- Email: [email protected]
Neoantigen profile of hepatocellular carcinoma reveals its correlation with tumour progression and clonal evolution
abstracts
Annals of Oncology
NCT03757936) combo-immunotherapy in advanced solid tumours; HLX10-002NSCLC301(Registration Number: NCT03952403) combo-immunotherapy in NSCLC. Legal entity responsible for the study: Shanghai Henlius Biotech, Inc; Taiwan Henlix Biotech., Co.,LTD. Funding: Shanghai Henlius Biotech, Inc. Disclosure: T.Y. Chao: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD.
/ Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Sirtex Medical; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lily; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Ipsen. D. Tai: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Ipsen; Research grant / Funding (self): Sirtex. J. Lee: Advisory / Consultancy: Ipsen; Research grant / Funding (self): Bayer. All other authors have declared no conflicts of interest.
326P 325P
Association between immune-related adverse events and efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma
L. Wong1, A. Ang1, K. Ng2, S.H. Tan3, S.P. Choo2, D. Tai2, J. Lee2 1 Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore (NUS), Singapore, 2Division of Medical Oncology, National Cancer Centre Singapore (NCCS), Singapore, 3Biostatistics and Epidemiology Unit, National Cancer Centre Singapore (NCCS), Singapore Background: More patients are receiving immune checkpoint inhibitors (ICI) for advanced hepatocellular carcinoma (HCC). We aim to explore whether an association exists between the presence of irAE and the efficacy of ICI in advanced HCC. Methods: We conducted a retrospective review of patients with advanced HCC who received ICIs between May 2015 - Nov 2018 at our centre. IrAE were graded according to the Common Terminology Criteria for Adverse Events v4.0. Response to ICI was evaluated based on RECIST v1.1 criteria. Results: Of the 114 patients studied, median age was 67.3yrs (23.5-84.9) and 78 (89.7%) were male. 68.4% experienced irAE of any grade (n ¼ 78), with 21.8% being grade 3-4 (n ¼ 17). None were grade 5. Patients in the any-irAE group had comparable ORR and significantly higher DCR than the no-irAE group (23.4 vs 10.0%, p ¼ 0.118 and 64.9 vs 30.0%, p ¼ 0.001). Median PFS and OS in the any-irAE group were significantly longer than the no-irAE group (4.0 vs 1.4mths, p < 0.001 and 16.4 vs 3.3mths, p < 0.001, respectively). Comparing against the no-irAE group, the G1/2-irAE and G3/ 4-irAE groups had significantly longer median PFS (G1/2 (3.7mths) vs no irAE (1.4mths), p < 0.001; G3/4 (11.6mths) vs. no irAE (1.4mths), p ¼ 0.001) and OS (G1/2 (14.5mths) vs no irAE (3.3mths), p < 0.001; G3/4 (20.9mths) vs. no irAE (3.3mths), p < 0.001). Multivariate analysis showed that the presence of irAE was associated with longer median PFS [HR: 0.52 (95% CI 0.31-0.90), p ¼ 0.018] and OS [HR: 0.38 (95% CI 0.20-0.71), p ¼ 0.003].
Table: 325P Cox regression analysis of the association between irAE and survival outcomes
PFS Any Hepatobiliary irAE Skin irAE Gastrointestinal irAE Endocrine irAE Lung irAE OS Any Hepatobiliary irAE
Univariate hazard ratio (95% CI)
p-value
0.37 (0.23-0.59) 0.75 (0.44-1.26) 0.29 (0.18-0.46) 0.76 (0.45-1.27) 0.27 (0.08-0.91) 0.24 (0.06-0.97)
<0.001 0.28 <0.001 0.29 0.035 0.046
0.27 (0.16-0.47) 0.56 (0.28-1.12)
<0.001 0.10
ix110 | Immunotherapy of cancer
Multivariate hazard ratio* (95% CI)
p-value
0.52 (0.31-0.90)
0.018
0.32 (0.20-0.52)
<0.001
0.34 (0.10-1.18) 0.29 (0.07-1.20)
0.091 0.087
0.38 (0.20-0.71)
0.003
Autologous V gamma 9 V delta 2 T cell therapy to target Epstein Barr Virus (EBV)-related malignancies
