, Chip Stewart, Sam Freeman, Mark Awad, Patrick Forde, Valsamo Anagnostou, Brian Henick, Jonathan Riess, Don Gibbons, Nathan Pennell, Vamsidhar Velcheti, Ignaty Leshchiner, Jaegil Kim, Subba Digumarthy, Mari Mino-Kenudson, John Heymach, Nir Hacohen, Naiyer Rizvi, Roy Herbst, Victor Velculescu, Julie Brahmer, Kurt Schalper, Pasi Jänne, Jedd Wolchok, Alice Shaw, Justin Gainor, Matthew Hellmann, Gad Getz. Integrative genomic analysis of checkpoint blockade in lung cancer: A multi-institution SU2C collaborative [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5902.

Gene signature of antigen processing and presentation machinery (APM) as highly predictive of response to checkpoint blockade in lung cancer and melanoma.

3121 Background: Treatment of non-small cell lung cancer (NSCLC) with immune checkpoint blockade (ICB) has resulted in striking clinical responses, but only in a subset of patients (pts), underscoring the need to identify genomic and molecular determinants of immune evasion. Limited data exist on the potential role of alterations in HLA Class I antigen processing and presentation machinery (APM) in mediating response to ICB. Methods: We conducted a retrospective cohort study analyzing transcriptional profiles from pre-treatment tumor samples of chemotherapy-refractory advanced NSCLC pts treated with ICB. RNA was analyzed using the AmpliSeq transcriptomic platform. An APM signature was generated utilizing 8 genes associated with antigen processing ( B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, HSP90AB1) and was examined for its association with response to therapy and progression-free and overall survival (PFS, OS). The APM signature was then evaluated in two independent melanoma cohorts treated with ICB. Results: We analyzed pre-treatment tumor samples from 51 advanced NSCLC pts treated with ICB, median age 64 (range 31-92), smokers (n = 43), adenocarcinoma (n = 31). There were 23 responders and 28 non-responders. The APM signature was significantly higher in responders compared to non-responders (average z-score 2.69 vs. -2.49, p = 0.0001). An APM score above the median value for the entire cohort was significantly associated with improved PFS (HR 0.24, 95% CI, 0.12-0.47, log-rank = 0.001) and OS (HR 0.34, 95% CI, 0.18-0.67, log-rank = 0.005). The APM score was significantly correlated with the well-validated T-cell-inflamed resistance gene expression profile (GEP) score (R2 = 0.32, p < 0.0001). However, the APM score demonstrated improved ability to predict response to ICB relative to the GEP score with AUCs of 0.83 and 0.69, respectively. In an independent cohort of 14 high-risk resectable stage III/IV melanoma pts treated with neoadjuvant anti-PD1 therapy, upregulation of genes involved in antigen processing was associated with improved disease free survival (HR: 0.08, 95% CI, 0.01-0.50, p = 0.0065). In an additional independent melanoma cohort of 28 metastatic pts treated with ICB, a higher APM score was associated with improved overall survival (HR 0.31, 95% CI, 0.09-0.89, log-rank = 0.044). Conclusions: Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma.

Checkpoint Blockade in Lung Cancer With Driver Mutation: Choose the Road Wisely.

Immune checkpoint blockade with PD-(L)1 antibodies has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Similarly, the identification and targeting of oncogene drivers in metastatic NSCLC has dramatically improved patient outcomes with an expanding list of potentially actionable alterations and targeted therapies. Many of these molecular aberrations are more common in patients with little or no smoking history and adenocarcinoma histology. Certain molecular subsets of NSCLC, though gaining greatly from targeted therapy approaches, may derive less benefit from immune checkpoint blockade. The optimal identification, targeting, and sequencing of targeted therapies, immunotherapy, and chemotherapy are essential to continue to improve patient outcomes in advanced NSCLC. Herein, we review the role of immunotherapy in locally advanced and metastatic disease for patients with actionable driver alterations. Never-smoking patients have a high probability of having lung cancer that harbors one of these molecular aberrations that can be matched to a tyrosine kinase inhibitor with greatly improved clinical outcomes. Some of these patients with driver mutations may derive less benefit from immune checkpoint inhibitor approaches (either alone or combined with chemotherapy), especially compared with smoking-associated NSCLC. Given that PD-1 blockade alone or with platinum-based chemotherapy is the de facto first-line therapy (depending on level of PD-L1 expression) for nontargetable metastatic NSCLC, we also review treatment in never-smoking patients for whom molecular testing results are pending and the likelihood of identifying a driver mutation is high.

