The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer and has abysmal survival rates. In the past two decades, immunotherapeutic agents with success in other cancer types have gradually been trialled against PDACs at different stages of cancer progression, either as a monotherapy or in combination with chemotherapy. Unfortunately, to this day, chemotherapy still prolongs the survival rates the most and is prescribed in clinics despite the severe side effects in other cancer types. The low success rates of immunotherapy against PDAC have been attributed most frequently to its complex and multi‐faceted tumour microenvironment (TME) and low mutational burden. In this review, we give a comprehensive overview of the immunotherapies tested in PDAC clinical trials thus far, their limitations, and potential explanations for their failure. We also discuss the existing classification of heterogenous PDACs into cancer, cancer‐associated fibroblast, and immune subtypes and their potential opportunity in patient selection as a form of personalisation of PDAC immunotherapy. © 2023 The Pathological Society of Great Britain and Ireland.

[1]  Z. Nwosu,et al.  Uridine-derived ribose fuels glucose-restricted pancreatic cancer , 2023, Nature.

[2]  M. Gönen,et al.  Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer , 2023, Nature.

[3]  T. Sugino,et al.  Characterization of pancreatic cancer with ultra-low tumor mutational burden , 2023, Scientific Reports.

[4]  A. Sadanandam,et al.  A Case Report on Longitudinal Collection of Tumour Biopsies for Gene Expression-Based Tumour Microenvironment Analysis from Pancreatic Cancer Patients Treated with Endoscopic Ultrasound Guided Radiofrequency Ablation , 2022, Current oncology.

[5]  S. Gerber,et al.  Toll-like receptor 7/8 agonist R848 alters the immune tumor microenvironment and enhances SBRT-induced antitumor efficacy in murine models of pancreatic cancer , 2022, Journal for ImmunoTherapy of Cancer.

[6]  A. Sadanandam,et al.  GREM1 is required to maintain cellular heterogeneity in pancreatic cancer , 2022, Nature.

[7]  Christopher R. Cabanski,et al.  Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial , 2022, Nature Medicine.

[8]  L. Shen,et al.  A phase 1b/2 trial of SHR-1701 in combination with gemcitabine and nab-paclitaxel in patients with untreated locally advanced or metastatic pancreatic cancer. , 2022, Journal of Clinical Oncology.

[9]  B. Gloor,et al.  High tumor mutational burden (TMB) identifies a microsatellite stable pancreatic cancer subset with prolonged survival and strong anti-tumor immunity. , 2022, European journal of cancer.

[10]  V. Singh,et al.  Survival Benefit of Pembrolizumab for Patients With Pancreatic Adenocarcinoma: A Case Series , 2022, Journal of medical cases.

[11]  F. Real,et al.  Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors , 2022, Journal for ImmunoTherapy of Cancer.

[12]  P. Shaik Syed Ali,et al.  Short report - Lethal and aggressive pancreatic cancer: molecular pathogenesis, cellular heterogeneity, and biomarkers of pancreatic ductal adenocarcinoma. , 2022, European review for medical and pharmacological sciences.

[13]  M. Hidalgo,et al.  VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects , 2021, Journal for ImmunoTherapy of Cancer.

[14]  Jeffrey W. Clark,et al.  Radiation Therapy Enhances Immunotherapy Response in Microsatellite-stable Colorectal and Pancreatic Adenocarcinoma in a Phase II Trial , 2021, Nature Cancer.

[15]  J. Feliu,et al.  Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer , 2021, World journal of gastroenterology.

[16]  Methichit Wattanapanitch,et al.  Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells , 2021, Frontiers in Immunology.

[17]  T. D. de Gruijl,et al.  Pancreatic Cancer and Immunotherapy: A Clinical Overview , 2021, Cancers.

[18]  Seung‐Mo Hong,et al.  Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions , 2021, Cancers.

[19]  E. Noessner,et al.  Vγ9Vδ2 T Cells Concurrently Kill Cancer Cells and Cross-Present Tumor Antigens , 2021, Frontiers in Immunology.

[20]  E. Sugar,et al.  A phase 2 study of cyclophosphamide (CY), GVAX, pembrolizumab (Pembro), and stereotactic body radiation (SBRT) in patients (pts) with locally advanced pancreas cancer (LAPC). , 2021 .

[21]  C. Slingluff,et al.  Randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer. , 2021 .

[22]  S. H. van der Burg,et al.  Therapeutic cancer vaccines , 2021, Nature Reviews Cancer.

[23]  A. Mahipal,et al.  A Patient With Locally Advanced Mismatch-Repair-Deficient Pancreatic Ductal Adenocarcinoma Successfully Treated With Neoadjuvant Immunotherapy , 2021, Cureus.

