Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission.

Abstract

PURPOSE:

In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Immunotherapy may have potential for consolidation therapy.

EXPERIMENTAL DESIGN:

This randomized open-label phase I/II trial evaluated responses of patients with advanced ovarian cancer in remission for vaccination with monocyte-derived dendritic cells (DC) loaded with Her2/neu, hTERT, and PADRE peptides, with or without low-dose intravenous cyclophosphamide. All patients also received pneumococcal vaccine and were randomized to cyclophosphamide 2 days prior to first vaccination. Blood samples were analyzed by ELISPOT and flow cytometry.

RESULTS:

Of 11 patients, 2 recurred during vaccination. Nine received all 4 doses: 3 patients recurred at 6, 17, and 26 months, respectively, and 6 have no evidence of disease at 36 months. No grade 3/4 vaccine-related toxicities were noted. The 3-year overall survival was 90%. Patients receiving cyclophosphamide showed a non-significant improvement in survival over controls. Patients receiving cyclophosphamide had a transient reduction in neutrophils, but no change in total lymphocytes or regulatory T cells. Modest T-cell responses to Her2/neu and hTERT were seen post-vaccine by IFN-γ ELISPOT. Patients demonstrated below normal responses to the diphtheria conjugate protein CRM197, a component of the pneumococcal vaccine.

CONCLUSIONS:

In this setting, peptide-loaded DC vaccination elicits modest immune responses, but survival is promising. Pneumococcal vaccination revealed substantial immune suppression, even in patients in remission. Rational design of consolidative strategies for ovarian cancer will need to overcome tolerance and immunosuppression.

• Authors: Christina S Chu, Jean Boyer, Daniel S Schullery, Phyllis A Gimotty, Victoria Gamerman, James Bender, Bruce L Levine, George Coukos, Stephen C Rubin, Mark A Morgan, Robert H Vonderheide, Carl H June
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 61 Issue 5 Pg. 629-41 (May 2012) ISSN: 1432-0851 [Electronic] Germany
• PMID: 22021066 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Bacterial Proteins
• Cancer Vaccines
• Malaria Vaccines
• PADRE 45
• Peptide Fragments
• Pneumococcal Vaccines
• CRM197 (non-toxic variant of diphtheria toxin)
• Interferon-gamma
• Cyclophosphamide
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adolescent
• Adult
• Bacterial Proteins (immunology)
• Cancer Vaccines (immunology, therapeutic use)
• Combined Modality Therapy
• Cyclophosphamide (therapeutic use)
• Dendritic Cells (immunology)
• Drug Synergism
• Female
• Humans
• Immunotherapy, Adoptive (methods)
• Interferon-gamma (immunology)
• Malaria Vaccines (immunology)
• Middle Aged
• Monocytes (immunology)
• Neoplasm Recurrence, Local (immunology, prevention & control)
• Neutrophils (immunology)
• Ovarian Neoplasms (immunology, therapy)
• Peptide Fragments (immunology)
• Pneumococcal Vaccines (immunology, therapeutic use)
• Receptor, ErbB-2 (immunology)
• Survival Rate
• T-Lymphocytes, Regulatory (immunology)
• Young Adult