Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

Munter, Stijn De; Buhl, Juliane L.; Cock, Laurenz De; Parys, Alexander Van; Daneels, Willem; Pascal, Eva; Deseins, Lucas; Ingels, Joline; Goetgeluk, Glenn; Billiet, Lore; Pille, Melissa; Vandamme, Niels; Dorpe, Jo Van; Offner, Fritz; Depla, Erik; Tavernier, Jan; Kerre, Tessa; Drost, Jarno; Vandekerckhove, Bart

doi:10.1101/2023.01.22.523482

Cited by 2 publications

(2 citation statements)

References 54 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bart Vandekerckhove (Department of Clinical Chemistry, Microbiology and Immunology, Ghent University) 20 . We specifically aimed to evaluate the impact of glyco-engineering via Mgat5 KO on the CAR T cell glycome and on their in vitro and in vivo activation, proliferation, differentiation and anti-tumor functionality.…”

Section: Introductionmentioning

confidence: 99%

“…To evaluate the impact of altered cell surface glycosylation on cytotoxic T cell functionality, specifically in a cancer immunotherapy setting, we used CD70 as the CAR target. Nanobodies targeting CD70 have been thoroughly evaluated as antigen-binding module in a CAR format (CD70 nanoCAR) in the lab of Prof. Dr. Bart Vandekerckhove (Department of Clinical Chemistry, Microbiology and Immunology, Ghent University) 20 . We specifically aimed to evaluate the impact of glyco-engineering via Mgat5 KO on the CAR T cell glycome and on their in vitro and in vivo activation, proliferation, differentiation and anti-tumor functionality.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

N-glycosylation engineering in chimeric antigen receptor T cells enhances anti-tumor activity

Bousser

Festjens

Meuris

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Recently, chimeric antigen receptor (CAR) T cell technology has revolutionized cancer immunotherapy. This strategy uses synthetic CARs to redirect T cells to specific antigens expressed on the surface of tumor cells. Despite impressive progress in the treatment of hematological malignancies with CAR T cells, scientific challenges still remain for use of CAR T cell therapy to treat solid tumors. This is mainly due to the hostile tumor microenvironment and CAR-related toxicities. As the glycans decorating the T cell surface are implicated in T cell activation, differentiation, proliferation, and in the interaction of human T cells with tumor cells, we studied the role of human T cell glycosylation in more depth by manipulating their glycome. In this context, there is in vitro evidence that beta-galactoside binding lectins (Galectins) can have a strong impact on the functionality of tumor-infiltrating T cells. The high-affinity poly-LacNAc N-linked galectin ligands are mainly synthesized onto the beta1,6-GlcNAc branch introduced by N-acetylglucosaminyltransferase V (GnTV, encoded by Mgat5). We showed that knocking out Mgat5 in CD70 targeting CAR T cells leads to lower densities of poly-LacNAc modifications on the CAR T cell surface. Most interestingly, our results indicate that MGAT5 KO CD70 CAR T cells show enhanced potency to control primary tumors and relapses.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N-glycosylation engineering in chimeric antigen receptor T cells enhances anti-tumor activity

Bousser

Festjens

Meuris

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts

Van den Eynde,

Gehrcken,

Verhezen

et al. 2024

J Hematol Oncol

View full text Add to dashboard Cite

Background It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma. Methods RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70+ tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs. Results In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70+ tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70+ tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner. Conclusions We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70+ cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.

show abstract

Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

Cited by 2 publications

References 54 publications

N-glycosylation engineering in chimeric antigen receptor T cells enhances anti-tumor activity

N-glycosylation engineering in chimeric antigen receptor T cells enhances anti-tumor activity

IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts

Contact Info

Product

Resources

About