[24]  Y. Lou,et al.  Next generation of immune checkpoint inhibitors and beyond , 2021, Journal of Hematology & Oncology.

[25]  E. Jaffee,et al.  Leukocyte Heterogeneity in Pancreatic Ductal Adenocarcinoma: Phenotypic and Spatial Features Associated with Clinical Outcome. , 2021, Cancer discovery.

[26]  A. Vahrmeijer,et al.  Immunotherapy for pancreatic cancer: chasing the light at the end of the tunnel , 2021, Cellular Oncology.

[27]  A. Varghese,et al.  Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer , 2021, Journal for ImmunoTherapy of Cancer.

[28]  I. Wistuba,et al.  PD-L1 as a biomarker of response to immune-checkpoint inhibitors , 2021, Nature Reviews Clinical Oncology.

[29]  Xiaowu Xu,et al.  Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications , 2021, Acta Pharmacologica Sinica.

[30]  Joon-Oh Park,et al.  Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA) , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Chen Liang,et al.  Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma , 2021, Cancer cell international.

[32]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[33]  K. Almhanna,et al.  Pancreatic cancer and immune checkpoint inhibitors-still a long way to go. , 2021, Translational gastroenterology and hepatology.

[34]  Christopher R. Cabanski,et al.  CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. , 2021, The Lancet. Oncology.

[35]  B. Leiby,et al.  A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer , 2020, Annals of surgery.

[36]  M. Makary,et al.  Vaccine-Induced Intratumoral Lymphoid Aggregates Correlate with Survival Following Treatment with a Neoadjuvant and Adjuvant Vaccine in Patients with Resectable Pancreatic Adenocarcinoma , 2020, Clinical Cancer Research.

[37]  Jessica S. Yu,et al.  Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer , 2020, Nature Cancer.

[38]  M. Xiong,et al.  Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma , 2020, Nature Communications.

[39]  H. Sugiyama,et al.  Dendritic Cell-based Immunotherapy Pulsed With Wilms Tumor 1 Peptide and Mucin 1 as an Adjuvant Therapy for Pancreatic Ductal Adenocarcinoma After Curative Resection: A Phase I/IIa Clinical Trial , 2020, AntiCancer Research.

[40]  J. Hecht,et al.  Immunologic and tumor responses of pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in pancreatic ductal adenocarcinoma (PDAC) , 2020, Investigational New Drugs.

[41]  M. Honda,et al.  Effect of adoptive T-cell immunotherapy on immunological parameters and prognosis in patients with advanced pancreatic cancer. , 2020, Cytotherapy.

[42]  C. Perreault,et al.  The Origin and Immune Recognition of Tumor-Specific Antigens , 2020, Cancers.

[43]  Kimberly R. Jordan,et al.  HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery , 2020, Journal for ImmunoTherapy of Cancer.

[44]  C. Robert.  A decade of immune-checkpoint inhibitors in cancer therapy , 2020, Nature Communications.

[45]  J. Schachter,et al.  Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia , 2020, Frontiers in Immunology.

[46]  J. Windsor,et al.  Recurrence Patterns for Pancreatic Ductal Adenocarcinoma after Upfront Resection Versus Resection Following Neoadjuvant Therapy: A Comprehensive Meta-Analysis , 2020, Journal of clinical medicine.

[47]  E. Jaffee,et al.  A Phase II Study of Allogeneic GM-CSF–Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer , 2020, Clinical Cancer Research.

[48]  Edward J. Kim,et al.  Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer , 2020, Clinical Cancer Research.

[49]  Stephen M. Shaw,et al.  BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial , 2020, Nature Medicine.

[50]  E. Jaffee,et al.  The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities , 2020, Nature Reviews Clinical Oncology.

[51]  Ludmila V. Danilova,et al.  Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer , 2020, Clinical Cancer Research.

[52]  J. Nemunaitis,et al.  First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody–Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  Jinkuk Kim,et al.  Tolerability and safety of EUS-injected adenovirus-mediated double-suicide gene therapy with chemotherapy in locally advanced pancreatic cancer: Phase I Trial. , 2020, Gastrointestinal endoscopy.

[54]  J. Neoptolemos,et al.  TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas (CT TG01-01): a single-arm, phase 1/2 trial , 2020, British Journal of Cancer.

[55]  V. Miller,et al.  PD-L1 expression, tumor mutational burden, and microsatellite instability status in 746 pancreas ductal adenocarcinomas. , 2020 .

