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

Purpose: The combination of chemotherapy and immunotherapy has not been examined in patients with advanced pancreatic cancer. We conducted a study of two granulocyte macrophage colony-stimulating factor–secreting pancreatic cancer cell lines (CG8020/CG2505) as immunotherapy administered alone or in sequence with cyclophosphamide in patients with advanced pancreatic cancer. Experimental Design: This was an open-label study with two cohorts: cohort A, 30 patients administered a maximum of six doses of CG8020/CG2505 at 21-day intervals; and cohort B, 20 patients administered 250 mg/m2 of cyclophosphamide i.v. 1 day before the same immunotherapy given as in cohort A. The primary objective was to evaluate safety and duration of immunity. Secondary objectives included time to disease progression and median overall survival. Results: The administration of CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity. Median survival values in cohort A and cohort B were 2.3 and 4.3 months, respectively. CD8+ T-cell responses to HLA class I–restricted mesothelin epitopes were identified predominantly in patients treated with cyclophosphamide + CG8020/CG2505 immunotherapy. Conclusion: Granulocyte macrophage colony-stimulating factor–secreting pancreatic cancer cell lines CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity in patients with advanced pancreatic cancer. Also, mesothelin-specific T-cell responses were detected/enhanced in some patients treated with CG8020/CG2505 immunotherapy. In addition, cyclophosphamide-modulated immunotherapy resulted in median survival in a gemcitabine-resistant population similar to chemotherapy alone. These findings support additional investigation of cyclophosphamide with CG8020/CG2505 immunotherapy in patients with advanced pancreatic cancer.

[1]  P. Murawa,et al.  Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  H. Kindler,et al.  Pancreatic cancer: An update , 2007, Current oncology reports.

[3]  Dervenis Ch..  Pancreatic Cancer: An update , 2007 .

[4]  S. Watson,et al.  G17DT: an antigastrin immunogen for the treatment of gastrointestinal malignancy , 2007, Expert opinion on biological therapy.

[5]  Eileen M O'Reilly,et al.  Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  H. Einsele,et al.  Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  A. Jemal,et al.  Cancer Statistics, 2006 , 2006, CA: a cancer journal for clinicians.

[8]  M. Tempero,et al.  Phase II study of fixed dose rate gemcitabine with cisplatin for metastatic adenocarcinoma of the pancreas. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  A. Dachman,et al.  Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  D. V. Von Hoff,et al.  A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  R. Labianca,et al.  Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  E. Jaffee,et al.  Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response , 2005, The Journal of experimental medicine.

[13]  J. Schlom,et al.  Phase I Study of Immunization with Dendritic Cells Modified with Fowlpox Encoding Carcinoembryonic Antigen and Costimulatory Molecules , 2005, Clinical Cancer Research.

[14]  H. Burris,et al.  Phase II trial of oral rubitecan in previously treated pancreatic cancer patients. , 2005, The oncologist.

[15]  R. Day,et al.  Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer , 2005, Cancer Immunology, Immunotherapy.

[16]  J. Marshall,et al.  Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  W. Miller,et al.  Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  S. Watson,et al.  The Biological and Therapeutic Importance of Gastrin Gene Expression in Pancreatic Adenocarcinomas , 2004, Cancer Research.

[19]  R. Hruban,et al.  Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients , 2004, The Journal of experimental medicine.

[20]  R. Wolff,et al.  Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  M. Reni,et al.  Salvage Chemotherapy with Mitomycin, Docetaxel, and Irinotecan (MDI Regimen) in Metastatic Pancreatic Adenocarcinoma: A Phase I and II Trial , 2004, Cancer investigation.

[22]  J. Hainsworth,et al.  Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  W. Scheithauer,et al.  Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma , 2003, British Journal of Cancer.

[24]  J. Abbruzzese,et al.  Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  P. Homel,et al.  Irinotecan combined with gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (G-FLIP) is an effective and noncrossresistant treatment for chemotherapy refractory metastatic pancreatic cancer. , 2001, The oncologist.

[26]  B. Sandmaier,et al.  Theratope® vaccine (STn-KLH) , 2001, Expert opinion on biological therapy.

[27]  S. Hammarström.  The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. , 1999, Seminars in cancer biology.

[28]  E. Jaffee,et al.  Enhanced tumor protection by granulocyte-macrophage colony-stimulating factor expression at the site of an allogeneic vaccine. , 1998, Human gene therapy.

[29]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  E. Jaffee,et al.  Enhanced immune priming with spatial distribution of paracrine cytokine vaccines. , 1996, Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy.

[31]  E. Thorsby,et al.  Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation , 1995, The Lancet.

[32]  R. Henderson,et al.  MUC‐1 Epithelial Tumor Mucin‐Based Immunity and Cancer Vaccines , 1995, Immunological reviews.

[33]  S. Goodman,et al.  K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. , 1993, The American journal of pathology.

[34]  E. Jaffee,et al.  Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Decaprio,et al.  Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II trial. , 1991, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  E. Casper,et al.  Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. , 1991, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[38]  H. Maguire,et al.  Induction of cell-mediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide. , 1986, Cancer research.

[39]  F. Mícek.  [Cancer of the pancreas]. , 1965, Bratislavske lekarske listy.

[40]  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.