Near-Infrared Photoimmunotherapy Combined with CTLA4 Checkpoint Blockade in Syngeneic Mouse Cancer Models

Abstract

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that induces necrotic/immunogenic cell death. It employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is activated by NIR light. Tumor-targeting NIR-PIT is also at least partly mediated by a profound immune response against the tumor. Cytotoxic T-lymphocyte antigen-4 (CTLA4) is widely recognized as a major immune checkpoint protein, which inhibits the immune response against tumors and is therefore, a target for systemic blockade. We investigated the effect of combining tumor-targeted NIR-PIT against the cell-surface antigen, CD44, which is known as a cancer stem cell marker, with a systemic CTLA4 immune checkpoint inhibitor in three syngeneic tumor models (MC38-luc, LL/2, and MOC1). CD44-targeted NIR-PIT combined with CTLA4 blockade showed greater tumor growth inhibition with longer survival compared with CTLA4 blockade alone in all tumor models. NIR-PIT and CTLA4 blockade produced more complete remission in MOC1 tumors (44%) than NIR-PIT and programmed cell death protein 1 (PD-1) blockade (8%), which was reported in our previous paper. However, the combination of NIR-PIT and CTLA4 blockade was less effective in MC38-luc tumors (11%) than the combination of NIR-PIT and PD-1 blockade (70%). Nonetheless, in many cases ineffective results with NIR-PIT and PD-1 blockade were reversed with NIR-PIT and CTLA4 blockade.

Increased Immunogenicity of a Minimally Immunogenic Tumor after Cancer-Targeting Near Infrared Photoimmunotherapy

“…CD44 is overexpressed in various cancers; however, it is also expressed on non-cancer cells in the TME, including some populations of activated lymphocytes [ 20 , 21 ]. Our previous study showed that CD44-targeted NIR-PIT indeed killed CD44-expressing CD8+ T cells, sparing CD44-negative CD8+ T cells which can be activated later on [ 22 ]. We actually observed additional multiclonal T cell expansion and infiltration after CD44-targeted NIR-PIT [ 12 ].…”

Near Infrared Photoimmunotherapy; A Review of Targets for Cancer Therapy

“…CD44-targeted NIR-PIT significantly suppressed tumor progression and prolonged survival in CD44-expressing syngeneic mouse models of oral squamous cell carcinoma [ 72 ]. Moreover, combined CD44-targeted NIR-PIT with programmed cell death protein 1 (PD-1) or CTLA4 checkpoint blockade was more effective in combination than as single therapies in syngeneic mouse models, including a minimally immunogenic tumor [ 21 , 73 , 74 ]. Combined CD44-targeted NIR-PIT with PD-1 blockade eradiated more than 70% of established tumors [ 21 ].…”

Near infrared photoimmunotherapy for cancers: A translational perspective

“…NIR-PIT has been successfully applied for EGFR expressing tumors (e.g., skin cancer [10] , lung cancer [17] , and breast cancer [8] ), human epidermal growth factor receptor 2 (HER2) (e.g., gastric cancer [18] and breast cancer [19] ), prostate-specific membrane antigen (PSMA) (e.g., prostate cancer) [20] , carcinoembryonic antigen (CEA) (e.g., colon cancer) [21] , [22] , [23] , mesothelin (MSLN) (e.g., mesothelioma, pancreatic, and ovarian cancers) [6] , Glypican 3 (GPC3) (e.g., hepatocellular carcinoma) [24] , CD20 (e.g., malignant lymphoma) [5] , tumour‐associated calcium signal transducer 2 (TROP2) (e.g., cholangiocarcinoma) [25] , delta-like protein 3 (DLL3) (e.g., small cell lung cancer) [22] , podoplanin (PDPN) (e.g., mesothelioma) [23] and G-protein coupled receptor 87 (GPR87) (e.g., lung cancer and mesothelioma) [24] , as shown in the Table 1 . NIR-PIT can also be used for programmed death-ligand 1 (PD-L1) expressing cancer cells [26] , for CD25 for regulatory T cells (Tregs) [ 7 , 27 , 28 ], and CD44 [ 4 , 12 , 16 , 29 , 30 ] and CD133 for cancer stem cells [31] .…”