TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial

Richard G Everson; Willy Hugo; Lu Sun; Joseph Antonios; Alexander Lee; Lizhong Ding; Melissa Bu; Sara Khattab; Carolina Chavez; Emma Billingslea-Yoon; Andres Salazar; Benjamin M Ellingson; Timothy F Cloughesy; Linda M Liau; Robert M Prins

doi:10.1038/s41467-024-48073-y

TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial

Nat Commun. 2024 May 8;15(1):3882. doi: 10.1038/s41467-024-48073-y.

Authors

Richard G Everson^#^{1

2}, Willy Hugo^#^{2

3

4}, Lu Sun¹, Joseph Antonios¹, Alexander Lee^{1

5}, Lizhong Ding³, Melissa Bu³, Sara Khattab¹, Carolina Chavez⁵, Emma Billingslea-Yoon¹, Andres Salazar⁶, Benjamin M Ellingson^{2

7}, Timothy F Cloughesy^{5

8}, Linda M Liau^{9

10}, Robert M Prins^{11

12

13

14}

Affiliations

¹ Department of Neurosurgery, 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.
³ Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁴ Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁵ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁶ Oncovir, Inc., Winchester, VA, USA.
⁷ Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁸ Department of Neurology/Neuro-Oncology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁹ Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. lliau@mednet.ucla.edu.
¹⁰ 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.
¹¹ Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. RPrins@mednet.ucla.edu.
¹² 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.
¹³ 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.
¹⁴ 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.

^# Contributed equally.

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.

Publication types

Clinical Trial, Phase II
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Brain Neoplasms / drug therapy
Brain Neoplasms / immunology
Brain Neoplasms / therapy
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Cancer Vaccines* / administration & dosage
Cancer Vaccines* / immunology
Cancer Vaccines* / therapeutic use
Carboxymethylcellulose Sodium / analogs & derivatives
Dendritic Cells* / drug effects
Dendritic Cells* / immunology
Female
Glioma* / immunology
Glioma* / therapy
Humans
Imidazoles / pharmacology
Imidazoles / therapeutic use
Immunotherapy / methods
Interferons*
Male
Middle Aged
Monocytes / drug effects
Monocytes / immunology
Poly I-C / administration & dosage
Poly I-C / pharmacology
Polylysine / analogs & derivatives
Toll-Like Receptor Agonists*
Vaccination

Substances

Cancer Vaccines
Carboxymethylcellulose Sodium
Imidazoles
Interferons
Poly I-C
poly ICLC
Polylysine
resiquimod
Toll-Like Receptor Agonists

Associated data

ClinicalTrials.gov/NCT01204684

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding