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

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Annals of surgery (Impact Factor: 8.33). 01/2011; 253(2):328-35. DOI: 10.1097/SLA.0b013e3181fd271c
Source: PubMed


Surgical resection provides the only possibility of cure for pancreas cancer. A standard adjuvant approach has not been established. We tested the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma.
A single institution phase II study of 60 patients with resected pancreatic adenocarcinoma was performed. Each immunotherapy treatment consisted of a total of 5 × 108 GM-CSF-secreting cells distributed equally among 3 lymph node regions. The first immunotherapy treatment was administered 8 to 10 weeks after surgical resection. Subsequently, patients received 5-FU based chemoradiation. Patients who remained disease-free after completion of chemoradiotherapy received treatments 2 to 4, each 1 month apart. A fifth and final booster was administered 6 months after the fourth immunotherapy. The primary endpoint was disease free survival and secondary endpoints were overall survival and toxicity, and the induction of mesothelin specific T cell responses.
The median disease-free survival is 17.3 months (95% CI, 14.6-22.8) with median survival of 24.8 months (95% CI, 21.2-31.6). The administration of immunotherapy was well tolerated. In addition, the post-immunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+patients correlates with disease-free survival.
An immunotherapy approach integrated with chemoradiation is safe and demonstrates an overall survival that compares favorably with published data for resected pancreas cancer. These data suggest additional boost immunotherapies given at regular intervals beyond 1 year postsurgery should be tested in future studies, and provide the rationale for conducting a multicenter phase II study.

Download full-text


Available from: Rajni B Sharma
  • Source
    • "In general, the tumor microenvironment shifts to immunosuppressive with an increase in the number of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) [36], [37] in accordance with cancer progression. However, the immunosuppressive state may vary among cancer types because a recent clinical trial reported no increase in the number of suppressor cells in pancreatic cancer [38]. It may be beneficial to co-administer anti-CTLA4/PD1 antibodies [39], [40] or a low dose of anti-cancer drugs such as cyclophosphamide or gemcitabine [41]–[43] to inhibit Treg- and MDSC-mediated immunosuppression, although there may be side effects of autoimmune-like disorders and bone marrow suppression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyplex micelles have demonstrated biocompatibility and achieve efficient gene transfection in vivo. Here, we investigated a polyplex micelle encapsulating genes encoding the tumor-associated antigen squamous cell carcinoma antigen recognized by T cells-3 (SART3), adjuvant CD40L, and granulocyte macrophage colony-stimulating factor (GM-CSF) as a DNA vaccine platform in mouse tumor models with different types of major histocompatibility antigen complex (MHC). Intraperitoneally administrated polyplex micelles were predominantly found in the lymph nodes, spleen, and liver. Compared with mock controls, the triple gene vaccine significantly prolonged the survival of mice harboring peritoneal dissemination of CT26 colorectal cancer cells, of which long-term surviving mice showed complete rejection when re-challenged with CT26 tumors. Moreover, the DNA vaccine inhibited the growth and metastasis of subcutaneous CT26 and Lewis lung tumors in BALB/c and C57BL/6 mice, respectively, which represent different MHC haplotypes. The DNA vaccine highly stimulated both cytotoxic T lymphocyte and natural killer cell activities, and increased the infiltration of CD11c+ DCs and CD4+/CD8a+ T cells into tumors. Depletion of CD4+ or CD8a+ T cells by neutralizing antibodies deteriorated the anti-tumor efficacy of the DNA vaccine. In conclusion, a SART3/CD40L+GM-CSF gene-loaded polyplex micelle can be applied as a novel vaccine platform to elicit tumor rejection immunity regardless of the recipient MHC haplotype.
    Full-text · Article · Jul 2014 · PLoS ONE
  • Source
    • "Dendritic cell/ autologous tumor cell fusions Myeloma/DC fusion Myeloma Avigan et al. (2004) Allogeneic GVAX (+GM-CSF) Pancreatic Laheru et al. (2008), Lutz et al. (2011), Emens et al. (2009) Recombinant vectors "
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic cancer vaccines have the potential of being integrated in the therapy of numerous cancer types and stages. The wide spectrum of vaccine platforms and vaccine targets is reviewed along with the potential for development of vaccines to target cancer cell "stemness," the epithelial-to-mesenchymal transition (EMT) phenotype, and drug-resistant populations. Preclinical and recent clinical studies are now revealing how vaccines can optimally be used with other immune-based therapies such as checkpoint inhibitors, and so-called nonimmune-based therapeutics, radiation, hormonal therapy, and certain small molecule targeted therapies; it is now being revealed that many of these traditional therapies can lyse tumor cells in a manner as to further potentiate the host immune response, alter the phenotype of nonlysed tumor cells to render them more susceptible to T-cell lysis, and/or shift the balance of effector:regulatory cells in a manner to enhance vaccine efficacy. The importance of the tumor microenvironment, the appropriate patient population, and clinical trial endpoints is also discussed in the context of optimizing patient benefit from vaccine-mediated therapy.
    Full-text · Article · Jun 2014 · Advances in Cancer Research
  • Source
    • "Other Phase II clinical trials were reported with less encouraging results. Lutz et al. [33] designed a single-institution adjuvant study of 60 patients with resected PDA who received an initial injection of an irradiated GM-CSF transfected whole cell vaccine followed by 5-FU-based chemo-radiation therapy and up to four additional immunizations. Median DFS and OS were 17.3 and 24.8 months, respectively. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the last couple of years, we have witnessed the availability of a wide variety of different therapeutic agents and the identification of effective combinations of existing ones that have transformed the way we approach and treat pancreatic cancer. Proof of this are the recent validations that combinations of conventional chemotherapy drugs, the FOLFIRINOX regimen and gemcitabine plus nab-paclitaxel, significantly improves clinical outcomes in patients with metastatic disease. However, deeper and more sophisticated understanding of the biology of this cancer as well as the ability to develop better and perhaps more precise drugs predict that the landscape may be changing even more. In this review, we will summarize the most recent treatment advances including FOLFIRINOX, gemcitabine plus nab-paclitaxel and discuss novel approaches such as immune-mediated therapies, drugs that disrupt the tumor-stromal compartment, PARP inhibitors for BRCA pathway-deficient pancreatic cancer and new generations of conventional chemotherapeutics, which are in early phases of clinical development and have shown promising early results. We will also discuss some examples of drugs that failed, despite very good preliminary data, in order to appraise the lessons learned from these negative clinical trials. Lastly, we will comment on ongoing adjuvant and neoadjuvant trials. We hope that at least some of these will result in positive trials and add to our armamentarium for treating this challenging malignancy.
    Preview · Article · Dec 2013 · Journal of Gastrointestinal Cancer
Show more