Journal Article

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

Garrett-Mayer, Elizabeth, Salem, Mohamed L., Rubinstein, Mark P., Paulos, Chrystal M., Thomas, Melanie B., Chin, Steve, Nishimura, Michael I., Scurti, Gina, Li, Zihai, Britten, Carolyn D., Cloud, Colleen A., Li, Mingli, Nelson, Michelle H., Cole, David J., Mehrotra, Shikhar, Salazar, Andres M.

2017

Overview

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 × 10 7 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).

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Aged / Antigens / Antigens, Neoplasm - immunology / Apheresis / Cancer Research / Cancer Vaccines - administration & dosage / Cancer Vaccines - pharmacology / Carboxymethylcellulose Sodium - administration & dosage / Carboxymethylcellulose Sodium - analogs & derivatives / Carboxymethylcellulose Sodium - pharmacology / Carcinoembryonic antigen / Clinical trials / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - transplantation / Fatigue / Female / Hematology / Histocompatibility antigen HLA / Humans / Immune Checkpoint Inhibitor / Immunotherapy / Immunotherapy, Active - methods / Leukapheresis / Lymphocyte Activation / Lymphocyte Count / Lymphocytes T / Major histocompatibility complex / Male / Medicine / Medicine & Public Health / Melanoma / Metastases / Metastasis / Middle Aged / Oncology / Pancreas Cancer / Pancreatic Cancer / Pancreatic Cancer Patient / Pancreatic Neoplasms - therapy / Peptides - immunology / Peripheral blood / Pilot Projects / Poly I-C - administration & dosage / Poly I-C - pharmacology / Polylysine - administration & dosage / Polylysine - analogs & derivatives / Polylysine - pharmacology / RNA-directed DNA polymerase / Survivin / Survivin Peptide / Telomerase / Telomerase reverse transcriptase / Toll-like receptors / Transplantation, Autologous / Tumors / Vaccination - methods / Vaccines