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


METHODS
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.


CONCLUSIONS
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.
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Eveline M
EM
Dijkgraaf
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Saskia J A M
SJ
Santegoets
Department of Clinical Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands.
An K L
AK
Reyners
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Renske
R
Goedemans
Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands.
Hans W
HW
Nijman
Department of Gynecology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Mariëtte I E
MI
van Poelgeest
Department of Radiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Arien R
AR
van Erkel
Department of Pathology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Vincent T H B M
VT
Smit
Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands.
Toos A H H
TA
Daemen
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Jacobus J M
JJ
van der Hoeven
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Cornelis J M
CJ
Melief
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Marij J P
MJ
Welters
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Judith R
JR
Kroep
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Sjoerd H
SH
van der Burg
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D009426:Netherlands; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017671:Platinum Compounds / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis; D000093542:Gemcitabine
D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D017671:Platinum Compounds; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000609547:p53 synthetic long peptide vaccine; D003841:Deoxycytidine; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b; D000093542:Gemcitabine
Clinical Section; chemoresistance; immunotherapy; ovarian cancer; p53; tumor immunity