Oncotarget

Clinical Research Papers:

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

Eveline M. Dijkgraaf, Saskia J.A.M. Santegoets, An K.L. Reyners, Renske Goedemans, Hans W. Nijman, Mariëtte I.E. van Poelgeest, Arien R. van Erkel, Vincent T.H.B.M. Smit, Toos A.H.H. Daemen, Jacobus J.M. van der Hoeven, Cornelis J.M. Melief, Marij J.P. Welters, Judith R. Kroep and Sjoerd H. van der Burg _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:32228-32243. https://doi.org/10.18632/oncotarget.4772

Metrics: PDF 1099 views  |   HTML 1281 views  |   ?  


Abstract

Eveline M. Dijkgraaf1, Saskia J.A.M. Santegoets1, An K.L. Reyners2, Renske Goedemans1, Hans W. Nijman3, Mariëtte I.E. van Poelgeest4, Arien R. van Erkel5, Vincent T.H.B.M. Smit6, Toos A.H.H. Daemen7, Jacobus J.M. van der Hoeven1, Cornelis J.M. Melief8, Marij J.P. Welters1, Judith R. Kroep1,*, Sjoerd H. van der Burg1,*

1Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

2Department of Clinical Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands

3Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands

4Department of Gynecology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

5Department of Radiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

6Department of Pathology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

7Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands

8Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

*These authors have contributed equally to this work

Correspondence to:

Sjoerd H. van der Burg, e-mail: shvdburg@lumc.nl

Judith R. Kroep, e-mail: j.r.kroep@lumc.nl

Keywords: ovarian cancer, p53, immunotherapy, chemoresistance, tumor immunity

Received: May 27, 2015     Accepted: August 03, 2015     Published: August 14, 2015

ABSTRACT

Purpose: 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).

Experimental design: 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.

Results: 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.

Conclusion: 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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4772