Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice

Abstract

Immunotherapy is gathering momentum as a primary therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that dual aOX40 (anti-CD134)/aCTLA-4 (anti-cytotoxic T-lymphocyte-associated protein 4) immunotherapy generated a potent antigen-specific CD8 T-cell response, enhancing expansion, effector function, and memory T-cell persistence. Importantly, OX40 and CTLA-4 expression on CD8 T cells was critical for promoting their maximal expansion following combination therapy. Animals treated with combination therapy and vaccination using anti-DEC-205 (dendritic and epithelial cells, 205 kDa)-HER2 (human epidermal growth factor receptor 2) had significantly improved survival in a mammary carcinoma model. Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment. Furthermore, this therapy was associated with extensive tumor destruction and T-cell infiltration into the tumor. Notably, in a spontaneous model of prostate adenocarcinoma, vaccination with combination therapy reversed anergy and enhanced the expansion and function of CD8 T cells recognizing a tumor-associated antigen. Collectively, these data demonstrate that the addition of a vaccine with combined aOX40/aCTLA-4 immunotherapy augmented antitumor CD8 T-cell function while limiting Th2 polarization in CD4 cells and improved overall survival.

An OX40/OX40L interaction directs successful immunity to hepatitis B virus

“…Our demonstration that an OX40 agonist can tilt the immune response toward HBV clearance in young mice and in adult chronic mice that encountered antigen when they were young opens new avenues for treating CHB in humans. Preclinical studies using tumor models demonstrate that tumor-associated, antigen-specific CD8 + T cells increase in quantity after OX40 agonist immunotherapy, and OX40 agonists, plus and minus checkpoint blockade, lead to reduced tumor growth and improved overall survival (25–28). Our data suggest that the OX40/OX40L pathway is crucial for effective HBV immunity and that OX40 agonists have potential in definitively treating CHB by augmenting the virus-specific T cell response.…”

OX40 triggering concomitant to IL12-engineered cell vaccine hampers the immunoprevention of HER2/neu-driven mammary carcinogenesis

“…Increased expression of IL10 and GM-CSF was reported by OX40 triggering in some studies. 21 , 24 It is worth noting that IL10, which is generally considered as a suppressor cytokine, also has antitumor activities. 25-27 …”

“…Using a tumor cell line derived from HER2/neu transgenic mice, an immunotherapeutic approach combining OX40 agonist and CTLA-4 blockade together with HER2 vaccination reversed T-cell anergy and extended survival of tumor-bearing mice. 21 …”

A system for detecting high impact-low frequency mutations in primary tumors and metastases

“…The spectrum of HLA-DR mutations observed in metastatic cells would likely disrupt antigen presentation and immune-tumor cell interactions. Deregulation in OX40 signaling network could impact therapeutic immunization strategies for metastasis 39 .…”