Matching or genetic engineering of HLA Class I and II facilitates successful allogeneic ‘off-the-shelf’ regulatory T cell therapy DOI Open Access
Oliver McCallion, Weijie Du, Viktor Glaser

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 6, 2023

Abstract The potential to harness regulatory T cells (Tregs) for the treatment of autoimmune diseases and transplant rejection has been restricted by several barriers: donor variability, manufacturing complications, time-consuming expansion processes. These issues further complicate use autologous Tregs during acute disease phases or when are low in number dysfunctional. Here we explore ‘off-the-shelf’ allogeneic Tregs, from healthy donors universal sources, provide a more practical solution. We discover that efficacy these is undermined recipient’s immune response, rigorous matching HLA classes I II overcomes this barrier. Importantly, genetically manipulating expression enables unmatched with vivo efficacy. Our findings underscore transformative HLA-engineered offering novel, ready-to-use therapeutic avenue treating wide array inflammatory diseases. One-Sentence Summary Matching engineering HLA-I HLA-II facilitates immunoregulation.

Language: Английский

Development of NK cell-based cancer immunotherapies through receptor engineering DOI Creative Commons
Audrey Page, Nicolas Chuvin, Jenny Valladeau‐Guilemond

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(4), P. 315 - 331

Published: March 5, 2024

Abstract Natural killer (NK) cell-based immunotherapies are attracting increasing interest in the field of cancer treatment. Early clinical trials have shown promising outcomes, alongside satisfactory product efficacy and safety. Recent developments greatly increased therapeutic potential NK cells by endowing them with enhanced recognition cytotoxic capacities. This review focuses on surface receptor engineering cell therapy discusses its impact, challenges, future directions. Most approaches based chimeric antigen receptors to allow target specific tumor antigens independent human leukocyte restriction. approach has precision potency NK-mediated elimination cells. In addition, T-cell also mediates intracellular epitopes, which broadens range peptides. Indirect peptide been improved optimizing immunoglobulin constant fragment expression signaling. Indeed, engineered an ability recognize destroy coated antibodies, thereby their antibody-dependent cellular cytotoxicity. The promote expansion, persistence, infiltration transferred microenvironment explored. Receptor-based strategies for sustained functionality within environment discussed, these providing perspectives counteract tumor-induced immunosuppression. Overall, led significant advances immunotherapies. As technical challenges addressed, innovative treatments will likely reshape immunotherapy.

Language: Английский

Citations

72
Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met? DOI Creative Commons
Caroline Lonez, Eytan Breman

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 146 - 146

Published: Jan. 12, 2024

This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this other malignancies and broader patient populations. However, several limitations remain, including those associated the time-consuming highly personalized manufacturing of autologous CAR-Ts. Technologies establish "off-the-shelf" allogeneic CAR-Ts low alloreactivity currently developed, strong focus on gene-editing technologies. Although these technologies have many advantages, they also limitations, double-strand breaks in DNA safety risks as well lack modulation. As an alternative, non-gene-editing provide interesting approach support development future, possibilities fine-tuning gene expression easy development. Here, we will review different ways can be manufactured discuss which used. The biggest hurdles successful summarized, finally, overview current clinical evidence comparison its counterpart given.

Language: Английский

Citations

21
Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy DOI Creative Commons
Tao Lei, Yazhuo Wang, Yuchen Zhang

et al.

Leukemia, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

Language: Английский

Citations

18
Advanced Delivery Systems for Gene Editing: A Comprehensive Review from the GenE-HumDi COST Action Working group DOI Creative Commons
Alessia Cavazza, Francisco J Molina-Estévez, Álvaro Plaza Reyes

et al.

Molecular Therapy — Nucleic Acids, Journal Year: 2025, Volume and Issue: 36(1), P. 102457 - 102457

Published: Jan. 18, 2025

Language: Английский

Citations

3
Base-editing mutagenesis maps alleles to tune human T cell functions DOI
Ralf Schmidt, Carl C. Ward, Rama Dajani

et al.