E. Rozali1, C.L.-L. Chiang1, P.W.-W. Wang1, H.C. Toh2 1 Division of Medical Oncology, NCCS - National Cancer Centre Singapore, Singapore, 2 Medical Oncology, NCCS - National Cancer Centre Singapore, Singapore Background: Analysis of 18,000 human tumors across 39 cancers identified tumor infiltrating cd T cells as the most favorable prognostic immune population. Sharing both innate and adaptive immune properties, cd T cells are an attractive candidate for direct adoptive cellular therapy as well as utilizing their professional antigen presenting cell (APC) property for ex vivo expansion of antigen-specific CD4þand CD8þ T cells for subsequent adoptive cellular therapy. Methods: Here, we report a Good Manufacturing Method (GMP) expansion protocol of Vc9Vd2 T cells from human PBMCs and its functional and transcriptomic characterization. Results: Following cytokine optimization experiments, we found that some combinations of IL-2, IL-15 and IL-21 led to optimal antigen presentation and effector functions. cd T cells produced in the presence of IL-2 alone or in combination with other cytokines showed increased APC markers compared to IL-15 combinations. In vitro, EBV-LMP2 peptide-pulsed cd T cells primed a more robust naı¨ve CD3þ T cell proliferation than monocyte-derived Dendritic Cells (moDC). Importantly, EBV-LMP2 peptide-pulsed cd T cells stimulated less T regulatory cells and exhausted CD8þ and CD4þ T cells compared to moDCs.Through gene expression profiling, we demonstrated that cd T cells express enhanced levels of markers of cross presentation pathway compared to moDCs which may explain the cross presentation phenotype. Finally, we demonstrated the potential of EBV-LMP2 peptide-pulsed Vc9Vd2 T cells as a therapeutic cancer vaccine in an autologous EBV-lymphoblastoid cell line tumor model in vivo. This therapeutic intervention resulted in increased tumor infiltration of gd, CD8þ and CD4þ T cells and improved control of primary tumor growth and metastasis of EBV LCLs tumor model in vivo. Conclusions: In summary, we demonstrated in our pre-clinical study cd T cell APC and effector functions in vitro and in vivo, indicating the potential of cd T cells as therapeutic immunotherapy against EBV-positive cancers. Legal entity responsible for the study: The authors. Funding: Tessa Therapeutics. Disclosure: P.W.-W. Wang: Advisory / Consultancy: Tessa Therapeutics. H.C. Toh: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Tessa Therapeutics. All other authors have declared no conflicts of interest.
327P
Neoantigen profile of hepatocellular carcinoma reveals its correlation with tumour progression and clonal evolution
X. Liu, Z. Li, Z. Cai, G. Chen, J. Liu Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian Medical University, Fuzhou, China Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China with poor prognosis. Recently, personalized neoantigen-based immunotherapy has been reported to induce robust anti-tumor immune responses to facilitate tumor rejection in several solid tumors. However, whether it possess therapeutic potential in HCC still remain unclear. Thus, a systemic understanding of neoantigen burden (TNB) in HCC microenvironment is in need. Methods: HCC and matched peritumor tissue collected from 59 HCC patients were subjected to DNA and RNA sequencing for identifying tumor associated neoantigens. Then the association between neoantigens and clinical features, immune signatures, as well as clonal evolution patterns in HCC were evaluated. Results: In enrolled HCC patients, a median of 106 somatic mutations and 15 neoantigens were identified in each patient. TNB was significantly correlated with tumor somatic mutation burden (R2 ¼ 0.893, P ¼ 3.0 10ˆ-24). Furthermore, the clinicopathological analysis revealed that patients with higher TNB was characterized with older age (p ¼ 0.006), decreased tumor size (p ¼ 0.020) and lower recurrence rate (p ¼ 0.019). Additionally, TNB was also significantly associated with relapse free survival (P ¼ 0.033) and overall survival (P ¼ 0.022) in HCC patients. Surprisingly, HCC tumor with high immune cell infiltration were more likely to have no tumor envelope
Volume 30 | Supplement 9 | November 2019
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C.L. Ho: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. W.H. Cheng: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. C.L. Chang: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. Y.Y. Hsieh: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S.F. Lin: Full / Part-time employment: Taiwan Henlix Biotech., Co., LTD. T.C. Hsieh: Full / Part-time employment: Taiwan Henlix Biotech., Co., LTD. E. Liu: Full / Part-time employment: Taiwan Henlix Biotech., Co., LTD.