A32 Evaluation of the Mutant KRAS-Driven NSCLC Tumor Immune Microenvironment Using Patient-Derived Cell Line Xenografts in a Humanized Mouse Preclinical Model for Development of New Immunotherapy Approaches

Tumor cell and tumor microenvironment (TME) features that influence the response to immune checkpoint blockade in lung cancer are incompletely defined. We wanted to develop preclinical models of lung cancer to explore the relationship of non-small cell lung cancer (NSCLC) molecular characteristics (oncogenotype such as mutant KRAS and LKB1/STK11, and mRNA expression profiles) to the human TME. We exploited the use of 8 (all KRAS mutant) molecularly characterized (whole-exome seq mutation and RNAseq analyses) patient-derived NSCLC lines grown as xenografts in vivo in humanized NSG-SGM3 mice in an effort to determine the effect of different NSCLCs on the immune landscape of lung cancer xenografts. The triple transgenic NSG-SGM3 (NSGS) mice express human IL3, GM-CSF, and SCF, which combine the features of the highly immunodeficient NOD scid gamma (NSG) mouse with cytokines that support the stable engraftment of human myeloid lineages and regulatory T-cell populations. Subcutaneous KRAS mutant-driven non-NSCLC xenografts grown in NSG-SGM3 mice “humanized” with CD34+ cord blood cells were subjected to immune landscape analysis through flow cytometry, multiplex immunohistochemistry, and cytokine analysis. The xenografts were also treated with various combinations of checkpoint inhibitors, radiation, and activation of the innate immune pathway with emricasan (pan caspase inhibitor). Our results show: that the 8 KRAS mutant NSCLCs each were associated with a different spectrum of human TME; 3 of the 8 xenografts had only 0.1% of immune cell infiltrates while other xenografts had 20% immune cell infiltrates; that tumor mutation burden (TMB, absolute mutation calls 233 to 2,076) is not predictive of CD8+ T-cell infiltration in KRAS mutant-driven NSCLC xenografts. In NSCLC xenografts with high CD8+ T-cell infiltrate, the CD8+ cells in the TME were not activated, resulting in limited responses to PD-1/PD-L1 therapy. However, stimulation of the cGAS-STING innate immune pathway with emricasan followed by radiation (15 cGy) resulted in dramatic antitumor response. NSCLC xenografts grown in “humanized” mice show great intertumor heterogeneity effects on the TME even within the KRAS mutant subgroup, and it is possible to demonstrate targeted therapy such as emricasan/radiation can lead to changes in improved antitumor responses.

Gene signatures of tumor inflammation and epithelial-to-mesenchymal transition (EMT) predict responses to immune checkpoint blockade in lung cancer with high accuracy

ObjectivesTreatment of non-small cell lung cancer (NSCLC) with immune checkpoint blockade (ICB) has resulted in striking clinical responses, but only in a subset of patients. The goal of this study was to evaluate transcriptional signatures previously reported in the literature in an independent cohort of NSCLC patients receiving ICB. Materials and methodsThis retrospective study analyzed transcriptional profiles from pre-treatment tumor samples of 52 chemotherapy-refractory advanced NSCLC patients treated with anti-PD1/PD-L1 therapy. Gene signatures based on published reports were created and examined for their association with response to therapy and progression-free and overall survival (PFS, OS). ResultsTwo signatures predicting response and outcomes were identified. One reflected the degree of immune infiltration and upregulation of interferon-gamma-induced genes. A second reflected the EMT status. Compared to those not responding to therapy, patients whose tumors responded to ICB had higher scores in an inflammatory gene signature (6.0 ± 2.9 vs -5.5 ± 3.4, p = 0.014) or a more epithelial phenotype (-1.7 ± 1.0 vs 2.1 ± 1.2, p = 0.016). Both signatures demonstrated a satisfactory predictive accuracy for response: AUC of 0.69 (95% CI: 0.54, 0.84) for the inflammatory and 0.70 (95% CI: 0.55, 0.85) for EMT signatures, respectively. A weighted score combining EMT and inflammatory signatures showed increased predictive value with AUC of 0.92 (95% CI: 0.85, 0.99). Kaplan-Meier curves for patients above and below the median combined score showed a significant separation for PFS and OS (all p < 0.01, log rank test). ConclusionsThe EMT/Inflammation signature score may be useful in directing checkpoint inhibitor therapy in lung cancer and suggests that reversal of EMT might augment efficacy of ICB.

