Abstract
Background
Despite continued investigation, limited progress has been made in the adjuvant treatment of resected pancreatic cancer. Novel or targeted therapies are needed.
Methods
Multi-institutional, open-label, dose-finding, phase 2 trial evaluating the use of algenpantucel-L (NewLink Genetics Corporation, Ames, IA) immunotherapy in addition to chemotherapy and chemoradiotherapy in the adjuvant setting for resected pancreatic cancer (ClinicalTrials.gov identifier, NCT00569387). The primary outcome was 12-month disease-free survival. Secondary outcomes included overall survival and toxicity.
Results
Seventy patients were treated with gemcitabine and 5-fluorouracil-based chemoradiotherapy as well as algenpantucel-L (mean 12 doses, range 1–14). After a median follow-up of 21 months, the 12-month disease-free survival was 62 %, and the 12-month overall survival was 86 %. The most common adverse events were injection site pain and induration.
Conclusions
The addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A multi-institutional, phase 3 study is ongoing (ClinicalTrials.gov identifier, NCT01072981).
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Discussant
Dr. Christopher Wolfgang (Baltimore, MD): I would like to congratulate Dr. Hardacre and his colleagues on this well-done and well-presented study. I would also like to commend you in bringing together the multiple institutions to complete this trial in such a brief time.
While the current study does not directly prove efficacy of the vaccine, it does demonstrate an encouraging 1-year DFS of 62 %. This is favorable in comparison to historical survival data, which are in the range of 50 %, and to the contemporary RTOG 9704 trial that consists of a population of patients with identical adjuvant therapy minus the vaccine. Moreover, the dose–response of vaccine is highly suggestive of a specific biological response of the treatment. If these findings stand up in the phase III trial, it will be a significant leap forward in adjuvant therapy.
I have three questions:
1. It would be nice to know early in therapy if a particular patient will respond to the vaccine. In this way, alternative therapies can be considered in the nonresponders. As part of this study, or the upcoming phase III trial, are you assessing any parameters such as serum antibodies that may have the potential to predict response?
2. Knowing that chemotherapy, and to a greater extent chemoradiotherapy, is immunosuppressive can you comment on the timing of the chemoradiation in relation the administration of vaccine. Was there any consideration given to treating with chemoradiation in the neoadjuvant setting or even administering the vaccine in the neoadjuvant setting? The second part of this question is will these patients get continued vaccine boosts for life?
3. Finally, would you be able to give us some insight on the design of your phase III trial?
Closing discussant
Dr. Jeffrey M. Hardacre: Please respond here.
Chris, thank you so much for your comments and questions.
With regard to your first question, a number of correlative studies were done during the phase 2 study and are being done during the phase 3 study. They include the measurement of anti-CEA antibodies, anti-mesothelin antibodies, and anti-alpha-gal antibodies. The data from the phase 2 study suggest some trends in terms of antibody levels and clinical outcome, but the numbers are too small to make any definitive statement. Hopefully, with the larger population in the phase 3 trial some clear correlations will appear so that we can perhaps better individualize treatment. We have also seen some suggestion of persistent eosinophilia correlating with clinical outcome, and that will also be further looked into.
Your question regarding the timing of vaccination is one that I also had a difficult time conceptualizing. It does seem odd to be trying to stimulate the immune system with the vaccine while suppressing it with the standard adjuvant therapy. The rationale is the emerging concept of chemoimmunotherapy. The basis for the effectiveness of chemoimmunotherapy has multiple parts. The first is the direct cytotoxic effect of the chemotherapy. The second is antigen shedding. That is to say that the lysis of cancer cells may release tumor-specific antigens that enhance a patient’s immune response. The third is that the lymphotoxic effect of the chemotherapy may impact to a greater degree suppressor T cells as compared to cytotoxic T cells or natural killer cells. Finally, there is the concept of chemosensitization. There is literature suggesting that immunotherapy may make subsequent chemotherapy more effective. Anecdotally, we have three patients who, after recurrence, achieved complete radiographic responses to subsequent chemotherapy with the duration of response being 6–36 months. For the last part of this question, thought is being given to using the vaccine in the neoadjuvant setting for patients with borderline resectable cancers.
The phase 3 trial differs in a number of ways from the phase 2. The most important is that this is a randomized trial of standard adjuvant therapy with or without vaccine. Other differences include the fact that the primary outcome is overall survival and that there are options for the standard therapy. For the phase 3 trial, the standard therapy may be either gemcitabine alone or gemcitabine combined with 5FU-based radiation therapy. The patient and oncologist will decide on the type of standard therapy; then, the randomization to vaccine or no vaccine occurs. Also, given the potential dose–response seen in the phase 2 study, the vaccine dose is 300 million cells in the phase 3, and patients will get booster vaccines monthly out to 1 year after completing the standard therapy. Lastly, the window for starting therapy after surgery has been extended to 10 weeks, which should allow a few more people to enroll that may not have recovered enough at 6–7 weeks.
Appendix: Participating Institutions
Appendix: Participating Institutions
University Hospitals Seidman Cancer Center/Case Western Reserve University
Northshore University Health System
Rhode Island Hospital
Northwestern University
University of Miami
Indiana University Melvin and Bren Simon Cancer Center
University of Southern California
Thomas Jefferson University
University of Colorado
Mayo Clinic-Scottsdale
California Pacific Medical Center
Baylor College of Medicine
Lahey Clinic
University of Texas-San Antonio
University of California-Irvine
University of New Mexico
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Hardacre, J.M., Mulcahy, M., Small, W. et al. Addition of Algenpantucel-L Immunotherapy to Standard Adjuvant Therapy for Pancreatic Cancer: a Phase 2 Study. J Gastrointest Surg 17, 94–101 (2013). https://doi.org/10.1007/s11605-012-2064-6
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DOI: https://doi.org/10.1007/s11605-012-2064-6