[56]  Jonathan M. Hernandez,et al.  Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma , 2020, Clinical Cancer Research.

[57]  P. Philip,et al.  Clinical and immune responses to anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) in pancreatic cancer patients , 2020, Oncoimmunology.

[58]  L. Diaz,et al.  Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  C. V. van Eijck,et al.  Nationwide trends in incidence, treatment and survival of pancreatic ductal adenocarcinoma. , 2019, European journal of cancer.

[60]  M. Hidalgo,et al.  A Multi-Center Phase IIA Trial to Assess the Safety and Efficacy of BL-8040 (a CXCR4 Inhibitor) in Combination with Pembrolizumab and Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma (PDAC) , 2019 .

[61]  Jennifer L Moseley,et al.  Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study , 2019, Clinical Cancer Research.

[62]  D. Torigian,et al.  Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[63]  Myung Ah Lee,et al.  Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. , 2019, JAMA oncology.

[64]  K. Muro,et al.  A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors , 2019, Clinical Cancer Research.

[65]  Brian J. Stevenson,et al.  A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma—A Proof of Antigen Discovery Feasibility in Three Patients , 2019, Front. Immunol..

[66]  P. Robson,et al.  Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. , 2019, Cancer discovery.

[67]  K. Hirata,et al.  Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA‐A24‐positive pancreatic adenocarcinoma , 2019, Cancer science.

[68]  A. Bullock,et al.  Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma , 2019, Investigational New Drugs.

[69]  J. Berlin,et al.  A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors , 2019, Oncology.

[70]  E. Jaffee,et al.  Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study) , 2019, Clinical Cancer Research.

[71]  J. Kleeff,et al.  Inter‐ and intra‐tumoural heterogeneity in cancer‐associated fibroblasts of human pancreatic ductal adenocarcinoma , 2019, The Journal of pathology.

[72]  Y. Hashimoto,et al.  Results from phase I study of the oncolytic viral immunotherapy agent canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer. , 2019, Journal of Clinical Oncology.

[73]  J. Wolchok,et al.  Acquired resistance to immunotherapy in MMR-D pancreatic cancer , 2018, Journal of Immunotherapy for Cancer.

[74]  D. Tuveson,et al.  IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. , 2018, Cancer discovery.

[75]  J. Tabernero,et al.  Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer , 2018, British Journal of Cancer.

[76]  S. Hanada,et al.  Long-term survival of pancreatic cancer patients treated with multimodal therapy combined with WT1-targeted dendritic cell vaccines , 2018, Human vaccines & immunotherapeutics.

[77]  D. Torigian,et al.  Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. , 2018, Gastroenterology.

[78]  J. Cameron,et al.  Implications of the Pattern of Disease Recurrence on Survival Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma , 2018, Annals of Surgical Oncology.

[79]  G. Nuovo,et al.  A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma , 2018, Cancers.

[80]  Y. Kodera,et al.  A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer , 2018, BMC Cancer.

[81]  J. Berlin,et al.  Phase 1b multi-indication study of the antibody drug conjugate anetumab ravtansine in patients with mesothelin-expressing advanced or recurrent malignancies. , 2018 .

[82]  H. Sugiyama,et al.  WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study. , 2018, Anticancer research.

[83]  J. Hecht,et al.  Overall survival of PEGylated human IL-10 (AM0010) with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC). , 2018 .

[84]  G. Weiss,et al.  Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma , 2018, Investigational New Drugs.

[85]  H. Eguchi,et al.  Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study , 2018, Cancer Immunology Research.

[86]  J. Schlom,et al.  Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors , 2018, Clinical Cancer Research.

[87]  Pier Federico Gherardini,et al.  High response rate to PD-1 blockade in desmoplastic melanomas , 2017, Nature.

[88]  A. Duval,et al.  Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas. , 2017, Gastroenterology.

[89]  A. Scarpa,et al.  Revealing unidentified heterogeneity in different epithelial cancers using heterocellular subtype classification , 2017, bioRxiv.

[90]  Ludmila V. Danilova,et al.  Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade , 2017, Science.

[91]  S. Halford,et al.  The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity , 2017, Cancer Immunology, Immunotherapy.

[92]  G. Weiss,et al.  A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus) , 2017, British Journal of Cancer.

[93]  M. Thomas,et al.  Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer , 2017, Journal of Hematology & Oncology.

[94]  K. Hasegawa,et al.  Adjuvant combination therapy with gemcitabine and autologous γδ T-cell transfer in patients with curatively resected pancreatic cancer. , 2017, Cytotherapy.

[95]  Hans Clevers,et al.  Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer , 2017, The Journal of experimental medicine.

