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MA15.02 Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade
ABSTRACTS
MINI ORAL ABSTRACT SESSION e WEDNESDAY, DECEMBER 7, 2016 MA15.01 Immunogram for Cancer-Immunity Cycle towards Personalized Immunotherapy of Lung Cancer Takahiro Karasaki,1 Kazuhiro Nagayama,1 Hideki Kuwano,1 Jun-Ichi Nitadori,1 Masaaki Sato,1 Masaki Anraku,1 Akihiro Hosoi,2 Hirokazu Matsushita,2 Yasuyuki Morishita,3 Kosuke Kashiwabara,4 Masaki Takazawa,5 Osamu Ohara,5 Kazuhiro Kakimi,2 Jun Nakajima1 1Thoracic Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo/Japan, 2 Immunotherapeutics, The University of Tokyo Hospital, Tokyo/Japan, 3Molecular Pathology, Graduate School of Medicine, the University of Tokyo, Tokyo/Japan, 4 Biostatistics, School of Public Health, the University of Tokyo, Tokyo/Japan, 5Technology Development, Kazusa Dna Research Institute, Kisarazu/Japan Background: The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of anti-tumor immunity as a dynamic spacio-temporal process is required for each individual patient. To this end, we developed an “immunogram for the cancer-immunity cycle” using next-generation sequencing. Methods: Whole-exome sequencing and RNA-Seq were performed in 20 non-small cell lung cancer patients (12 adenocarcinoma, 7 squamous cell carcinoma, and 1 large cell neuroendocrine carcinoma). Mutated neoantigens and cancer-germline antigens expressed in the tumor were assessed for predicted binding to patients’ HLA molecules. The expression of genes related to cancerimmunity was assessed and normalized; immunogram was drawn in a radar chart composed of 8 axes reflecting 7 steps of cancer-immunity cycle. Results: Distinctive patterns of immunogram were observed in lung cancer patients: T-cell-rich and T-cellpoor. Patients with T-cell-rich pattern had gene signatures of abundant T cells, Tregs and MDSCs, checkpoint molecules and immune-inhibitory molecules in the tumor, suggesting the presence of counter regulatory immunosuppressive microenvironment. Unleashing of counter regulations, i.e. checkpoint inhibitors, may be indicated for these patients (Figure A). Immunogram of T-cell-poor phenotype reflected
Journal of Thoracic Oncology
Vol. 12 No. 1S: S428-S447
lack of anti-tumor immunity, inadequate DC activation, and insufficient antigen presentation in the tumor (Figure B). When the immunograms were overlaid within each tumor histology, no typical pattern was elucidated. Both T-cell-rich and T-cell-poor phenotypes were present in each histology, suggesting that histology cannot necessarily reflect the cancer-immunity status of the tumor (Figure C,D). These results were consistent with previous studies showing that clinical responses of checkpoint blockade were not easily predicted by the histology.
Conclusion: Utilizing the immunogram, the landscape of the tumor microenvironment in each patient can be appreciated. Immunogram for the cancer-immunity cycle can be used as an integrated biomarker and thus may become a helpful resource toward optimal personalized immunotherapy. Keywords: cancer-immunity cycle, neoantigen, immunogram, transcriptome
MA15.02 Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade Navin Mahadevan,1 Anika Adeni,2 Peter Hammerman,2 Mark Awad,3 Leena Gandhi,2 Lynette Sholl4 1Pathology, Brigham and Women’s Hospital, Boston/United States of America, 2Medical Oncology, Dana-Farber Cancer Institute, Boston/MA/
January 2017
United States of America, 3Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston/MA/ United States of America, 4Pathology, Brigham and Women’s Hospital, Boston/MA/United States of America Background: Recent evidence indicates that efficacy and durability of responses to immune checkpoint inhibitors in lung carcinomas correlate with increased nonsynonymous mutation (NSM) burden, putative neoantigen number, and in some tumor types, PD-L1 protein expression. In this study, we retrospectively analyzed the relationship of lung carcinoma mutation burden, PD-L1 expression and immune infiltrates with clinical response in patients receiving immune checkpoint blockade.
