Simultaneously Combined Cancer Cell- and CTLA4-Targeted NIR-PIT Causes a Synergistic Treatment Effect in Syngeneic Mouse Models.
Takuya KatoRyuhei OkadaAki FurusawaFuyuki InagakiHiroaki WakiyamaHideyuki FurumotoShuhei OkuyamaHiroshi FukushimaPeter C BlackHisataka KobayashiPublished in: Molecular cancer therapeutics (2021)
Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that utilizes antibody-IRDye700DX (IR700) conjugates. The clinical use of NIR-PIT has recently been approved in Japan for patients with inoperable head and neck cancer targeting human epidermal growth factor receptor (hEGFR). Previously, cytotoxic T-lymphocyte antigen 4 (CTLA4)-targeted NIR-PIT has been shown to strongly inhibit tumor progression and prolonged survival was seen in different tumor models due to enhanced T-cell-mediated antitumor immunity. In this study, combined NIR-PIT targeting CTLA4 expressing cells and cancer cells was investigated in four tumor models including a newly established hEGFR-expressing murine oropharyngeal cancer cell (mEERL-hEGFR). While single molecule-targeted therapy (NIR-PIT targeting hEGFR or CTLA4) did not inhibit tumor progression in poorly immunogenic mEERL-hEGFR tumor, dual (CTLA4/hEGFR)-targeted NIR-PIT significantly suppressed tumor growth and prolonged survival resulting in a 38% complete response rate. After the dual-targeted NIR-PIT, depletion of CTLA4 expressing cells, which were mainly regulatory T cells (Tregs), and an increase in the CD8+/Treg ratio in the tumor bed were observed, suggesting enhanced host antitumor immunity. Furthermore, dual-targeted NIR-PIT showed antitumor immunity in distant untreated tumors of the same type. Thus, simultaneous cancer cell-targeted NIR-PIT and CTLA4-targeted NIR-PIT is a promising new cancer therapy strategy, especially in poorly immunogenic tumors where NIR-PIT monotherapy is suboptimal.
Keyphrases
- cancer therapy
- photodynamic therapy
- drug release
- drug delivery
- fluorescent probe
- fluorescence imaging
- living cells
- regulatory t cells
- epidermal growth factor receptor
- single molecule
- induced apoptosis
- endothelial cells
- randomized controlled trial
- squamous cell carcinoma
- tyrosine kinase
- lymph node
- clinical trial
- cell cycle arrest
- open label
- mouse model
- oxidative stress
- combination therapy
- atomic force microscopy
- poor prognosis
- cell death
- signaling pathway
- immune response
- long non coding rna
- high resolution
- cell proliferation
- locally advanced
- replacement therapy