Development of a Novel Anti-CD19 CAR Containing a Fully Human scFv and Three Costimulatory Domains

Wutti-in, Yupanun; Sujjitjoon, Jatuporn; Sawasdee, Nunghathai; Panya, Aussara; Kongkla, Katesara; Yuti, Pornpimon; Yongpitakwattana, Petlada; Thepmalee, Chutamas; Junking, Mutita; Chieochansin, Thaweesak; Poungvarin, Naravat; Yamabhai, Montarop; Yenchitsomanus, Pa‐thai

doi:10.3389/fonc.2021.802876

Cited by 12 publications

(10 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, lowering the affinity of an anti-CD19 scFv led to lower TNF-α release in a recent study. The anti-CD19 scFv FMC63 used in this study has a binding affinity in the nanomolar order [ 63 ], while the affinity/avidity of the lectins for Gb3 ranges from the nanomolar to milimolar order [ 64 ]; these differences may help to understand disparities in TNF-α release.…”

Section: Resultsmentioning

confidence: 99%

Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells

Meléndez

Cárdenas

Lagies

et al. 2022

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The link between cancer and aberrant glycosylation has recently become evident. Glycans and their altered forms, known as tumour-associated carbohydrate antigens (TACAs), are diverse, complex and difficult to target therapeutically. Lectins are naturally occurring glycan-binding proteins that offer a unique opportunity to recognise TACAs. T cells expressing chimeric antigen receptors (CARs) have proven to be a successful immunotherapy against leukaemias, but so far have shown limited success in solid tumours. We developed a panel of lectin-CARs that recognise the glycosphingolipid globotriaosylceramide (Gb3), which is overexpressed in various cancers, such as Burkitt's lymphoma, colorectal, breast and pancreatic. We have selected the following lectins: Shiga toxin's B-subunit from Shigella dysenteriae, LecA from Pseudomonas aeruginosa, and the engineered lectin Mitsuba from Mytilus galloprovincialis as antigen-binding domains and fused them to a well-known second-generation CAR. The Gb3-binding lectin-CARs have demonstrated target-specific cytotoxicity against Burkitt's lymphoma-derived cell lines as well as solid tumour cells from colorectal and triple-negative breast cancer. Our findings reveal the big potential of lectin-based CARs as therapeutical applications to target Gb3 and other TACAs expressed in haematological malignancies and solid tumours.

show abstract

Section: Resultsmentioning

confidence: 99%

Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells

Meléndez

Cárdenas

Lagies

et al. 2022

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…The persistence of CAR costimulated by CD28 was identical to that achieved with CD3ζ alone, indicating that CD28 does not support human T-cell survival in vivo [ 172 , 173 ]. The persistence of CD28-costimulated CAR-T cells can be improved by replacing CD28 with 4-1BB [ 174 , 175 ] or CD27 [ 176 ] or by adding 4-1BB alone [ 175 ] or a combination of 4-1BB and CD27 [ 177 ]. CARs harboring the 4-1BB costimulatory domain mediate long-term survival of T cells in the circulation by maintaining central memory phenotype and relying on oxidative metabolism, whereas CD28-costimulated CARs promote effector memory differentiation and rely on aerobic glycolysis [ 50 , 169 , 178 ].…”

Section: Structural Elements Contribute To Car’s Potencymentioning

confidence: 99%

CAR-T cell potency: from structural elements to vector backbone components

Mazinani

Rahbarizadeh

2022

Biomark Res

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T cell therapy, in which a patient’s own T lymphocytes are engineered to recognize and kill cancer cells, has achieved remarkable success in some hematological malignancies in preclinical and clinical trials, resulting in six FDA-approved CAR-T products currently available in the market. Once equipped with a CAR construct, T cells act as living drugs and recognize and eliminate the target tumor cells in an MHC-independent manner. In this review, we first described all structural modular of CAR in detail, focusing on more recent findings. We then pointed out behind-the-scene elements contributing to CAR expression and reviewed how CAR expression can be drastically affected by the elements embedded in the viral vector backbone.

show abstract

“…Similarly, a few other studies have highlighted the significance of human antigen recognition domain in CAR design in order to overcome the immunological barriers caused by CARs that are not entirely human in origin ( 80 ). Overall, fully human scFvs can minimize immunogenicity while also extending the longevity of CAR-T cells and improving therapeutic output in patients.…”

Section: Strategies To Overcome the Immunogenicity-related Risk Of Ca...mentioning

confidence: 99%

Immunogenicity of CAR-T Cell Therapeutics: Evidence, Mechanism and Mitigation

et al. 2022

View full text Add to dashboard Cite

Chimeric antigen receptor T cell (CAR-T) therapy demonstrated remarkable success in long-term remission of cancers and other autoimmune diseases. Currently, six products (Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, and Carvykti) are approved by the US-FDA for treatment of a few hematological malignancies. All the six products are autologous CAR-T cell therapies, where delivery of CAR, which comprises of scFv (single-chain variable fragment) derived from monoclonal antibodies for tumor target antigen recognition is through a lentiviral vector. Although available CAR-T therapies yielded impressive response rates in a large number of patients in comparison to conventional treatment strategies, there are potential challenges in the field which limit their efficacy. One of the major challenges is the induction of humoral and/or cellular immune response in patients elicited due to scFv domain of CAR construct, which is of non-human origin in majority of the commercially available products. Generation of anti-CAR antibodies may lead to the clearance of the therapeutic CAR-T cells, increasing the likelihood of tumor relapse and lower the CAR-T cells efficacy upon reinfusion. These immune responses influence CAR-T cell expansion and persistence, that might affect the overall clinical response. In this review, we will discuss the impact of immunogenicity of the CAR transgene on treatment outcomes. Finally, this review will highlight the mitigation strategies to limit the immunogenic potential of CARs and improve the therapeutic outcome.

show abstract

Development of a Novel Anti-CD19 CAR Containing a Fully Human scFv and Three Costimulatory Domains

Cited by 12 publications

References 47 publications

Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells

Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells

CAR-T cell potency: from structural elements to vector backbone components

Immunogenicity of CAR-T Cell Therapeutics: Evidence, Mechanism and Mitigation

Contact Info

Product

Resources

About