A Pilot Study of MUC-1/CEA/TRICOM Poxviral-Based Vaccine in Patients with Metastatic Breast and Ovarian Cancer

Purpose: PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients. Experimental design: Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated. Results: These patients were heavily pretreated, with 21 of 26 patients having 3 or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1–37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remained on study for 37 months or more, with a significant drop in serum interleukin (IL)-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. For the ovarian cancer patients (n = 14), the median time to progression was 2 months (1–6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months. Conclusions: Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted. Clin Cancer Res; 17(22); 7164–73. ©2011 AACR.

[1]  J. Schlom,et al.  Impact of tumour volume on the potential efficacy of therapeutic vaccines. , 2011, Current oncology.

[2]  J. Marshall,et al.  Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  R. Amato,et al.  MVA–5T4-induced immune responses are an early marker of efficacy in renal cancer patients , 2011, Cancer Immunology, Immunotherapy.

[4]  Laurence Zitvogel,et al.  Immune parameters affecting the efficacy of chemotherapeutic regimens , 2011, Nature Reviews Clinical Oncology.

[5]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[6]  P. Kantoff,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010, The New England journal of medicine.

[7]  S. Steinberg,et al.  Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer , 2010, Cancer Immunology, Immunotherapy.

[8]  P. Kantoff,et al.  Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  P. Schellhammer,et al.  Integrated data from 2 randomized, double‐blind, placebo‐controlled, phase 3 trials of active cellular immunotherapy with sipuleucel‐T in advanced prostate cancer , 2009, Cancer.

[10]  L. Yin,et al.  Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. , 2009, Cancer research.

[11]  R. Weichselbaum,et al.  MUC1-induced transcriptional programs associated with tumorigenesis predict outcome in breast and lung cancer. , 2009, Cancer research.

[12]  J. Schlom,et al.  Combination of Docetaxel and Recombinant Vaccine Enhances T-Cell Responses and Antitumor Activity: Effects of Docetaxel on Immune Enhancement , 2008, Clinical Cancer Research.

[13]  S. Steinberg,et al.  Pilot Study of Vaccination with Recombinant CEA-MUC-1-TRICOM Poxviral-Based Vaccines in Patients with Metastatic Carcinoma , 2008, Clinical Cancer Research.

[14]  J. Schlom,et al.  Enhanced Functionality of CD4+CD25highFoxP3+ Regulatory T Cells in the Peripheral Blood of Patients with Prostate Cancer , 2008, Clinical Cancer Research.

[15]  G. Andriole,et al.  Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer: Small EJ, Schellhammer PF, Higano CS, et al (Univ of California San Francisco; Sharp Healthcare, San Diego, Calif; Eastern Virginia Med , 2007 .

[16]  B. Blumenstein,et al.  Lessons from randomized phase III studies with active cancer immunotherapies--outcomes from the 2006 meeting of the Cancer Vaccine Consortium (CVC). , 2007, Vaccine.

[17]  D. Kufe,et al.  Evolution of the human MUC1 oncoprotein. , 2007, International journal of oncology.

[18]  J. Schlom,et al.  Cancer Vaccines: Moving Beyond Current Paradigms , 2007, Clinical Cancer Research.

[19]  R. Madan,et al.  PANVAC™-VF: poxviral-based vaccine therapy targeting CEA and MUC1 in carcinoma , 2007, Expert opinion on biological therapy.

[20]  P. Schellhammer,et al.  Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  J. Gulley,et al.  A randomized phase II study of docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in patients with metastatic breast cancer (NCI 05-C-0229). , 2006, Clinical breast cancer.

[22]  S. Steinberg,et al.  A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  U. Karsten,et al.  What Makes MUC1 a Tumor Antigen? , 2005, Tumor Biology.

[24]  J. Gribben,et al.  Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy , 2005, Clinical Cancer Research.

[25]  J. Schlom,et al.  Multiple Costimulatory Modalities Enhance CTL Avidity , 2005, The Journal of Immunology.

[26]  H. Fujii,et al.  Distribution of CD4+CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. , 2005, The Journal of surgical research.

[27]  J. Schlom,et al.  Sublethal Irradiation of Human Tumor Cells Modulates Phenotype Resulting in Enhanced Killing by Cytotoxic T Lymphocytes , 2004, Cancer Research.

[28]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[29]  J. Manola,et al.  Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  H. Kaufman,et al.  Poxvirus vaccines for cancer and HIV therapy , 2004, Expert opinion on biological therapy.

[31]  C. N. Coleman,et al.  Irradiation of Tumor Cells Up-Regulates Fas and Enhances CTL Lytic Activity and CTL Adoptive Immunotherapy , 2003, The Journal of Immunology.

[32]  J. Marshall Carcinoembryonic antigen-based vaccines. , 2003, Seminars in oncology.

[33]  J. Schlom,et al.  Vaccine therapy of established tumors in the absence of autoimmunity. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  S. Steinberg,et al.  Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV‐PSA) in patients with metastatic androgen‐independent prostate cancer , 2002, The Prostate.

[35]  J. Schlom,et al.  Synergy of vaccine strategies to amplify antigen-specific immune responses and antitumor effects. , 2001, Cancer research.

[36]  E. Jaffee,et al.  Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. , 2001, Cancer research.

[37]  J. Schlom,et al.  The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  S. Steinberg,et al.  The use of a rapid ELISPOT assay to analyze peptide-specific immune responses in carcinoma patients to peptide vs. recombinant poxvirus vaccines , 2000, Cancer Immunology, Immunotherapy.

[39]  E. Gehan,et al.  Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  M. Peshwa,et al.  Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  J. Schlom,et al.  A triad of costimulatory molecules synergize to amplify T-cell activation. , 1999, Cancer research.

[42]  J. Schlom,et al.  Diversified prime and boost protocols using recombinant vaccinia virus and recombinant non-replicating avian pox virus to enhance T-cell immunity and antitumor responses. , 1997, Vaccine.

[43]  D. Baxby Recombinant poxvirus vaccines , 1993 .

[44]  Abraham Fuks,et al.  Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule , 1989, Cell.

[45]  T. Wölfel,et al.  The use of HLA-A*0201-transfected K562 as standard antigen-presenting cells for CD8(+) T lymphocytes in IFN-gamma ELISPOT assays. , 2002, Journal of immunological methods.

[46]  J. Schlom,et al.  Granulocyte/macrophage-colony stimulating factor produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-presenting cells and acts as an immunoadjuvant. , 2001, Cancer research.