Abstracts
S429
clinical benefit to immune checkpoint inhibitors. In this limited cohort, PD-L1 expression using clone E1L3N does not predict response to these therapies. We add to growing evidence that increased somatic mutations in carcinomas influence response to immune checkpoint blockade. Keywords: Mutation burden, Immunotherapy, next generation sequencing
MA15.03 The Predictive Value of Mutation/ Neoantigen Burden from ctDNA on the Methods: Tumor nonsynonymous mutation data derived Efficacy of PD-1 Blockade in Advanced from clinical targeted next generation sequencing NSCLC (309 genes) of lung carcinomas from 94 patients treated
with immune checkpoint inhibitors was correlated with clinical outcomes, including durable clinical benefit (DCB; >6 months partial or stable response) and progressionfree survival (PFS). PD-L1 immunohistochemistry (clone E1L3N, Cell Signaling Technology, Envision+ detection, Dako) was considered positive if 1% of tumor cells and/or tumor-infiltrating immune cells (IC) stained. PU.1, CD3, and FOXP3 immunohistochemistry was used to highlight tumor-associated macrophages and nonregulatory and regulatory T cell populations, which were manually quantified per mm2. Results: The mean patient age was 62 years (range: 32-91 years). Lung tumor types included 69 adenocarcinomas, 11 squamous cell carcinomas, 5 small cell carcinomas, and 9 of other/combined histology. Therapies included PD1 inhibitors (82), a PD-L1 inhibitor (5) and multiple agents (7). Across all tumor types, patients with DCB had a significantly higher number of NSM (range: 1-42) than patients who showed no durable benefit (NDB) [DCB: 12; NDB: 8, p ¼ 0.0027]. Patients with greater than the median number of NSM (9) had significantly longer PFS than those with 9 (p ¼ 0.015). Increasing smoking history correlated with higher mutation load (p ¼ 0.047) and patients with a longer smoking history tended to have longer PFS although this trend did not reach statistical significance (p ¼ 0.07). Expression of PD-L1 in either tumor cells or ICs was not associated with NSM burden (p ¼ 0.47) or PFS (p ¼ 0.92). PD-L1 expression in the tumor microenvironment was associated with increased numbers of tumor-associated macrophages (p ¼ 0.0002), and nonregulatory and regulatory T cells (p ¼ 0.0038 and 0.01 respectively). Conclusion: The non-synonymous mutation burden in lung carcinoma as assessed by targeted next generation sequencing is associated with increased PFS and durable
Weijing Cai,1 Caicun Zhou,1 Chunxia Su,1 Feng Ying Wu,1 Shengxiang Ren,1 Xiaoxia Chen,1 Fred R. Hirsch2 1Medical Oncology, Shanghai Pulmonary Hospital, Shanghai/China, 2Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora/ CO/United States of America Background: Immune checkpoint, PD-1, inhibitors, have been approved to treat advanced NSCLC patients without oncogenic driver in the second-line setting based on durable clinical benefit. It has been demonstrated that the overall mutational burden in tumor tissue was significantly associated with progression free survival (PFS) of advanced NSCLC patients treated with PD-1 inhibitor. However, tumor tissue may not be available from all patients at any time during PD-1 blockade therapy. Therefore, the purpose of this study was to explore the predictive value of mutation/neoantigen burden from ctDNA on efficacy of PD-1 inhibitors. Methods: We treated advanced NSCLC patients without oncogenic drivers with PD-1 inhibitor in the second or more line setting. The whole-exome of tumor tissues and ctDNA at baseline and ctDNA at every time of efficacy evaluation from these patients were sequenced by NGS. The hybrid-capture-enriched libraries were sequenced on the Illumina HiSeq 4000 platform with 75-base paired-end reads, sequencing depth was 300 for ctDNA whole-exome sequencing. We compared the results of whole-exome sequencing between patients who achieved objective response to PD-1 inhibitor and patients who experienced disease progression. Besides, we also compared the results of whole-exome sequencing between baseline ctDNA and ctDNA extracted at efficacy evaluation. Results: Up to now, a total of 23 patients treated with PD-1 inhibitor received efficacy evaluation at least once
