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Brain tumor immunotherapy with type-1 polarizing strategies
1University of Pittsburgh School of Medicine, Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. okadah@upmc.edu
Annals of the New York Academy of Sciences
|September 23, 2009
Summary
Enhancing T cell homing to brain tumors using poly-ICLC and glioma antigen vaccines improved survival in mice. This strategy is now being tested in a clinical trial for recurrent malignant glioma.
Area of Science:
- Neuro-oncology
- Immunology
- Vaccine Development
Background:
- Central nervous system (CNS) tumor vaccine success relies on effector T cells reaching tumors.
- Cytotoxic T lymphocytes (CTLs) with a type 1 phenotype (Tc1) show efficient CNS tumor homing, linked to CXCL10/IP-10 response and VLA-4 expression.
- Intratumoral dendritic cell (DC) delivery secreting IFN-alpha enhances Tc1 homing by upregulating CXCL10/IP-10.
Purpose of the Study:
- To investigate a clinically feasible method for inducing IFN-alpha and CXCL10/IP-10 in the CNS tumor microenvironment.
- To evaluate the combination of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose (poly-ICLC) with glioma-associated antigen (GAA) peptide vaccination.
- To assess the impact on systemic induction of GAA-specific Tc1s, their homing to CNS tumors, and overall survival in a preclinical model.
Main Methods:
- Administered poly-ICLC, a TLR3 and MDA5 ligand, in combination with subcutaneous vaccination targeting GAA-derived CTL epitopes.
- Assessed systemic induction of GAA-specific Tc1s expressing VLA-4.
- Evaluated Tc1 homing to CNS tumors and survival in tumor-bearing mice.
- Initiated a phase I/II clinical trial combining type 1 polarizing DCs loaded with GAA peptides and poly-ICLC for recurrent malignant glioma.
Main Results:
- The combination therapy promoted systemic induction of GAA-specific Tc1s expressing VLA-4.
- These engineered Tc1s effectively homed to CNS tumors in mice.
- Combination treatment significantly improved survival in tumor-bearing mice.
- No detectable autoimmunity was observed in the preclinical model.
Conclusions:
- Subcutaneous vaccination combined with intramuscular poly-ICLC administration is a promising strategy for enhancing CNS tumor-specific CTL responses.
- This approach effectively promotes Tc1 homing to CNS tumors and improves survival.
- The findings support the clinical application of this combination therapy in patients with malignant glioma.
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