Conclusions: The presence of irAE in advanced HCC patients treated with ICI could possibly predict better response and survival outcomes. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: S.P. Choo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant
abstracts
Annals of Oncology
328P
A retrospective analysis of patients with non-small cell lung cancer who developed drug-induced lung disorder by immune checkpoint inhibitors
F. Hayashi1, H. Taniguchi1, S. Takayuki1, Y. Umeyama1, Y. Dotsu1, H. Gyotoku1, H. Senju1, S. Takemoto1, H. Yamaguchi1, S. Ono2, H. Tomono2, M. Shimada2, H. Soda2, M. Fukuda3, M. Hiroshi1 1 Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan, 2 Department of Respiratory Medicine, Sasebo City General Hospital, Sasebo, Japan, 3 Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan Background: The presence of the immune-related adverse events (irAEs) has been reported as a preferred marker of the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients. However, there are only a few studies that focused on the relationship between the efficacy of ICIs and the severity or a highresolution computed tomography (HRCT) scan pattern of drug-induced lung disorder (DILD). Methods: We conducted a retrospective study of patients with NSCLC who were treated with ICIs between January 2016 and June 2019 in our institution. We especially focused on the patients who developed DILD during ICIs treatment, and analyzed the clinical information and HRCT pattern of DILD to investigate the prognosis of patients who developed DILD. Assessment of treatment response was evaluated using the response evaluation criteria in solid tumors version 1.1. Severity of DILD was classified by grade according to pneumonitis in Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: Total 182 patients were enrolled, including 20 patients who received chemotherapy with ICIs. Among the 182 patients, 32 patients (17.6 %) developed DILD and CTCAE grade 1/2/3/4/5 were 10/7/9/2/4 patients, respectively. The median progression-free survival was 100 and 93 days, (P ¼ 0.324, Log-rank Test) and overall survival was 415 and 501 days (P ¼ 0.0951, Log-rank Test) in patients with or without DILD, respectively. The median period from the first ICI treatment to onset of DILD was significantly shorter in the Grade 3/4/5 group than Grade 1/2 group; 22 and 72.5 days, respectively (P ¼ 0.029, Mann-Whitney U test). Analyzing HRCT findings according to ATS/ERS/JRS/ALAT GUIDLINE, patients who presented consolidation had better prognosis than those with comprehensive GGO. In 4 patients with Grade 5 pneumonitis developed with comprehensive GGO and the period from onset of DILD to death was extremely short; median 2 days. Conclusions: Our retrospective study suggested that development of DILD was not preferred in terms of prognosis in NSCLC patients. Physician should be alerted for the patients who developed early-onset, severe DILD with comprehensive GGO during ICI treatment. Legal entity responsible for the study: Hiroyuki Yamaguchi. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
329P
High-level expression of HDAC10 is associated with PD-L1 expression and poor prognosis in patients with non-small cell lung cancer receiving pulmonectomy
Results: Our results showed that HDAC10 expression level in cancer tissue was significantly higher than that in para-cancer tissue. HDAC10 expression level was also positively correlated with the PD-L1 expression level (r ¼ 0.213, P < 0.05). Multivariate analysis showed that expression level of HDAC10 was an independent prognostic factor and HDAC10 overexpression indicated a poor overall survival in pulmonary carcinoma (r ¼ 0.540, P < 0.001). Conclusions: To our knowledge, this is the first time to associate HDAC10 with lung cancer patients’ survival status and to explore correlation between HDAC10 and PDL1 expression. Our findings indicated that HDAC10 could be a valuable predicting marker that might provide help for clinicians to design effective therapeutic modality against NSCLC. Treatment response might be especially prominent in patients overexpressing HDAC10 in cancer cells. Our study suggest clinical relevance for the immune effects of HDAC10 and provide a rationale for the clinical evaluation of PD-L1 blockade in combination with HDAC10 inhibition. Legal entity responsible for the study: The First Affiliated Hospital of Jinzhou Medical University. Funding: This study was supported by the CSCO-HANSOH PHARMA Science Foundation of China (number Y-HS2019-29). Disclosure: The author has declared no conflicts of interest.
