Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies

Abstract

The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)–based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.

Influencing Factors and Prognostic Significance of TIL Subset Abundance in Head and Neck Squamous Cell Carcinoma

“…In addition, several preclinical trials have shown that docetaxel also enhances CD8 + T-cell responses and antitumor activity [27,28], although our results showed that the frequency of CD8 + TILs and CD103 + cells in the sub-group that received PC was not decreased signi cantly than that in the non-PC sub-population. Brie y, PC may be the main reason for the transformation of the T-cell landscape, as substantiated previously [29,30]. with the smoking history of the patients with HNSCC.…”

High-Density Lipoprotein-Mimicking Nanodiscs for Chemo-immunotherapy against Glioblastoma Multiforme

“…35 Previously, DTX has been shown to enhance antitumor T cell responses against lung cancer by eliciting immunogenic cell death (ICD). 36 We examined whether the tumor regression caused by DTX-sHDL-CpG treatment (Figure 5B–C) was due to the release of danger signals ( e.g., CRT and HMGB1) associated with ICD. Briefly, mice bearing GL26 tumors harboring a surrogate tumor antigen, ovalbumin (OVA), were treated with saline or DTX-sHDL-CpG nanodiscs at the indicated doses and schedule (Figure 6A); mice were euthanized one day after the end of the treatment and brains were processed for flow cytometry analysis.…”

“…Cytotoxic T lymphocytes are crucial for mediating tumor-specific adaptive immunity; however, their activity is suppressed in the presence of GBM . Previously, DTX has been shown to enhance antitumor T cell responses against lung cancer by eliciting immunogenic cell death (ICD) . We examined whether the tumor regression caused by DTX-sHDL-CpG treatment (Figure B,C) was due to the release of danger signals ( e.g ., CRT and HMGB1) associated with ICD.…”

“…36 Under this mechanism, dying tumor cells that express calreticulin (CRT) on their surface are engulfed by DCs and macrophages. 36 It has been previously demonstrated that GBM cells undergoing cell death, both in vitro and in vivo, release an endogenous damage associated molecular pattern molecule (DAMP), e.g., high-mobility group boxl (HMGB1) 6 and ATP. 48 HMGB1 binds to TLR2/4 and RAGE, while ATP binds to PTRX7 to elicit DC activation required for effective adaptive immune response.…”

“…36 Furthermore, DTX has been shown to enhance antitumor T cell responses against lung cancer through eliciting immunogenic cell death (ICD). 36 Under this mechanism, dying tumor cells that express calreticulin (CRT) on their surface are engulfed by DCs and macrophages. 36 It has been previously demonstrated that GBM cells undergoing cell death, both in vitro and in vivo, release an endogenous damage associated molecular pattern molecule (DAMP), e.g., high-mobility group box1 (HMGB1) 6 and ATP.…”