Annals of Surgical Oncology

, Volume 20, Supplement 3, pp 725–730 | Cite as

Low Total Lymphocyte Count Is Associated with Poor Survival in Patients with Resected Pancreatic Adenocarcinoma Receiving a GM-CSF Secreting Pancreatic Tumor Vaccine

  • Aaron J. Schueneman
  • Elizabeth A. Sugar
  • Jennifer Uram
  • Elaine Bigelow
  • Joseph M. Herman
  • Barish H. Edil
  • Elizabeth M. Jaffee
  • Lei Zheng
  • Daniel A. Laheru
Translational Research and Biomarkers



Low total lymphocyte count (TLC) and lymphocyte-to-neutrophil ratio have been found to be poor prognostic indicators in several different tumor types at various stages. Although immune-based therapies are under rapid development, it is not known whether baseline complete blood counts, particularly lymphocytes, are associated with the clinical outcomes of patients receiving immunotherapies.


We performed a retrospective analysis of complete blood count for 59 patients enrolled onto a phase II trial evaluating the integration of an adjuvant immunotherapy—irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor vaccine (GVAX)—with standard chemoradiation.


After adjusting for nodal status, individuals with a TLC of <1,500 cells/mm3 (10 patients) had significantly higher risk, both in terms of overall survival (OS) [adjusted hazard ratio 2.63, 95 % confidence interval (CI) 1.22–5.67, p = 0.013] and progression-free survival (adjusted hazard ratio 3.07, 95 % CI 1.03–6.93, p = 0.003), compared to those with a TLC of ≤1,500 cells/mm3 (49 patients). Adjuvant chemoradiation significantly reduced lymphocyte counts from baseline values. Patients with suppression of their lymphocytes to <500 cells/mm3 after chemoradiation also had shorter disease-free and OS.


Immunosuppressive conditions associated with surgical procedures and chemoradiation may affect the efficacy of immunotherapy.


Overall Survival Pancreatic Cancer Complete Blood Count Lymphocyte Count Ipilimumab 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by the NCI SPORE in Gastrointestinal Cancers P50 CA062924-14 (E. M. J.), Viragh Foundation (D. L., E. M. J., E. A. S), NIH K23 CA93566 (D. L.), the Sol Goldman Pancreatic Cancer Center (L. Z.), NIH K23 CA148964 (L. Z.) and a Johns Hopkins University School of Medicine Clinician Scientist Award (L. Z.). Dr. Jaffee is the first recipient of the Dana and Albert “Cubby” Broccoli Endowed Professorship.


Under a licensing agreement between Aduro BioTech and the Johns Hopkins University, Dr. Jaffee and the university are entitled to milestone payments and royalty on sales of the vaccine product described in this article. We do not have any other relevant conflicts of interest to be disclosed.

Supplementary material

10434_2013_3262_MOESM1_ESM.pdf (63 kb)
Supplementary material 1 (PDF 62 kb)