MS31.05 Vaccination and Antibody-Based Therapy in Mesothelioma

The concept of antibody based therapy hints on two concepts, on the one hand precluding the function of the ligand it binds to, which is for instance the case in VEGF targeting antibodies. And on the other hand the induction of antibody dependent cellular toxicity (ADCC) which may be induced by these antibodies. The latter is caused by activation of the immune system after an antibody binds to its ligand. Here I will focus on the role of antibodies targeting the immune checkpoints. Immunotherapy is now considered a standard treatment in many malignancies. Also in mesothelioma, different antibodies are now being explored [Yap 2017]. The most clinically used type of immunotherapy in oncology are checkpoint inhibitors, mostly PD-(l)1 and CTLA-4 directed antibodies. Concerning the latter, a recently published randomised trial failed to show an benefit of the anti-CTLA-4 antibody tremilimumab, compared to placebo in second and third line treatment in mesothelioma [Maio 2017]. Small and single arm studies on PD-(l)1 have been presented and did show clinical meaningful responses in patients. However this was only present in a minority of patients [Lievense 2017]. The role of ADCC in the functioning of the antibodies is not well established nor investigated, but for instance a regulatory T-cell depletion due to CTLA-4 antibodies has been described. The lack of benefit in the majority of patients is ascribed to the absence of a tumor directed T-cell response present in the majority of mesothelioma patients [Aerts 2013, Yap 2017]. This lack of tumor directed T-cells is related to the immunosuppressive environment caused by mesothelioma. One way of increasing the tumor directed T-cell responses is via vaccination. However in thoracic malignancies the effects of peptide vaccinations were found to be rather limited again due to the immunosuppressive environment created by the tumor. Cellular vaccinations were found to be more effective in this setting [Dammeijer 2016]. In mesothelioma studies on cellular vaccination with dendritic cell vaccination have indeed shown that an increase in tumor directed T-cells can be achieved with clinically relevant responses [Le 2012, Peikert 2016, Aerts 2018]. This concept is now taken forward in a large randomised trial comparing dendritic cell vaccination with best supportive care as maintenance treatment after chemotherapy in patients with mesothelioma. In conclusion antibody based therapy and vaccination hold promise in mesothelioma, and given the dismal prognosis of these patients these options should be investigated and explored further. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Maio M, Scherpereel A, Calabrò L, Aerts J, Cedres Perez S, Bearz A, Nackaerts K, Fennell DA, Kowalski D, Tsao AS, Taylor P, Grosso F, Antonia SJ, Nowak AK, Taboada M, Puglisi M, Stockman PK, Kindler HL. Lancet Oncol. 2017 Sep;18(9):1261-1273 A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Le DT, Brockstedt DG, Nir-Paz R, Hampl J, Mathur S, Nemunaitis J, Sterman DH, Hassan R, Lutz E, Moyer B, Giedlin M, Louis JL, Sugar EA, Pons A, Cox AL, Levine J, Murphy AL, Illei P, Dubensky TW Jr, Eiden JE, Jaffee EM, Laheru DA.Clin Cancer Res. 2012 Feb 1;18(3):858-68. Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human. Aerts JGJV, de Goeje PL, Cornelissen R, Kaijen-Lambers MEH, Bezemer K, van der Leest CH, Mahaweni NM, Kunert A, Eskens FALM, Waasdorp C, Braakman E, van der Holt B, Vulto AG, Hendriks RW, Hegmans JPJJ, Hoogsteden HC. Clin Cancer Res. 2018 Feb 15;24(4):766-776 Checkpoint Blockade in Lung Cancer and Mesothelioma.Lievense LA, Sterman DH, Cornelissen R, Aerts JG. Am J Respir Crit Care Med. 2017 Aug 1;196(3):274-282. Efficacy of Tumor Vaccines and Cellular Immunotherapies in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Dammeijer F, Lievense LA, Veerman GD, Hoogsteden HC, Hegmans JP, Arends LR, Aerts JG. J Clin Oncol. 2016 Sep 10;34(26):3204-12. Harnessing the Power of the Host: Improving Dendritic Cell Vaccines for Malignant Pleural Mesothelioma. Peikert T, Sterman DH. Am J Respir Crit Care Med. 2016 May 1;193(9):943-5 Novel insights into mesothelioma biology and implications for therapy. Yap TA, Aerts JG, Popat S, Fennell DA. Nat Rev Cancer. 2017 Jul 25;17(8):475-488. Tumor-specific cytotoxic T cells are crucial for efficacy of immunomodulatory antibodies in patients with lung cancer. Aerts JG, Hegmans JP. Cancer Res. 2013 Apr 15;73(8):2381-2382 Mesothelioma, vaccination, dendritic cell

