Elsevier

Seminars in Oncology

Volume 41, Issue 5, October 2014, Pages 559-575
Seminars in Oncology

Specificity Delivers: Therapeutic Role of Tumor Antigen-Specific Antibodies in Pancreatic Cancer,☆☆

https://doi.org/10.1053/j.seminoncol.2014.07.001Get rights and content

Pancreatic ductal adenocarcinoma (PDA) is among the most deadly cancers with less than 5% of the patients living beyond 5 years post-diagnosis. Lack of early diagnostic biomarkers and resistance to current therapies help explain these disappointing numbers. Thus, more effective and better-targeted therapies are needed quickly. Monoclonal antibodies offer an attractive alternative targeted therapy option for PDA because they are highly specific and potent. However, currently available monoclonal antibody therapies for PDA are still in their infancy with a low success rate and low likelihood of being approved. The challenges faced by these therapies include the following: lack of predictive and response biomarkers, unfavorable safety profiles, expression of targets not restricted to the cancer cells, flawed preclinical model systems, drug resistance, and PDA’s complex nature. Additionally, discovery of novel PDA-specific antigen targets, present on the cell surface or in the extracellular matrix, is needed. Predictive and response markers also need to be determined for PDA patient subgroups so that the most appropriate effective therapy can be delivered. Serologic approaches, recombinant antibody-producing technologies, and advances in antibody engineering techniques will help to identify these predictive biomarkers and aid in the development of new therapeutic antibodies. A combinatorial approach simultaneously targeting antigens on the PDA cell, stroma, and immunosuppressive cells should be employed.

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

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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.

    ☆☆

    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.

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