331P
S. Ono1, H. Senju2, H. Taniguchi2, H. Tomono1, M. Shimada1, F. Hayashi2, T. Suyama2, N. Honda2, Y. Umeyama2, Y. Dotsu2, H. Gyotoku2, S. Takemoto2, H. Yamaguchi2, M. Fukuda3, H. Soda1, H. Mukae2 1 Department of Respiratory Medicine, Sasebo City General Hospital, Sasebo, Japan, 2 Department of Respiratory Medicine, Nagaski University Hospital, Nagasaki, Japan, 3 Clinical Oncology Center, Nagaski University Hospital, Nagasaki, Japan Background: Previous reports suggested that development of an immune-related adverse event (irAE), including thyroid disorder (TD), is associated with better outcomes of immune checkpoint inhibitor (ICI) therapy. Though TD has been reported most frequently as an irAE, it has not been well analyzed compared to life-threatening adverse events such as interstitial lung disease or colitis. Methods: We conducted a chart-based retrospective analysis of patients (Pts) with advanced or recurrent non-small cell lung cancer (NSCLC), who are treated with monotherapy using nivolumab, pembrolizumab, or atezolizumab between January 2016 and June 2019 in two facilities in Japan. TD emerging after the first treatment with an ICI was considered as an irAE. Tumor response was evaluated with Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) on ICIs were evaluated with Kaplan-Meier method. The correlations between time to onset of TD and PFS or OS were analyzed with Spearman’s rank correlation coefficient. Results: In total, 164 consecutive Pts were enrolled. The median age was 68 (range: 3484) years, and 40 (24.4%) were women. TD of any grade occurred in 26 Pts (15.8%); 11/15/0/0/0 cases were classified as Grade 1/2/3/4/5, respectively, according to Common Terminology Criteria for Adverse Events version 5.0. Onset of TD ranged from 6 to 455 (median: 77.5) days after the first treatment with an ICI. Objective response rates in Pts with and without TD were 28.0% and 18.1%; disease control rates were 68.0% and 50.7%, respectively. Median PFS and OS were significantly longer in Pts with TD (PFS: 226 vs 100 days, p ¼ 0.029; OS: not reached vs 434 days, p ¼ 0.050, log-rank test). Among TD Pts, however, a positive correlation between time to onset of TD and PFS was identified (p ¼ 0.0015). Significantly shorter PFS was observed in Pts with earlier TD onset, especially within 30 days, compared to Pts with later TD onset (median PFS: 72.5 vs 329 days, p ¼ 0.00096, log-rank test). Conclusions: Development of TD caused by ICIs was associated with longer PFS. Nevertheless, the prognosis of Pts with early onset of TD was poor. This study suggested that physicians should consider the onset of TD in Pts using ICIs. Legal entity responsible for the study: Hiroyuki Yamaguchi. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
X. Liu Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China Background: Recent studies showed that stimulation of HDACs could induce PD-1 dynamic expression on DCs, macrophages, colonic stromal cells, and cancer cells. Surprisingly, it is little is known about the specific expression of important HDAC10 in NSCLC tissue. In this study, we evaluated the expression level of HDAC10 and the correlation of HDAC10 and PD-L1 in NSCLC tissues and analyzed the predicting role of HDAC10 in cancer cells on postoperative survival in NSCLC patients receiving pulmonary lobectomy. Methods: A total of 180 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection between April 2004 and August 2009 were enrolled. All the patients had integrated clinicopathological records and follow-up data. HDAC10 and PD-L1 expression on NSCLC samples were determined by using immunohistochemistry.
Volume 30 | Supplement 9 | November 2019
A retrospective analysis of immune checkpoint therapy in patients with non-small cell lung cancer: Focus on thyroid disorder
332P
Analyse the association between adverse events (AEs) and survival in patients treated with immune checkpoint inhibitors (ICIs)
C-Y. Cheng1, P-J. Su2, K-C. Chang3, T-C. Tsai3, H-Y. Chen3, S-T. Deng3, W-C. Chang4 Pharmacy, Chang Gung Medical Foundation - Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan, 2Medical Oncology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, 3Pharmacy, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan, 4Medical Oncology, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
1
Background: ICIs with a programmed death protein 1 (PD-1) or programmed death protein ligand 1 (PD-L1) antibodies have shown survival benefits for various metastatic cancer patients. However, some patients treated with ICIs may suffer from AEs. We investigated the association between AEs and survival in metastatic cancer patients treated with PD-1/PD-L1 inhibitors.
doi:10.1093/annonc/mdz438 | ix111
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(P ¼ 0.027) and resulted in shorter overall survival time after surgery (P ¼ 0.025); the patients with lower immune cell signatures related to antigen-processing have relatively higher TNB in HCC. Meanwhile, clonal evolution analysis revealed that the clonal mutations were more likely to be neoantigens ( P ¼ 9.2 10ˆ-5) than subclonal mutations, suggesting higher immunogenicity for clonal mutations. And tumors with higher proportion of neoantigens in clonal mutations were more likely to involved in clonal evolution, which may due to the immunoediting of neoantigens (P ¼ 0.002). Conclusions: Our results demonstrated that neoantigens play an important role in tumor clonal evolution and immune response in HCC, which could provide insights for future HCC immunotherapy. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
NCT03757936) combo-immunotherapy in advanced solid tumours; HLX10-002NSCLC301(Registration Number: NCT03952403) combo-immunotherapy in NSCLC. Legal entity responsible for the study: Shanghai Henlius Biotech, Inc; Taiwan Henlix Biotech., Co.,LTD. Funding: Shanghai Henlius Biotech, Inc. Disclosure: T.Y. Chao: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD.
/ Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Sirtex Medical; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lily; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Ipsen. D. Tai: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Ipsen; Research grant / Funding (self): Sirtex. J. Lee: Advisory / Consultancy: Ipsen; Research grant / Funding (self): Bayer. All other authors have declared no conflicts of interest.
326P 325P
Association between immune-related adverse events and efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma
L. Wong1, A. Ang1, K. Ng2, S.H. Tan3, S.P. Choo2, D. Tai2, J. Lee2 1 Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore (NUS), Singapore, 2Division of Medical Oncology, National Cancer Centre Singapore (NCCS), Singapore, 3Biostatistics and Epidemiology Unit, National Cancer Centre Singapore (NCCS), Singapore Background: More patients are receiving immune checkpoint inhibitors (ICI) for advanced hepatocellular carcinoma (HCC). We aim to explore whether an association exists between the presence of irAE and the efficacy of ICI in advanced HCC. Methods: We conducted a retrospective review of patients with advanced HCC who received ICIs between May 2015 - Nov 2018 at our centre. IrAE were graded according to the Common Terminology Criteria for Adverse Events v4.0. Response to ICI was evaluated based on RECIST v1.1 criteria. Results: Of the 114 patients studied, median age was 67.3yrs (23.5-84.9) and 78 (89.7%) were male. 68.4% experienced irAE of any grade (n ¼ 78), with 21.8% being grade 3-4 (n ¼ 17). None were grade 5. Patients in the any-irAE group had comparable ORR and significantly higher DCR than the no-irAE group (23.4 vs 10.0%, p ¼ 0.118 and 64.9 vs 30.0%, p ¼ 0.001). Median PFS and OS in the any-irAE group were significantly longer than the no-irAE group (4.0 vs 1.4mths, p < 0.001 and 16.4 vs 3.3mths, p < 0.001, respectively). Comparing against the no-irAE group, the G1/2-irAE and G3/ 4-irAE groups had significantly longer median PFS (G1/2 (3.7mths) vs no irAE (1.4mths), p < 0.001; G3/4 (11.6mths) vs. no irAE (1.4mths), p ¼ 0.001) and OS (G1/2 (14.5mths) vs no irAE (3.3mths), p < 0.001; G3/4 (20.9mths) vs. no irAE (3.3mths), p < 0.001). Multivariate analysis showed that the presence of irAE was associated with longer median PFS [HR: 0.52 (95% CI 0.31-0.90), p ¼ 0.018] and OS [HR: 0.38 (95% CI 0.20-0.71), p ¼ 0.003].
Table: 325P Cox regression analysis of the association between irAE and survival outcomes
PFS Any Hepatobiliary irAE Skin irAE Gastrointestinal irAE Endocrine irAE Lung irAE OS Any Hepatobiliary irAE
Univariate hazard ratio (95% CI)
p-value
0.37 (0.23-0.59) 0.75 (0.44-1.26) 0.29 (0.18-0.46) 0.76 (0.45-1.27) 0.27 (0.08-0.91) 0.24 (0.06-0.97)
<0.001 0.28 <0.001 0.29 0.035 0.046
0.27 (0.16-0.47) 0.56 (0.28-1.12)
<0.001 0.10
ix110 | Immunotherapy of cancer
Multivariate hazard ratio* (95% CI)
p-value
0.52 (0.31-0.90)
0.018
0.32 (0.20-0.52)
<0.001
0.34 (0.10-1.18) 0.29 (0.07-1.20)
0.091 0.087
0.38 (0.20-0.71)
0.003
Autologous V gamma 9 V delta 2 T cell therapy to target Epstein Barr Virus (EBV)-related malignancies
E. Rozali1, C.L.-L. Chiang1, P.W.-W. Wang1, H.C. Toh2 1 Division of Medical Oncology, NCCS - National Cancer Centre Singapore, Singapore, 2 Medical Oncology, NCCS - National Cancer Centre Singapore, Singapore Background: Analysis of 18,000 human tumors across 39 cancers identified tumor infiltrating cd T cells as the most favorable prognostic immune population. Sharing both innate and adaptive immune properties, cd T cells are an attractive candidate for direct adoptive cellular therapy as well as utilizing their professional antigen presenting cell (APC) property for ex vivo expansion of antigen-specific CD4þand CD8þ T cells for subsequent adoptive cellular therapy. Methods: Here, we report a Good Manufacturing Method (GMP) expansion protocol of Vc9Vd2 T cells from human PBMCs and its functional and transcriptomic characterization. Results: Following cytokine optimization