MINI ORAL ABSTRACT SESSION e WEDNESDAY, DECEMBER 7, 2016 MA15.01 Immunogram for Cancer-Immunity Cycle towards Personalized Immunotherapy of Lung Cancer Takahiro Karasaki,1 Kazuhiro Nagayama,1 Hideki Kuwano,1 Jun-Ichi Nitadori,1 Masaaki Sato,1 Masaki Anraku,1 Akihiro Hosoi,2 Hirokazu Matsushita,2 Yasuyuki Morishita,3 Kosuke Kashiwabara,4 Masaki Takazawa,5 Osamu Ohara,5 Kazuhiro Kakimi,2 Jun Nakajima1 1Thoracic Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo/Japan, 2 Immunotherapeutics, The University of Tokyo Hospital, Tokyo/Japan, 3Molecular Pathology, Graduate School of Medicine, the University of Tokyo, Tokyo/Japan, 4 Biostatistics, School of Public Health, the University of Tokyo, Tokyo/Japan, 5Technology Development, Kazusa Dna Research Institute, Kisarazu/Japan Background: The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of anti-tumor immunity as a dynamic spacio-temporal process is required for each individual patient. To this end, we developed an “immunogram for the cancer-immunity cycle” using next-generation sequencing. Methods: Whole-exome sequencing and RNA-Seq were performed in 20 non-small cell lung cancer patients (12 adenocarcinoma, 7 squamous cell carcinoma, and 1 large cell neuroendocrine carcinoma). Mutated neoantigens and cancer-germline antigens expressed in the tumor were assessed for predicted binding to patients’ HLA molecules. The expression of genes related to cancerimmunity was assessed and normalized; immunogram was drawn in a radar chart composed of 8 axes reflecting 7 steps of cancer-immunity cycle. Results: Distinctive patterns of immunogram were observed in lung cancer patients: T-cell-rich and T-cellpoor. Patients with T-cell-rich pattern had gene signatures of abundant T cells, Tregs and MDSCs, checkpoint molecules and immune-inhibitory molecules in the tumor, suggesting the presence of counter regulatory immunosuppressive microenvironment. Unleashing of counter regulations, i.e. checkpoint inhibitors, may be indicated for these patients (Figure A). Immunogram of T-cell-poor phenotype reflected
Journal of Thoracic Oncology
Vol. 12 No. 1S: S428-S447
lack of anti-tumor immunity, inadequate DC activation, and insufficient antigen presentation in the tumor (Figure B). When the immunograms were overlaid within each tumor histology, no typical pattern was elucidated. Both T-cell-rich and T-cell-poor phenotypes were present in each histology, suggesting that histology cannot necessarily reflect the cancer-immunity status of the tumor (Figure C,D). These results were consistent with previous studies showing that clinical responses of checkpoint blockade were not easily predicted by the histology.
Conclusion: Utilizing the immunogram, the landscape of the tumor microenvironment in each patient can be appreciated. Immunogram for the cancer-immunity cycle can be used as an integrated biomarker and thus may become a helpful resource toward optimal personalized immunotherapy. Keywords: cancer-immunity cycle, neoantigen, immunogram, transcriptome
MA15.02 Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade Navin Mahadevan,1 Anika Adeni,2 Peter Hammerman,2 Mark Awad,3 Leena Gandhi,2 Lynette Sholl4 1Pathology, Brigham and Women’s Hospital, Boston/United States of America, 2Medical Oncology, Dana-Farber Cancer Institute, Boston/MA/
January 2017
United States of America, 3Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston/MA/ United States of America, 4Pathology, Brigham and Women’s Hospital, Boston/MA/United States of America Background: Recent evidence indicates that efficacy and durability of responses to immune checkpoint inhibitors in lung carcinomas correlate with increased nonsynonymous mutation (NSM) burden, putative neoantigen number, and in some tumor types, PD-L1 protein expression. In this study, we retrospectively analyzed the relationship of lung carcinoma mutation burden, PD-L1 expression and immune infiltrates with clinical response in patients receiving immune checkpoint blockade.