Nature, Journal Year: 2023, Volume and Issue: 625(7996), P. 805 - 812

Published: Dec. 13, 2023

Language: Английский

Citations

38
Combining different CRISPR nucleases for simultaneous knock-in and base editing prevents translocations in multiplex-edited CAR T cells DOI Creative Commons
Viktor Glaser, Christian Flugel, Jonas Kath

et al.

Genome biology, Journal Year: 2023, Volume and Issue: 24(1)

Published: April 24, 2023

Multiple genetic modifications may be required to develop potent off-the-shelf chimeric antigen receptor (CAR) T cell therapies. Conventional CRISPR-Cas nucleases install sequence-specific DNA double-strand breaks (DSBs), enabling gene knock-out or targeted transgene knock-in. However, simultaneous DSBs provoke a high rate of genomic rearrangements which impede the safety edited cells.

Language: Английский

Citations

31
Integration of ζ-deficient CARs into the CD3 ζ gene conveys potent cytotoxicity in T and NK cells DOI Creative Commons
Jonas Kath, Clemens Franke, Vanessa Drosdek

et al.

Blood, Journal Year: 2024, Volume and Issue: 143(25), P. 2599 - 2611

Published: March 17, 2024

Abstract Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling limits their accessibility due to logistical challenges, high costs biosafety requirements. Random transfer modalities pose a risk malignant transformation by insertional mutagenesis. Here, we propose novel approach utilizing CRISPR-Cas editing redirect T natural killer (NK) with CARs. By transferring shorter, truncated CAR-transgenes lacking main activation domain into the human CD3ζ (CD247) gene, functional CAR fusion-genes are generated that exploit endogenous as CAR’s domain. Repurposing this T/NK-cell lineage facilitated physiological expression redirection various cell types, including conventional cells, TCRγ/δ regulatory NK cells. In in-frame fusion eliminated TCR surface expression, reducing graft-versus-host disease allogeneic off-the-shelf settings. CD3ζ-CD19-CAR-T exhibited comparable leukemia control TCRα chain constant (TRAC)-replaced lentivirus-transduced vivo. Tuning CD3ζ-CAR-expression levels significantly improved vivo efficacy. Notably, enabled without impairing canonical functions. Thus, is promising platform development redirected lymphocytes.

Language: Английский

Citations

14
Allogeneic CAR-T cells with of HLA-A/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies DOI Creative Commons
Xinfeng Chen,

Binghe Tan,

Haizhou Xing

et al.

Cancer Immunology Immunotherapy, Journal Year: 2024, Volume and Issue: 73(1)

Published: Jan. 1, 2024

Abstract Background Although chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot patients could not benefit from it because failure in CAR-T manufacturing, disease progression, and unaffordable price. The study aimed explore universal products extend the clinical accessibility. Methods antitumor activity CRISPR/Cas9-edited allogeneic anti-CD19 (CAR-T19) was assessed vitro, animal models, with relapsed/refractory (R/R) acute lymphoblastic leukemia (B-ALL) or diffuse large lymphoma. Results B2M − /TRAC CAR-T19 (U-CAR-T19) exhibited powerful anti-leukemia abilities both vitro as did primary CD19 + patients. However, expansion, efficacy, graft-versus-host-disease (GvHD) observed six R/R malignancies after U-CAR-T19 infusion. Accordingly, significant activation natural killer (NK) by clinically vitro. HLA-A /B novel (nU-CAR-T19) were constructed similar tumoricidal capacity but resistance NK Surprisingly, robust expansion nU-CAR-T19 cells, along rapid eradication abnormal peripheral blood bone marrow another three B-ALL. achieved complete remission no detectable minimal residual 14 days infusion cells. Two had grade 2 cytokine release syndrome, which managed using IL-6 blocker. Most importantly, GvHD any patient, suggesting safety TRAC -disrupted generated CRISPR/Cas9 method for application. Conclusions showed strong response potential promising new approach malignancies.

Language: Английский

Citations

12
Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens DOI
Zachary Walsh, Parin Shah, Neeharika Kothapalli

et al.

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: May 23, 2024

Language: Английский

Citations

9
Development of multiplexed orthogonal base editor (MOBE) systems DOI
Quinn T. Cowan, Sifeng Gu,

Wanjun Gu

et al.

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: May 21, 2024

Language: Английский

Citations

7