Abstract CT077: Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227

Abstract Background: Nivo + ipi showed promising clinical activity and tolerability as 1L tx for advanced NSCLC in a phase 1 study. Tumor mutation burden (TMB) has emerged as an important biomarker for benefit of immune checkpoint blockade in lung cancer. CheckMate 227 (NCT02477826) is a large, open-label, phase 3 study of 1L nivo + ipi, nivo, or nivo + PT-DC vs PT-DC in advanced NSCLC. A preplanned co-primary endpoint was based on TMB to evaluate progression-free survival (PFS) of nivo + ipi vs PT-DC. This is the first phase 3 study to evaluate TMB as a predictive biomarker for immunotherapy as a co-primary endpoint. We report initial results from Part 1 of the study. Methods: Patients (pts; N=1739) with chemotherapy-naive, histologically confirmed stage IV or recurrent NSCLC, ECOG PS 0−1, and no known sensitizing EGFR/ALK mutations were enrolled in 2 groups: PD-L1 ≥1% or PD-L1 &amp;lt;1%. Pts with ≥1% tumor PD-L1 expression were randomized 1:1:1 to nivo + ipi, nivo, or PT-DC; pts with &amp;lt;1% tumor PD-L1 expression were randomized 1:1:1 to nivo + ipi, nivo + PT-DC, or PT-DC. Tx regimens were nivo 3 mg/kg Q2W + ipi 1 mg/kg Q6W, nivo 240 mg Q2W, or nivo 360 mg Q3W with PT-DC. Pts were treated until disease progression or unacceptable toxicity, up to 2 y. TMB was determined from tumor tissue using the validated FoundationOne CDx™ assay (Foundation Medicine, Inc.). Co-primary endpoints were overall survival (OS) for nivo + ipi vs PT-DC in pts with PD-L1-selected tumors and PFS (blinded independent central review) for nivo + ipi vs PT-DC in pts with TMB ≥10 mutations (mut)/Mb. Results: Baseline characteristics were similar in pts with evaluable TMB and all randomized pts and were balanced between nivo + ipi and PT-DC arms. Minimum follow-up was 11.5 mo. PFS was significantly longer with nivo + ipi vs PT-DC in pts with TMB ≥10 mut/Mb (HR=0.58 [97.5% CI: 0.41, 0.81]; P=0.0002); results were broadly consistent across subgroups, including PD-L1 and histology. The HR for PFS was 1.07 (95% CI: 0.84, 1.35) in pts with TMB &amp;lt;10 mut/Mb. In all randomized pts, the HR for PFS with nivo + ipi vs PT-DC was 0.83 (95% CI: 0.72, 0.96). Objective response rate was 45.3% with nivo + ipi vs 26.9% with PT-DC in pts with TMB ≥10 mut/Mb; median duration of response (95% CI) was not reached (12.2 mo, NR) vs 5.4 (4.2, 6.9) mo, respectively. In treated pts, grade 3-4 treatment-related adverse events rates were 31.3% and 36.1% with nivo + ipi and PT-DC, respectively. Part 1 continues for final OS in the PD-L1-selected co-primary population. Conclusions: CheckMate 227 met its co-primary endpoint of significantly prolonged PFS with 1L nivo + ipi vs PT-DC in NSCLC with TMB ≥10 mut/Mb regardless of PD-L1 expression. Safety was consistent with previous reports of 1L nivo + ipi for this dose regimen. These results validate the benefit of dual immune checkpoint blockade and the role of TMB as a biomarker to select pts in 1L NSCLC. Citation Format: Matthew D. Hellmann, Tudor Eliade Ciuleanu, Adam Pluzanski, Jong Seok Lee, Gregory Otterson, Clarisse Audigier-Valette, Elisa Minenza, Helena Linardou, Sjaak Burgers, Pamela Salman, Hossein Borghaei, Suresh S. Ramalingam, Julie Brahmer, Martin Reck, Kenneth J. O'Byrne, William J. Geese, George Green, Han Chang, Joseph D. Szustakowski, Prabhu Bhagavatheeswaran, Diane Healey, Yali Fu, Faith Nathan, Luis Paz-Ares. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT077.