Abstracts
S429
clinical benefit to immune checkpoint inhibitors. In this limited cohort, PD-L1 expression using clone E1L3N does not predict response to these therapies. We add to growing evidence that increased somatic mutations in carcinomas influence response to immune checkpoint blockade. Keywords: Mutation burden, Immunotherapy, next generation sequencing
MA15.03 The Predictive Value of Mutation/ Neoantigen Burden from ctDNA on the Methods: Tumor nonsynonymous mutation data derived Efficacy of PD-1 Blockade in Advanced from clinical targeted next generation sequencing NSCLC (309 genes) of lung carcinomas from 94 patients treated
with immune checkpoint inhibitors was correlated with clinical outcomes, including durable clinical benefit (DCB; >6 months partial or stable response) and progressionfree survival (PFS). PD-L1 immunohistochemistry (clone E1L3N, Cell Signaling Technology, Envision+ detection, Dako) was considered positive if 1% of tumor cells and/or tumor-infiltrating immune cells (IC) stained. PU.1, CD3, and FOXP3 immunohistochemistry was used to highlight tumor-associated macrophages and nonregulatory and regulatory T cell populations, which were manually quantified per mm2. Results: The mean patient age was 62 years (range: 32-91 years). Lung tumor types included 69 adenocarcinomas, 11 squamous cell carcinomas, 5 small cell carcinomas, and 9 of other/combined histology. Therapies included PD1 inhibitors (82), a PD-L1 inhibitor (5) and multiple agents (7). Across all tumor types, patients with DCB had a significantly higher number of NSM (range: 1-42) than patients who showed no durable benefit (NDB) [DCB: 12; NDB: 8, p ¼ 0.0027]. Patients with greater than the median number of NSM (9) had significantly longer PFS than those with 9 (p ¼ 0.015). Increasing smoking history correlated with higher mutation load (p ¼ 0.047) and patients with a longer smoking history tended to have longer PFS although this trend did not reach statistical significance (p ¼ 0.07). Expression of PD-L1 in either tumor cells or ICs was not associated with NSM burden (p ¼ 0.47) or PFS (p ¼ 0.92). PD-L1 expression in the tumor microenvironment was associated with increased numbers of tumor-associated macrophages (p ¼ 0.0002), and nonregulatory and regulatory T cells (p ¼ 0.0038 and 0.01 respectively). Conclusion: The non-synonymous mutation burden in lung carcinoma as assessed by targeted next generation sequencing is associated with increased PFS and durable
Weijing Cai,1 Caicun Zhou,1 Chunxia Su,1 Feng Ying Wu,1 Shengxiang Ren,1 Xiaoxia Chen,1 Fred R. Hirsch2 1Medical Oncology, Shanghai Pulmonary Hospital, Shanghai/China, 2Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora/ CO/United States of America Background: Immune checkpoint, PD-1, inhibitors, have been approved to treat advanced NSCLC patients without oncogenic driver in the second-line setting based on durable clinical benefit. It has been demonstrated that the overall mutational burden in tumor tissue was significantly associated with progression free survival (PFS) of advanced NSCLC patients treated with PD-1 inhibitor. However, tumor tissue may not be available from all patients at any time during PD-1 blockade therapy. Therefore, the purpose of this study was to explore the predictive value of mutation/neoantigen burden from ctDNA on efficacy of PD-1 inhibitors. Methods: We treated advanced NSCLC patients without oncogenic drivers with PD-1 inhibitor in the second or more line setting. The whole-exome of tumor tissues and ctDNA at baseline and ctDNA at every time of efficacy evaluation from these patients were sequenced by NGS. The hybrid-capture-enriched libraries were sequenced on the Illumina HiSeq 4000 platform with 75-base paired-end reads, sequencing depth was 300 for ctDNA whole-exome sequencing. We compared the results of whole-exome sequencing between patients who achieved objective response to PD-1 inhibitor and patients who experienced disease progression. Besides, we also compared the results of whole-exome sequencing between baseline ctDNA and ctDNA extracted at efficacy evaluation. Results: Up to now, a total of 23 patients treated with PD-1 inhibitor received efficacy evaluation at least once