Specificity Delivers: Therapeutic Role of Tumor Antigen-Specific Antibodies in Pancreatic Cancer☆,☆☆
Section snippets
Mononclonal Antibody Developments Facing Challenges
Although tremendous efforts have been made in the clinical development of monoclonal antibody therapies to target neoplastic cells of PDA, the efficacy of these antibody therapies in treating PDA still needs to be demonstrated. Indeed, several monoclonal antibodies already have failed to prove their efficacy in phase III studies.
Lessons Learned From Current Antibody Therapy Developments
Multiple successful phase I and II trials have not resulted in any successful phase III trials. A thorough examination of the current monoclonal antibody PDA therapies sheds light on the challenges and drawbacks faced by these therapies. Understanding these issues will help design improved antibody drugs and trials going forward. At least five challenges stand out from this examination.
First, patients are not always screened for expression of the antibody targets; in some cases this is due to a
Where to Look for Potential Antigen Targets
A thorough genetic analysis of several PDAs revealed 12 cell signaling cascades that are frequently dysregulated in PDA.23 Proteins that are integral components of these commonly modified pathways provide a list of potential targets for PDA treatment.24 In addition, there has been growing evidence in the literature pointing towards the important role of the stromal compartment in PDA progression and metastasis.81, 82, 83 The majority of PDA consists of the stroma instead of the PDA cells and
Conclusion and Future Directions
Despite the numerous preclinical studies showing strong efficacy data for new monoclonal antibody therapies, similar successes have not been mirrored in clinical trials. Furthermore, favorable phase I and II clinical trials have not translated into successful phase III studies. PDA is a very complex cancer where not only the tumor cells, but also the tumor microenvironment, contribute substantively to PDA initiation, progression, and metastasis. This complexity helps explain why single-agent
References (158)
- et al.
Pancreatic cancer: progress in cancer therapy
Crit Rev Oncol Hematol
(2008) - et al.
Rituximab: ongoing and future clinical development
Semin Oncol
(2002) - et al.
Epidermal growth factor receptor: pathway, therapies, and pipeline
Clin Therapeut
(2013) - et al.
Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma
Ann Oncol
(2012) - et al.
Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial
Lancet Oncol
(2008) Improving treatment of pancreatic cancer
Lancet Oncol
(2008)- et al.
A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer
Ann Oncol
(2012) - et al.
Mesothelin targeted cancer immunotherapy
Eur J Cancer
(2008) - et al.
Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer
Ann Oncol
(2013) - et al.
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma
Cancer Cell
(2012)
Tumour–stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies
Cancer Treat Rev
Pancreatic cancer: the role of pancreatic stellate cells in tumor progression
Pancreatology
The role of the tumor microenvironment in the progression of pancreatic cancer
J Surg Res
Inflammatory networks and immune surveillance of pancreatic carcinoma
Curr Opin Immunol
Regulatory T cells in cancer
Blood
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial
J Clin Oncol
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer
N Engl J Med
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine
N Engl J Med
Comparing antibody and small-molecule therapies for cancer
Nat Rev Cancer
Current and future anti-HER2 therapy in breast cancer
J Buon
Clinical status and optimal use of rituximab for B-cell lymphomas
Oncology (Williston Park, NY)
EGFR-targeted therapies in colorectal cancer
Dis Colon Rect
American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy
J Clin Oncol
Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer
J Clin Oncol
Improved survival with ipilimumab in patients with metastatic melanoma
N Engl J Med
Ipilimumab and its toxicities: a multidisciplinary approach
Oncologist
Monoclonal antibody therapy of pancreatic cancer with cetuximab: potential for immune modulation
J Immunother
Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial
J Clin Oncol
Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205
J Clin Oncol
Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study
Br J Cancer
Phase II study of gemcitabine, oxaliplatin, and cetuximab in advanced pancreatic cancer
Am J Clin Oncol
Core signaling pathways in human pancreatic cancers revealed by global genomic analyses
Science (New York, NY)
Monoclonal antibodies and other targeted therapies for pancreatic cancer
Cancer J
KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy
Oncology
Cetuximab: still an option in the treatment of pancreatic cancer?
Exp Opin Biol Ther
AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells
Mol Cancer Ther
Epitope-specific mechanisms of IGF1R inhibition by ganitumab
PloS One
Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1
J Clin Oncol
Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types
Cancer Biol Ther
Insulin-like growth factor axis gene polymorphisms and clinical outcomes in pancreatic cancer
Gastroenterology
Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor
Clin Cancer Res
Insulin-like growth factor receptor inhibitors: baby or the bathwater?
J Natl Cancer Inst
Insulin-like growth factor: current concepts and new developments in cancer therapy
Recent Patents Anti-cancer Drug Disc
Anticancer IGF1R classes take more knocks
Nat Rev Drug Discov
VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells
Ann Surg Oncol
Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer
J Clin Oncol
The effects of bevacizumab on postoperative complications in patients undergoing colorectal and pancreatic cancer resection
J Surg Oncol
Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study
Br J Cancer
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Financial disclosures: Under a licensing agreement between Aduro BioTech, Inc and the Johns Hopkins University, Dr Jaffee and the University are entitled to milestone payments and royalty on sales of the vaccine product described here. The authors have no other relevant conflicts of interest to be disclosed.
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This work was supported by NIH K23 CA148964-01 (L.Z.), Johns Hopkins School of Medicine Clinical Scientist Award (L.Z.), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (E.M.J., L.Z.), The National Pancreas Foundation (L.Z.), Lefkofsky Family Foundation (L.Z.), the NCI SPORE in Gastrointestinal Cancers P50 CA062924 (E.M.J., L.Z.), Lustgarten Foundation (E.M.J., L.Z.), and the Sol Goldman Pancreatic Cancer Center (L.Z.), Dr Jaffee is the first recipient of the Dana and Albert “Cubby” Broccoli Endowed Professorship.