  1. 1.
    Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.PubMedCrossRefGoogle Scholar
  3. 3.
    Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedCrossRefGoogle Scholar
  4. 4.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedCrossRefGoogle Scholar
  5. 5.
    Pierantoni C, Pagliacci A, Scartozzi M, Berardi R, Bianconi M, Cascinu S. Pancreatic cancer: progress in cancer therapy. Crit Rev Oncol Hematol. 2008;67:27–38.PubMedCrossRefGoogle Scholar
  6. 6.
    Picozzi VJ, Pisters PW, Vickers SM, Strasberg SM. Strength of the evidence: adjuvant therapy for resected pancreatic cancer. J Gastrointest Surg. 2008;12:657–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Jaffee EM, Hruban RH, Biedrzycki B, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol. 2001;19:145–56.PubMedGoogle Scholar
  8. 8.
    Laheru D, Lutz E, Burke J, 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. Clin Cancer Res. 2008;14:1455–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Lutz E, Yeo CJ, Lillemoe KD, 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. Ann Surg. 2011;253:328–35.PubMedCrossRefGoogle Scholar
  10. 10.
    Thomas AM, Santarsiero LM, Lutz ER, et al. Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med. 2004;200:297–306.PubMedCrossRefGoogle Scholar
  11. 11.
    Grossman SA, Ye X, Lesser G, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res. 2011;17:5473–80.PubMedCrossRefGoogle Scholar
  12. 12.
    Sato H, Tsubosa Y, Kawano T. Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg. 2012;36:617–22.PubMedCrossRefGoogle Scholar
  13. 13.
    Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non–small cell lung cancer. J Thorac Cardiovasc Surg. 2009;137:425–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Garcea G, Ladwa N, Neal CP, et al. Preoperative neutrophil-to-lymphocyte ratio (NLR) is associated with a reduced disease-free survival following curative resection of pancreatic adenocarcinoma. World J Surg. 2011;35:868–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Fabris N, Piantanelli L. Differential effect of pancreatectomy on humoral and cell-mediated immune responses. Clin Exp Immunol. 1977;28:315–25.PubMedGoogle Scholar
  16. 16.
    Takahashi K, Toyokawa H, Takai S, et al. Surgical influence of pancreatectomy on the function and count of circulating dendritic cells in patients with pancreatic cancer. Cancer Immunol Immunother. 2006;55:775–84.PubMedCrossRefGoogle Scholar
  17. 17.
    Terando A, Mule JJ. On combining antineoplastic drugs with tumor vaccines. Cancer Immunol Immunother. 2003;52:680–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Emens LA, Machiels JP, Reilly RT, Jaffee EM. Chemotherapy: friend or foe to cancer vaccines? Curr Opin Mol Ther. 2001;3:77–84.PubMedGoogle Scholar
  19. 19.
    Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019–26.PubMedCrossRefGoogle Scholar
  20. 20.
    Lissoni P, Brivio F, Fumagalli L, et al. Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors. Int J Biol Markers. 2004;19:135–40.PubMedGoogle Scholar
  21. 21.
    De Angulo G, Hernandez M, Morales-Arias J, et al. Early lymphocyte recovery as a prognostic indicator for high-risk Ewing sarcoma. J Pediatr Hematol Oncol. 2007;29:48–52.PubMedCrossRefGoogle Scholar
  22. 22.
    Clark EJ, Connor S, Taylor MA, Madhavan KK, Garden OJ, Parks RW. Preoperative lymphocyte count as a prognostic factor in resected pancreatic ductal adenocarcinoma. HPB (Oxford). 2007;9:456–60.CrossRefGoogle Scholar
  23. 23.
    Bhatti I, Peacock O, Lloyd G, Larvin M, Hall RI. Preoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil–lymphocyte versus platelet–lymphocyte ratio. Am J Surg. 2010;200:197–203.PubMedCrossRefGoogle Scholar
  24. 24.
    Kanda M, Fujii T, Kodera Y, Nagai S, Takeda S, Nakao A. Nutritional predictors of postoperative outcome in pancreatic cancer. Br J Surg. 2011;98:268–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Balmanoukian A, Ye X, Herman J, Laheru D, Grossman SA. The association between treatment-related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas. Cancer Invest. 2012;30:571–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Porrata LF, Markovic SN. Is absolute lymphocyte count just another prognostic factor in cancer? SRX Med. 2010. doi: 10.3814/2010/812304.Google Scholar
  27. 27.
    Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Miyazaki M. Immunosuppression following surgical and traumatic injury. Surg Today. 2010;40:793–808.PubMedCrossRefGoogle Scholar
  28. 28.
    Tashiro T, Yamamori H, Takagi K, et al. Changes in immune function following surgery for esophageal carcinoma. Nutrition. 1999;15:760–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Corrigan M, Cahill RA, Redmond HP. The immunomodulatory effects of laparoscopic surgery. Surg Laparosc Endosc Percutan Tech. 2007;17:256–61.PubMedCrossRefGoogle Scholar
  30. 30.
    Hegarty N, Dasgupta P. Immunological aspects of minimally invasive oncologic surgery. Curr Opin Urol. 2008;18:129–33.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2013

Authors and Affiliations

  • Aaron J. Schueneman
    • 2
  • Elizabeth A. Sugar
    • 1
    • 5
    • 7
  • Jennifer Uram
    • 1
    • 5
  • Elaine Bigelow
    • 1
    • 5
  • Joseph M. Herman
    • 1
    • 4
    • 5
    • 6
  • Barish H. Edil
    • 1
    • 5
    • 6
    • 8
  • Elizabeth M. Jaffee
    • 1
    • 5
    • 6
  • Lei Zheng
    • 1
    • 5
    • 6
    • 3
  • Daniel A. Laheru
    • 1
    • 5
    • 6
  1. 1.Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of SurgeryJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Department of Radiation OncologyJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.The Skip Viragh Center for Pancreatic Cancer Research and Clinical CareJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.The Sol Goldman Pancreatic Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA
  7. 7.Departments of Biostatistics and Epidemiology, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA
  8. 8.Pancreas and Biliary Surgery Program, Department of SurgeryUniversity of ColoradoAuroraUSA

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