experiments, we found that some combinations of IL-2, IL-15 and IL-21 led to optimal antigen presentation and effector functions. cd T cells produced in the presence of IL-2 alone or in combination with other cytokines showed increased APC markers compared to IL-15 combinations. In vitro, EBV-LMP2 peptide-pulsed cd T cells primed a more robust naı¨ve CD3þ T cell proliferation than monocyte-derived Dendritic Cells (moDC). Importantly, EBV-LMP2 peptide-pulsed cd T cells stimulated less T regulatory cells and exhausted CD8þ and CD4þ T cells compared to moDCs.Through gene expression profiling, we demonstrated that cd T cells express enhanced levels of markers of cross presentation pathway compared to moDCs which may explain the cross presentation phenotype. Finally, we demonstrated the potential of EBV-LMP2 peptide-pulsed Vc9Vd2 T cells as a therapeutic cancer vaccine in an autologous EBV-lymphoblastoid cell line tumor model in vivo. This therapeutic intervention resulted in increased tumor infiltration of gd, CD8þ and CD4þ T cells and improved control of primary tumor growth and metastasis of EBV LCLs tumor model in vivo. Conclusions: In summary, we demonstrated in our pre-clinical study cd T cell APC and effector functions in vitro and in vivo, indicating the potential of cd T cells as therapeutic immunotherapy against EBV-positive cancers. Legal entity responsible for the study: The authors. Funding: Tessa Therapeutics. Disclosure: P.W.-W. Wang: Advisory / Consultancy: Tessa Therapeutics. H.C. Toh: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Tessa Therapeutics. All other authors have declared no conflicts of interest.
327P
Neoantigen profile of hepatocellular carcinoma reveals its correlation with tumour progression and clonal evolution
X. Liu, Z. Li, Z. Cai, G. Chen, J. Liu Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian Medical University, Fuzhou, China Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China with poor prognosis. Recently, personalized neoantigen-based immunotherapy has been reported to induce robust anti-tumor immune responses to facilitate tumor rejection in several solid tumors. However, whether it possess therapeutic potential in HCC still remain unclear. Thus, a systemic understanding of neoantigen burden (TNB) in HCC microenvironment is in need. Methods: HCC and matched peritumor tissue collected from 59 HCC patients were subjected to DNA and RNA sequencing for identifying tumor associated neoantigens. Then the association between neoantigens and clinical features, immune signatures, as well as clonal evolution patterns in HCC were evaluated. Results: In enrolled HCC patients, a median of 106 somatic mutations and 15 neoantigens were identified in each patient. TNB was significantly correlated with tumor somatic mutation burden (R2 ¼ 0.893, P ¼ 3.0 10ˆ-24). Furthermore, the clinicopathological analysis revealed that patients with higher TNB was characterized with older age (p ¼ 0.006), decreased tumor size (p ¼ 0.020) and lower recurrence rate (p ¼ 0.019). Additionally, TNB was also significantly associated with relapse free survival (P ¼ 0.033) and overall survival (P ¼ 0.022) in HCC patients. Surprisingly, HCC tumor with high immune cell infiltration were more likely to have no tumor envelope
Volume 30 | Supplement 9 | November 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_9/mdz438.010/5638604 by university of winnipeg user on 29 November 2019
C.L. Ho: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. W.H. Cheng: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. C.L. Chang: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. Y.Y. Hsieh: Research grant / Funding (institution): Taiwan Henlix Biotech., Co., LTD. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S.F. Lin: Full / Part-time employment: Taiwan Henlix Biotech., Co., LTD. T.C. Hsieh: Full / Part-time employment: Taiwan Henlix Biotech., Co., LTD. E. Liu: Full / Part-time employment: Taiwan Henlix Biotech., Co., LTD.
