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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Hematology & Oncology 1/2017

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2017
Autoren:
Shikhar Mehrotra, Carolyn D. Britten, Steve Chin, Elizabeth Garrett-Mayer, Colleen A. Cloud, Mingli Li, Gina Scurti, Mohamed L. Salem, Michelle H. Nelson, Melanie B. Thomas, Chrystal M. Paulos, Andres M. Salazar, Michael I. Nishimura, Mark P. Rubinstein, Zihai Li, David J. Cole
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-017-0459-2) contains supplementary material, which is available to authorized users.

Abstract

Background

Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).

Methods

We generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells.

Results

Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I –tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease.

Conclusion

Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.

Trial registration

NCT01410968; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).

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Zusatzmaterial
Additional file 1: Figure S1. Cytokine secretion by DCs. Frozen DCs obtained from patients were thawed and cultured with GM-CSF/IL-4 overnight before adding poly (IC:LC) for maturation overnight. The supernatant was collected after 16 hrs. and evaluated for cytokines IL12 (upper panel), and IL10 (lower panel) as per the manufacturer’s protocol. Figure S2. PFS and OS details. The raw data showing details of progression free survival (PFS) and the median overall survival (OS) is presented in tabular form. Figure S3. Gating scheme for flow cytometry analysis. PBMC was obtained from patients post vaccination and cryopreserved cells were stained using the multiple fluorochrome-conjugated antibodies. Cells were gated based on singlets (FSC-A vs FSC-H), size (SSC vs FSC-H), a live-dead stain (L/D), and subsequently markers to determine specific cell phenotypes. A) CD3+ T cells were phenotyped for CD4 and CD8. B) CD19 B cells were identified. C) NK cells were identified based on their CD56 and CD16 expression. The data was acquired using BD FACS Aria and analyzed using FlowJo software. (PDF 351 kb)
13045_2017_459_MOESM1_ESM.pdf
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