Highlights of This Issue

Cytotoxic chemotherapy is known to induce pro-metastatic changes resulting in poor survival. Harney, Karagiannis and colleagues show that the TIE2 kinase inhibitor rebastinib reduces primary tumor growth and metastasis in a preclinical breast cancer model, and is synergistic in combination with taxane chemotherapy. They demonstrate that taxane chemotherapy is associated with metastasis through recruitment of tumor-infiltrating TIE2+ macrophages that promote angiogenesis, TMEM-dependent tumor cell intravasation and lung metastasis, events reversed by rebastinib. In an adjuvant study, rebastinib in combination with eribulin led to a significant improvement in survival compared to single agent eribulin. Thus, rebastinib is a promising therapy for inhibiting pro-metastatic microenvironments in cancer patients.Epithelial-mesenchymal transition (EMT) plays an important role in cancer progression, relapse, and metastasis. By using the myxobacterial natural compound Archazolid A as a tool, Merk and colleagues discovered the V-ATPase, a multimeric proton pump that regulates lysosomal acidification, as a crucial player in EMT and Archazolid A as a promising strategy to block EMT through the inhibition of VATPase. Mechanistic studies found that Archazolid A disrupts the process of EMT, the generation of tumor-initiating cells and the turnover of E-cadherin. These evidences suggest that Archazolid A is a promising cancer therapeutic agent that is worth further investigation.The extracellular matrix limits the efficacy of chemotherapy in pancreatic ductal adenocarcinoma (PDA) in part by active cell signaling. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds fibrillar collagens and is expressed by PDA tumor cells. Aguilera, Huang and colleagues demonstrate that pharmacologic inhibition of DDR1 with the small molecule 7rh substantially improves the efficacy of standard chemotherapy in robust preclinical models of PDA in the absence of additional normal tissue toxicity. These results suggest that inhibition of collagen signaling with 7rh has the potential to improve efficacy of conventional chemotherapy in PDA patients.High tumor mutational burden (TMB) predicts response to checkpoint blockade in lung cancer and melanoma. Our study demonstrates that TMB can be used to predict response to checkpoint blockade independent of tumor histology. Higher TMB was independently and linearly associated with improved response rates and progression-free survival on multivariate analysis. Response rates were 67% with very high TMB (&gt;50 mutations/mb). Further, the median TMB was significantly higher for patients who responded to anti-PD-1/PD-L1 monotherapy compared to those who did not. Interestingly, benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB.

Checkpoint Blockade in Lung Cancer and Mesothelioma.

In the last decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors (CPIs), antibodies that unleash the antitumor immune response. After the success in melanoma, numerous clinical trials are being conducted investigating CPIs in lung cancer and mesothelioma. The programmed death protein (PD) 1-PD ligand 1/2 pathway and cytotoxic T lymphocyte-associated protein 4 are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer, anti-PD-1 antibodies have become part of the approved treatment arsenal. In small cell lung cancer and mesothelioma, the efficacy of checkpoint inhibition has not yet been proven. In this Concise Clinical Review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Because response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of CPIs. To increase efficacy, multiple clinical trials investigating the combination of cytotoxic T lymphocyte-associated protein 4 inhibitors and PD-1/PD ligand 1 blockade in lung cancer and mesothelioma are being conducted. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential for moving forward.