Conclusions: The presence of irAE in advanced HCC patients treated with ICI could possibly predict better response and survival outcomes. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: S.P. Choo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant
abstracts
Annals of Oncology
328P
A retrospective analysis of patients with non-small cell lung cancer who developed drug-induced lung disorder by immune checkpoint inhibitors
F. Hayashi1, H. Taniguchi1, S. Takayuki1, Y. Umeyama1, Y. Dotsu1, H. Gyotoku1, H. Senju1, S. Takemoto1, H. Yamaguchi1, S. Ono2, H. Tomono2, M. Shimada2, H. Soda2, M. Fukuda3, M. Hiroshi1 1 Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan, 2 Department of Respiratory Medicine, Sasebo City General Hospital, Sasebo, Japan, 3 Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan Background: The presence of the immune-related adverse events (irAEs) has been reported as a preferred marker of the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients. However, there are only a few studies that focused on the relationship between the efficacy of ICIs and the severity or a highresolution computed tomography (HRCT) scan pattern of drug-induced lung disorder (DILD). Methods: We conducted a retrospective study of patients with NSCLC who were treated with ICIs between January 2016 and June 2019 in our institution. We especially focused on the patients who developed DILD during ICIs treatment, and analyzed the clinical information and HRCT pattern of DILD to investigate the prognosis of patients who developed DILD. Assessment of treatment response was evaluated using the response evaluation criteria in solid tumors version 1.1. Severity of DILD was classified by grade according to pneumonitis in Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: Total 182 patients were enrolled, including 20 patients who received chemotherapy with ICIs. Among the 182 patients, 32 patients (17.6 %) developed DILD and CTCAE grade 1/2/3/4/5 were 10/7/9/2/4 patients, respectively. The median progression-free survival was 100 and 93 days, (P ¼ 0.324, Log-rank Test) and overall survival was 415 and 501 days (P ¼ 0.0951, Log-rank Test) in patients with or without DILD, respectively. The median period from the first ICI treatment to onset of DILD was significantly shorter in the Grade 3/4/5 group than Grade 1/2 group; 22 and 72.5 days, respectively (P ¼ 0.029, Mann-Whitney U test). Analyzing HRCT findings according to ATS/ERS/JRS/ALAT GUIDLINE, patients who presented consolidation had better prognosis than those with comprehensive GGO. In 4 patients with Grade 5 pneumonitis developed with comprehensive GGO and the period from onset of DILD to death was extremely short; median 2 days. Conclusions: Our retrospective study suggested that development of DILD was not preferred in terms of prognosis in NSCLC patients. Physician should be alerted for the patients who developed early-onset, severe DILD with comprehensive GGO during ICI treatment. Legal entity responsible for the study: Hiroyuki Yamaguchi. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
329P
High-level expression of HDAC10 is associated with PD-L1 expression and poor prognosis in patients with non-small cell lung cancer receiving pulmonectomy
Results: Our results showed that HDAC10 expression level in cancer tissue was significantly higher than that in para-cancer tissue. HDAC10 expression level was also positively correlated with the PD-L1 expression level (r ¼ 0.213, P < 0.05). Multivariate analysis showed that expression level of HDAC10 was an independent prognostic factor and HDAC10 overexpression indicated a poor overall survival in pulmonary carcinoma (r ¼ 0.540, P < 0.001). Conclusions: To our knowledge, this is the first time to associate HDAC10 with lung cancer patients’ survival status and to explore correlation between HDAC10 and PDL1 expression. Our findings indicated that HDAC10 could be a valuable predicting marker that might provide help for clinicians to design effective therapeutic modality against NSCLC. Treatment response might be especially prominent in patients overexpressing HDAC10 in cancer cells. Our study suggest clinical relevance for the immune effects of HDAC10 and provide a rationale for the clinical evaluation of PD-L1 blockade in combination with HDAC10 inhibition. Legal entity responsible for the study: The First Affiliated Hospital of Jinzhou Medical University. Funding: This study was supported by the CSCO-HANSOH PHARMA Science Foundation of China (number Y-HS2019-29). Disclosure: The author has declared no conflicts of interest.
