A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer

Preclinical tumor models show that chemotherapy has immune modulatory properties which can be exploited in the context of immunotherapy. The purpose of this study was to determine the feasibility and immunogenicity of combinations of such an immunomodulatory chemotherapeutic agent with immunotherapy...

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Published in:Oncotarget 2015-10, Vol.6 (31), p.32228-32243
Main Authors: Dijkgraaf, Eveline M, Santegoets, Saskia J A M, Reyners, An K L, Goedemans, Renske, Nijman, Hans W, van Poelgeest, Mariëtte I E, van Erkel, Arien R, Smit, Vincent T H B M, Daemen, Toos A H H, van der Hoeven, Jacobus J M, Melief, Cornelis J M, Welters, Marij J P, Kroep, Judith R, van der Burg, Sjoerd H
Format: Article
Language:English
Subjects:
Aged
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biomarkers, Tumor - analysis
Cancer Vaccines - administration & dosage
Cancer Vaccines - adverse effects
Cells, Cultured
Clinical Research Paper
Deoxycytidine - administration & dosage
Deoxycytidine - adverse effects
Deoxycytidine - analogs & derivatives
Drug Administration Schedule
Drug Resistance, Neoplasm
Feasibility Studies
Female
Humans
Interferon-alpha - administration & dosage
Interferon-alpha - adverse effects
Lymphocytes, Tumor-Infiltrating - drug effects
Lymphocytes, Tumor-Infiltrating - immunology
Middle Aged
Netherlands
Ovarian Neoplasms - chemistry
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - immunology
Ovarian Neoplasms - pathology
Platinum Compounds - therapeutic use
Polyethylene Glycols - administration & dosage
Polyethylene Glycols - adverse effects
Recombinant Proteins - administration & dosage
Recombinant Proteins - adverse effects
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
Time Factors
Treatment Outcome
Tumor Suppressor Protein p53 - administration & dosage
Tumor Suppressor Protein p53 - adverse effects
Tumor Suppressor Protein p53 - analysis
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Summary:Preclinical tumor models show that chemotherapy has immune modulatory properties which can be exploited in the context of immunotherapy. The purpose of this study was to determine the feasibility and immunogenicity of combinations of such an immunomodulatory chemotherapeutic agent with immunotherapy, p53 synthetic long peptide (SLP) vaccine and Pegintron (IFN-α) in patients with platinum-resistant p53-positive epithelial ovarian cancer (EOC). This is a phase 1/2 trial in which patients sequential 6 cycles of gemcitabine (1000 mg/kg2 iv; n = 3), gemcitabine with Pegintron before and after the first gemcitabine cycle (Pegintron 1 μg/kg sc; n = 6), and gemcitabine and Pegintron combined with p53 SLP vaccine (0.3 mg/peptide, 9 peptides; n = 6). At baseline, 22 days after the 2nd and 6th cycle, blood was collected for immunomonitoring. Toxicity, CA-125, and radiologic response were evaluated after 3 and 6 cycles of chemotherapy. None of the patients enrolled experienced dose-limiting toxicity. Predominant grade 3/4 toxicities were nausea/vomiting and dyspnea. Grade 1/2 toxicities consisted of fatigue (78%) and Pegintron-related flu-like symptoms (72%). Gemcitabine reduced myeloid-derived suppressor cells (p = 0.0005) and increased immune-supportive M1 macrophages (p = 0.04). Combination of gemcitabine and Pegintron stimulated higher frequencies of circulating proliferating CD4+ and CD8+ T-cells but not regulatory T-cells. All vaccinated patients showed strong vaccine-induced p53-specific T-cell responses. Combination of gemcitabine, the immune modulator Pegintron and therapeutic peptide vaccination is a viable approach in the development of combined chemo-immunotherapeutic regimens to treat cancer.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.4772