[96]  H. Imaoka,et al.  Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients , 2017, International journal of cancer.

[97]  Yusuke Nakamura,et al.  Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS‐PC study , 2016, Cancer science.

[98]  P. Sharma,et al.  Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, phase 1/2 trial , 2016, The Lancet. Oncology.

[99]  A. Dalgleish,et al.  Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer , 2016, British Journal of Cancer.

[100]  G. Lesinski,et al.  Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma. , 2016, Molecular therapy : the journal of the American Society of Gene Therapy.

[101]  A. Rademaker,et al.  Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. , 2016, The oncologist.

[102]  Kathryn J Fowler,et al.  Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. , 2016, The Lancet. Oncology.

[103]  Nicolai J. Birkbak,et al.  Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade , 2016, Science.

[104]  R. Gibbs,et al.  Genomic analyses identify molecular subtypes of pancreatic cancer , 2016, Nature.

[105]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[106]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[107]  Jen Jen Yeh,et al.  Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma , 2015, Nature Genetics.

[108]  Bert Vogelstein,et al.  PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. , 2015, The New England journal of medicine.

[109]  M. Curran,et al.  4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity , 2015, Front. Oncol..

[110]  A. Rademaker,et al.  Results of the phase Ib study of ipilimumab and gemcitabine for advanced pancreas cancer. , 2015 .

[111]  H. Ueno,et al.  Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study , 2015, Cancer science.

[112]  E. Jaffee,et al.  Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[113]  Qiao Li,et al.  Prospective study of the safety and efficacy of a pancreatic cancer stem cell vaccine , 2015, Journal of Cancer Research and Clinical Oncology.

[114]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[115]  G. Lesinski,et al.  Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma , 2015, Cancer Immunology, Immunotherapy.

[116]  T. Sakurai,et al.  Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer , 2015, Cancer science.

[117]  E. Furth,et al.  Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma , 2015, Cancer Immunology Research.

[118]  A. Thakur,et al.  Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial , 2015, Clinical Cancer Research.

[119]  D. Schadendorf,et al.  Nivolumab in previously untreated melanoma without BRAF mutation. , 2015, The New England journal of medicine.

[120]  J. Wolchok,et al.  Genetic basis for clinical response to CTLA-4 blockade in melanoma. , 2014, The New England journal of medicine.

[121]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[122]  M. Sawyer,et al.  A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[123]  T. Misawa,et al.  Treatment with Chemotherapy and Dendritic Cells Pulsed with Multiple Wilms' Tumor 1 (WT1)–Specific MHC Class I/II–Restricted Epitopes for Pancreatic Cancer , 2014, Clinical Cancer Research.

[124]  T. Hickish,et al.  Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. , 2014, The Lancet. Oncology.

[125]  Benjamin D. Smith,et al.  Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. , 2014, Cancer research.

[126]  S. Yamada,et al.  Phase I Dose-escalation Clinical Trial of HF10 Oncolytic Herpes Virus in 17 Japanese Patients with Advanced Cancer. , 2014, Hepato-gastroenterology.

[127]  Y. Takeda,et al.  Wilms Tumor Gene (WT1) Peptide–based Cancer Vaccine Combined With Gemcitabine for Patients With Advanced Pancreatic Cancer , 2014, Journal of immunotherapy.

[128]  D. Torigian,et al.  Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies , 2013, Cancer Immunology Research.

[129]  M. Oka,et al.  A Phase I Clinical Trial of Vaccination With KIF20A-derived Peptide in Combination With Gemcitabine For Patients With Advanced Pancreatic Cancer , 2013, Journal of immunotherapy.

[130]  H. Yamaue,et al.  Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancer , 2013, Journal of Translational Medicine.

[131]  David Goldstein,et al.  Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. , 2013, The New England journal of medicine.

[132]  L. Diaz,et al.  Evaluation of Ipilimumab in Combination With Allogeneic Pancreatic Tumor Cells Transfected With a GM-CSF Gene in Previously Treated Pancreatic Cancer , 2013, Journal of immunotherapy.

[133]  T. Sasada,et al.  A phase II study of a personalized peptide vaccination for chemotherapy-resistant advanced pancreatic cancer patients. , 2013, Oncology reports.

[134]  A. Alavi,et al.  A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma , 2013, Clinical Cancer Research.

[135]  Y. Qiu,et al.  Pancreatic carcinoma-specific immunotherapy using synthesised alpha-galactosyl epitope-activated immune responders: findings from a pilot study , 2013, International Journal of Clinical Oncology.

[136]  T. Karrison,et al.  A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma , 2013, Journal of Immunotherapy for Cancer.