331P
S. Ono1, H. Senju2, H. Taniguchi2, H. Tomono1, M. Shimada1, F. Hayashi2, T. Suyama2, N. Honda2, Y. Umeyama2, Y. Dotsu2, H. Gyotoku2, S. Takemoto2, H. Yamaguchi2, M. Fukuda3, H. Soda1, H. Mukae2 1 Department of Respiratory Medicine, Sasebo City General Hospital, Sasebo, Japan, 2 Department of Respiratory Medicine, Nagaski University Hospital, Nagasaki, Japan, 3 Clinical Oncology Center, Nagaski University Hospital, Nagasaki, Japan Background: Previous reports suggested that development of an immune-related adverse event (irAE), including thyroid disorder (TD), is associated with better outcomes of immune checkpoint inhibitor (ICI) therapy. Though TD has been reported most frequently as an irAE, it has not been well analyzed compared to life-threatening adverse events such as interstitial lung disease or colitis. Methods: We conducted a chart-based retrospective analysis of patients (Pts) with advanced or recurrent non-small cell lung cancer (NSCLC), who are treated with monotherapy using nivolumab, pembrolizumab, or atezolizumab between January 2016 and June 2019 in two facilities in Japan. TD emerging after the first treatment with an ICI was considered as an irAE. Tumor response was evaluated with Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) on ICIs were evaluated with Kaplan-Meier method. The correlations between time to onset of TD and PFS or OS were analyzed with Spearman’s rank correlation coefficient. Results: In total, 164 consecutive Pts were enrolled. The median age was 68 (range: 3484) years, and 40 (24.4%) were women. TD of any grade occurred in 26 Pts (15.8%); 11/15/0/0/0 cases were classified as Grade 1/2/3/4/5, respectively, according to Common Terminology Criteria for Adverse Events version 5.0. Onset of TD ranged from 6 to 455 (median: 77.5) days after the first treatment with an ICI. Objective response rates in Pts with and without TD were 28.0% and 18.1%; disease control rates were 68.0% and 50.7%, respectively. Median PFS and OS were significantly longer in Pts with TD (PFS: 226 vs 100 days, p ¼ 0.029; OS: not reached vs 434 days, p ¼ 0.050, log-rank test). Among TD Pts, however, a positive correlation between time to onset of TD and PFS was identified (p ¼ 0.0015). Significantly shorter PFS was observed in Pts with earlier TD onset, especially within 30 days, compared to Pts with later TD onset (median PFS: 72.5 vs 329 days, p ¼ 0.00096, log-rank test). Conclusions: Development of TD caused by ICIs was associated with longer PFS. Nevertheless, the prognosis of Pts with early onset of TD was poor. This study suggested that physicians should consider the onset of TD in Pts using ICIs. Legal entity responsible for the study: Hiroyuki Yamaguchi. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
X. Liu Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China Background: Recent studies showed that stimulation of HDACs could induce PD-1 dynamic expression on DCs, macrophages, colonic stromal cells, and cancer cells. Surprisingly, it is little is known about the specific expression of important HDAC10 in NSCLC tissue. In this study, we evaluated the expression level of HDAC10 and the correlation of HDAC10 and PD-L1 in NSCLC tissues and analyzed the predicting role of HDAC10 in cancer cells on postoperative survival in NSCLC patients receiving pulmonary lobectomy. Methods: A total of 180 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection between April 2004 and August 2009 were enrolled. All the patients had integrated clinicopathological records and follow-up data. HDAC10 and PD-L1 expression on NSCLC samples were determined by using immunohistochemistry.
Volume 30 | Supplement 9 | November 2019
A retrospective analysis of immune checkpoint therapy in patients with non-small cell lung cancer: Focus on thyroid disorder
332P
Analyse the association between adverse events (AEs) and survival in patients treated with immune checkpoint inhibitors (ICIs)
C-Y. Cheng1, P-J. Su2, K-C. Chang3, T-C. Tsai3, H-Y. Chen3, S-T. Deng3, W-C. Chang4 Pharmacy, Chang Gung Medical Foundation - Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan, 2Medical Oncology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, 3Pharmacy, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan, 4Medical Oncology, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
1
Background: ICIs with a programmed death protein 1 (PD-1) or programmed death protein ligand 1 (PD-L1) antibodies have shown survival benefits for various metastatic cancer patients. However, some patients treated with ICIs may suffer from AEs. We investigated the association between AEs and survival in metastatic cancer patients treated with PD-1/PD-L1 inhibitors.
doi:10.1093/annonc/mdz438 | ix111
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(P ¼ 0.027) and resulted in shorter overall survival time after surgery (P ¼ 0.025); the patients with lower immune cell signatures related to antigen-processing have relatively higher TNB in HCC. Meanwhile, clonal evolution analysis revealed that the clonal mutations were more likely to be neoantigens ( P ¼ 9.2 10ˆ-5) than subclonal mutations, suggesting higher immunogenicity for clonal mutations. And tumors with higher proportion of neoantigens in clonal mutations were more likely to involved in clonal evolution, which may due to the immunoediting of neoantigens (P ¼ 0.002). Conclusions: Our results demonstrated that neoantigens play an important role in tumor clonal evolution and immune response in HCC, which could provide insights for future HCC immunotherapy. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.