The Era of Checkpoint Blockade in Lung Cancer: Taking the Brakes Off the Immune System.

Despite recent advances with targeted kinase inhibitors and better-tolerated chemotherapy, the treatment of metastatic non-small-cell lung cancer remains suboptimal. One recent advance that holds great promise is immunotherapy-an approach that enhances a patient's immune system to better recognize and react to abnormal cells. The most successful immunotherapeutic strategy to date uses antibodies to block inhibitory receptors (also called "checkpoints") that are up-regulated on the T cells that infiltrate the tumor. Two examples of such molecules are programmed cell death-1 (PD1) and cytotoxic T lymphocyte-associated protein-4. With more than a dozen clinical trials in non-small-cell lung cancer completed, checkpoint blockade targeting PD1 has demonstrated durable responses and superior survival compared with traditional chemotherapy agents when used as first-line therapy in individuals with more than 50% PD1 ligand (PDL1) expression by immunohistochemical staining and as second-line therapy independent of PDL1 status. Antibodies to PDL1 have shown similar activity. Combinations of anti-PD1 and anti-PDL1 with anti-cytotoxic T lymphocyte-associated protein-4 and chemotherapy are being actively tested. These agents have generally tolerable safety profiles; pneumonitis, although rare, remains the most feared adverse effect. PDL1 expression on tumors has been identified as a biomarker predictive of response. Although PDL1 expression has traditionally been measured on resected tumor specimens, the pulmonologist has a growing role in obtaining samples for testing via minimally invasive means.

Abstract NG01: Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer

Abstract NG01: Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer

Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

Purpose: Antibodies that target immune checkpoint molecules have demonstrated significant and durable clinical benefit through re-activation and proliferation of pre-existing tumor-infiltrating CD8+ T cells in a broad range of tumor types including lung cancer. Detailed characterization of T cell dynamics at clonal levels using nextgeneration T cell receptor (TCR) sequencing in large cohorts of lung cancer patients is yet reported.Methods: We performed TCR sequencing of peripheral blood samples (and some tumors) obtained from 27 lung cancer patients undergoing single/combined immune checkpoint blockade therapies.Results: In one responder, we found expansion of a single T cell clone (approximately 20% of the all TCR reads) in a metastatic subcutaneous lesion that showed pathologic complete response on day 17 of treatment. The same TCR CDR3 sequence was detected in 6.1% of TCR reads in the peripheral blood prior to treatment initiation and the expansion remained persistent in peripheral blood at 21.0% at week 10 and 24.3% at week 48. In other patients who showed durable response, we also found persistent oligoclonal T cell expansion in their peripheral blood which was not observed in non-responders even while they remained on therapy.Conclusion: We found sustained expansion of oligoclonal T cell clones in lung cancer patients who had durable response to immune checkpoint blockade. This suggests possible use of longitudinal TCR sequencing to assist clinical decision-making, assess synergism with other agents, and most importantly facilitate rational development of alternative treatment strategies for non-responders.

Primary and adaptive resistance to checkpoint blockade in lung cancer

In CT-based lung cancer screening and incidentally detected indeterminate pulmonary nodules, radiomics has shown value in improving diagnostic accuracy to discriminate cancer from benign pulmonary nodules. We have analyzed data from the National Lung Screening Trial, NLST, to identify subjects with cancerous and benign nodules, and have organized them into cohorts based on their screening history. Patients who are diagnosed with cancer following a prior nodule-negative screen have significantly worse outcome than patients who develop cancer following a prior nodule-positive/ cancer-negative screen. In cohorts of patients with nodules not diagnosed as cancer in the first screen, we have identified significant radiomic features that can discriminate those who will subsequently develop cancer from those that remain benign with an accuracy of 80%, and this can be the basis for a “radiomics risk score” to predict subsequent cancer development. However, even the seemingly large “big data” NLST data set is underpowered once cohorts are assembled with similar histories, and co-variates are accounted for. Solutions to the problem of generating sufficiently powered data sets include capturing the radiomic data at the point of care (i.e. by the radiologists) and inter-institutional sharing of images, data, features and algorithms, which have yet to be reliably implemented.