Everson and Hugo et al. evaluated safety and systemic immune responses in 23 patients with grade III-IV malignant glioma vaccinated with autologous tumor lysate-pulsed dendritic cells (ATL-DC) plus or minus adjuvant TLR agonists (poly-ICLC or resiquimod). ATL-DC vaccination with either adjuvant TLR agonist was safe and well tolerated. ATL-DC plus poly-ICLC promoted IFNα/β- and IFNγ-induced genes in peripheral monocytes and T lymphocytes, increasing PD-1 levels on CD4+ T cells and decreasing CD38 and CD39 (exhaustion markers) on CD8+ T cells. IFN activation also correlated with prolonged survival and delayed disease progression.
Contributed by Katherine Turner
ABSTRACT: In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.
Author Info: (1) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. Jonsson Comprehensive Cancer Center, Dav
Author Info: (1) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (2) Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (3) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (4) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (5) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (6) Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (7) Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (8) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (9) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (10) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (11) Oncovir, Inc., Winchester, VA, USA. (12) Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (13) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. Department of Neurology/Neuro-Oncology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. (14) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. lliau@mednet.ucla.edu. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. lliau@mednet.ucla.edu. (15) Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. RPrins@mednet.ucla.edu. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. RPrins@mednet.ucla.edu. Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. RPrins@mednet.ucla.edu. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. RPrins@mednet.ucla.edu.