[137]  Jonathan B. Mitchem,et al.  A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma , 2013, Investigational New Drugs.

[138]  K. Hirata,et al.  Immunotherapeutic benefit of α‐interferon (IFNα) in survivin2B‐derived peptide vaccination for advanced pancreatic cancer patients , 2013, Cancer science.

[139]  M. Pfreundschuh,et al.  Mutated Ras-transfected, EBV-transformed lymphoblastoid cell lines as a model tumor vaccine for boosting T-cell responses against pancreatic cancer: a pilot trial. , 2012, Human gene therapy.

[140]  Wenchuan Wu,et al.  A phase I pilot trial of MUC1-peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer , 2012, Clinical and Experimental Medicine.

[141]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

[142]  Y. Yonemitsu,et al.  Clinical and Immunologic Evaluation of Dendritic Cell–Based Immunotherapy in Combination With Gemcitabine and/or S-1 in Patients With Advanced Pancreatic Carcinoma , 2012, Pancreas.

[143]  E. Jaffee,et al.  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 , 2011, Clinical Cancer Research.

[144]  G. Abou-Alfa,et al.  Targeting Mutated K-ras in Pancreatic Adenocarcinoma Using an Adjuvant Vaccine , 2011, American journal of clinical oncology.

[145]  Pierre Michel,et al.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. , 2011, The New England journal of medicine.

[146]  T. Mussack,et al.  Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study , 2011, Cancer Immunology, Immunotherapy.

[147]  P. Spellman,et al.  Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy , 2011, Nature Medicine.

[148]  Drew A. Torigian,et al.  CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans , 2011, Science.

[149]  S. Yamada,et al.  A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer , 2011, Cancer Gene Therapy.

[150]  G. Gaudernack,et al.  Long‐term follow‐up of patients with resected pancreatic cancer following vaccination against mutant K‐ras , 2011, International journal of cancer.

[151]  K. Lillemoe,et al.  A Lethally Irradiated Allogeneic Granulocyte-Macrophage Colony Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Adenocarcinoma: A Phase II Trial of Safety, Efficacy, and Immune Activation , 2011, Annals of surgery.

[152]  H. Ueno,et al.  Phase 1 Trial of Wilms Tumor 1 (WT1) Peptide Vaccine and Gemcitabine Combination Therapy in Patients With Advanced Pancreatic or Biliary Tract Cancer , 2011, Journal of immunotherapy.

[153]  S. Rosenberg,et al.  Phase 2 Trial of Single Agent Ipilimumab (Anti-CTLA-4) for Locally Advanced or Metastatic Pancreatic Adenocarcinoma , 2010, Journal of immunotherapy.

[154]  T. Tani,et al.  A phase II study of personalized peptide vaccination combined with gemcitabine for non-resectable pancreatic cancer patients. , 2010, Oncology reports.

[155]  Yusuke Nakamura,et al.  Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer , 2010, Cancer science.

[156]  E. Jaffee,et al.  Allogeneic Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Immunotherapy Alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation , 2008, Clinical Cancer Research.

[157]  G. Gaudernack,et al.  Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study , 2006, British Journal of Cancer.

[158]  J. Wolchok,et al.  Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. , 2006, Cancer research.

[159]  K. Sugano,et al.  Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway. , 2006, Biochemical and biophysical research communications.

[160]  T. Taguchi,et al.  [Phase I study]. , 1995, Gan to kagaku ryoho. Cancer & chemotherapy.

[161]  J. Kench,et al.  Hypermutation In Pancreatic Cancer. , 2017, Gastroenterology.

[162]  L. Zheng,et al.  PD-L1 Expression in Pancreatic Cancer. , 2017, Journal of the National Cancer Institute.

[163]  Wei Zhu,et al.  Clinical outcome of immunotherapy with dendritic cell vaccine and cytokine-induced killer cell therapy in hepatobiliary and pancreatic cancer. , 2016, Molecular and clinical oncology.

[164]  M. Simpson,et al.  Emerging roles for hyaluronidase in cancer metastasis and therapy. , 2014, Advances in cancer research.

[165]  M. Talamonti,et al.  Addition of Algenpantucel-L Immunotherapy to Standard Adjuvant Therapy for Pancreatic Cancer: a Phase 2 Study , 2012, Journal of Gastrointestinal Surgery.

[166]  L. Grochow,et al.  Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[167]  G. Adler,et al.  Platelet-Derived Growth Factors Stimulate Proliferation and Extracellular Matrix Synthesis of Pancreatic Stellate Cells: Implications in Pathogenesis of Pancreas Fibrosis , 2000, Laboratory Investigation.