Click CAR-T cell engineering for robustly boosting cell immunotherapy in blood and subcutaneous xenograft tumor

Abstract

The adoptive transfer of chimeric antigen receptor-T (CAR-T) cells has shown remarkable clinical responses in hematologic malignancies. However, unsatisfactory curative results and side effects for tumor treatment are still unsolved problems. Herein we develop a click CAR-T cell engineering strategy via cell glycometabolic labeling for robustly boosting their antitumor effects and safety in vivo. Briefly, paired chemical groups (N 3 /BCN) are separately incorporated into CAR-T cell and tumor via nondestructive intrinsic glycometabolism of exogenous Ac 4 GalNAz and Ac 4 ManNBCN, serving as an artificial ligand-receptor. Functional groups anchored on cell surface strengthen the interaction of CAR-T cell and tumor via bioorthogonal click chemistry, further enhancing specific recognition, migration and selective antitumor effects of CAR-T cells. In vivo, click CAR-T cell completely removes lymphoma cells and minimizes off-target toxicity via selective and efficient bioorthogonal targeting in blood cancer. Surprisingly, compared to unlabeled cells, artificial bioorthogonal targeting significantly promotes the accumulation, deep penetration and homing of CAR-T cells into tumor tissues, ultimately improving its curative effect for solid tumor. Click CAR-T cell engineering robustly boosts selective recognition and antitumor capabilities of CAR T cells in vitro and in vivo, thereby holding a great potential for effective clinical cell immunotherapy with avoiding adverse events in patients.

Cell/Bacteria‐Based Bioactive Materials for Cancer Immune Modulation and Precision Therapy

“…To solve these problems, CAR-T cells need to be further armed through biochemical decoration and other engineering modifications to improve their targeting and antitumor capabilities. In our laboratory, [129][130][131] we have developed a novel bioorthogonal chemistry strategy to generate engineered CAR-T cells and artificial targeting for boosting antitumor efficacy and safety by facilitating the interaction between CAR-T cells and tumor cells using cell glycometabolic labeling (Figure 8). In addition, Zhang's group reported a strategy in which liposomal avasimibe was clicked onto the surface of CAR-T cells without interfering with the functions of the T cells.…”

How Can We Engineer CAR T Cells to Overcome Resistance?

“…○ Dual targeting CARs [209][210][211][212][213] ○ Trivalent CARs 214,215 ○ Tandem CARs 216,217 ○ Universal CARs/BiTEs [219][220][221][222] • Expression of artificial ligand/receptors 223,224 • Promotion of epitope spread 226 https://doi.org/10.2147/BTT.S252568…”

“…Incorporation of artificial receptor and ligand into CD19 CAR T cells and target tumour cells improved selectivity, infiltration and homing. 223 The introduction of artificial targets also has the potential to avoid off-tumour/on-target toxicity. Park et al 224 used an oncolytic virus to deliver a target antigen, specifically truncated CD19, into solid tumours and demonstrated successful tumour eradication in both human xenograft models and a mouse immunocompetent model.…”

Polysaccharide-based nanomedicines for cancer immunotherapy: A review

“…Among them, immunotherapy, using human immune systems to treat cancer, blocks certain immune inhibitory checkpoints or pathways [ 2 , 3 ], promote T cells killing ability towards tumor cells (i.e. CAR-T therapy) [ 4 , 5 ] and increase innate immune processes by tumor associated macrophages (TAMs) and natural killer (NK) cells [ 6 , 7 ] to accomplish targeting immune suppression or elimination of tumor cells. Some of these immunotherapy strategies have been adopted in clinical practices and demonstrated to be efficacious for cancer diseases.…”