Despite recent advances made in surgical, radiological and chemotherapeutic approaches, the prognosis of central nervous system (CMS) malignancies remains dismal. Although the safety of vaccine-approaches for CNS malignancies has been established in early phase clinical trials, the success of a vaccine strategy will depend critically on the ability of effector T-cells to home to CNS tumors and exert anti-tumor effects. Based on our recent studies, efficient CNS tumor-homing is characteristic of CTLs with a type-1 phenotype (Tc1) as opposed to ones with the type-2 phenotype (Tc2), and appears to be mediated by a type-1 chemokine, CXCL10. In addition, direct intratumoral delivery of dendritic cells (DC) ex vivo engineered to secrete interferon (IFN)-alpha further enhances Tc1-homing via up-regulation of a type-1 chemokine CXCL10/IP-10 in the tumor environment. While CNS-tumor infiltrating antigen presenting cells (APCs), such as microglia and macrophage, exhibit type-2 (M2) phenotype, our data suggest that substantial improvements in the efficacy of vaccine strategies can be achieved by efforts to convert the type-2-deviated microenvironment of central nervous system (CNS) tumors. Hence, we will focus on potential means of converting a type-2 to a type-1 microenvironment in preclinical mouse CNS tumor models, including a novel de novo mouse glioma model that phenotypically and histologically resembles human glioblastoma multiforme (GBM). Our central hypothesis is that the efficacy of T-cell based anti-CNS tumor therapy can be improved by: (a) intratumoral administration of a potent class of DCs expressing type-1 cytokines/chemokines (DC1), (b) administration of type-1 promoting factors, including the adjuvant polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose (poly-ICLC), or (c) combination of both Dd-delivery and administration of type-1 promoting factors. We will evaluate the following Specific Aims (SA). SA 1: Determine whether intratumoral delivery of ex vivo generated DC1 can enhance the therapeutic efficacy of systemic type-1 CTL (Tc1) therapy;SA 2: Determine whether delivery of type-1 promoting factors can lead to M1 phenotype of CNS tumor-infiltrating ARC s. SA 3: Determine whether the re-directed CNS-APCs enhance the therapeutic efficacy of Tc1 therapy and/or peripheral DC 1-based vaccinations.

Public Health Relevance

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
United States
Zip Code
Liu, Zuqiang; Ravindranathan, Roshni; Kalinski, Pawel et al. (2017) Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun 8:14754
Wong, Jeffrey L; Obermajer, NataĊĦa; Odunsi, Kunle et al. (2016) Synergistic COX2 Induction by IFN? and TNF? Self-Limits Type-1 Immunity in the Human Tumor Microenvironment. Cancer Immunol Res 4:303-11
Downs-Canner, Stephanie; Guo, Zong Sheng; Ravindranathan, Roshni et al. (2016) Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers. Mol Ther 24:1492-501
Francis, Lily; Guo, Zong Sheng; Liu, Zuqiang et al. (2016) Modulation of chemokines in the tumor microenvironment enhances oncolytic virotherapy for colorectal cancer. Oncotarget 7:22174-85
Radomski, Michal; Zeh, Herbert J; Edington, Howard D et al. (2016) Prolonged intralymphatic delivery of dendritic cells through implantable lymphatic ports in patients with advanced cancer. J Immunother Cancer 4:24
Zeh, Herbert J; Downs-Canner, Stephanie; McCart, J Andrea et al. (2015) First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. Mol Ther 23:202-14
Kalinski, Pawel; Gingrich, Jeffrey R (2015) Toward improved effectiveness of bladder cancer immunotherapy. Immunotherapy 7:1039-42
Liu, J Y; Li, F; Wang, L P et al. (2015) CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer 113:747-55
Okada, Hideho; Butterfield, Lisa H; Hamilton, Ronald L et al. (2015) Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC. Clin Cancer Res 21:286-94
Ohkuri, Takayuki; Ghosh, Arundhati; Kosaka, Akemi et al. (2014) STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res 2:1199-208

Showing the most recent 10 out of 58 publications