Progress and challenges in developing allogeneic cell therapies

Cell stem cell, Journal Year: 2025, Volume and Issue: 32(4), P. 513 - 528

Published: April 1, 2025

The new era of cell therapeutics has started with autologous products to avoid immune rejection. However, derived from allogeneic cells could be scaled and made available for a much larger patient population if rejection reliably overcome. In this review, we outline gene engineering concepts aimed at generating immune-evasive cells. First, summarize the current state therapies, second, compile still limited data replacement therapies. We emphasize advances in fast-developing field provide an optimistic outlook future

Language: Английский

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Engineering Lipid Nanoparticles for mRNA Immunotherapy

Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology, Journal Year: 2025, Volume and Issue: 17(2)

Published: March 1, 2025

ABSTRACT Over the last decades, messenger RNA (mRNA) has emerged as a promising therapeutic modality, enabling delivery of genetic instructions to cells for producing proteins or antigens. As such, mRNA‐based therapies can be developed wide range conditions, including infections, cancer, metabolic disorders, and diseases. Nevertheless, using mRNA therapeutically requires chemical modifications reduce immunostimulatory effects nanotechnology prevent degradation ensure intracellular delivery. Lipid nanoparticles (LNPs) have become most effective platform therapeutics, which are primarily employed vaccine purposes following local administration hepatic applications systemic administration. Here, we review state‐of‐the‐art LNP‐mRNA technology discuss its potential immunotherapy. We first outline requirements used therapeutically, role LNP‐mediated Next, highlight immunotherapy approaches vaccination, immuno‐oncology, autoimmune disorders. In addition, challenges that limiting LNP‐mRNA's widespread use, tunable biodistribution effects. Finally, provide an outlook on how implementing such library screening machine learning will guide development next‐generation therapeutics.

Language: Английский

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Cell therapies against brain tumors: Clinical development and emerging prospects

Bioengineering & Translational Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Abstract Malignant brain tumors, particularly glioblastoma multiforme (GBM), are aggressive and fatal cancers. The clinical efficacy of current standard‐of‐care treatments against tumors has been minimal, with no significant improvement over the past 30 years. Driven by success chimeric antigen receptor (CAR)‐T cells in clinic for treating certain types cancer, adoptive cell therapies have interest as a hopeful therapeutic modality tumors. Clinical trials GBM‐targeting therapies, including CAR‐T cells, initiated; however, none them approved yet, new challenges emerged from completed trials. These issues being addressed ongoing recent preclinical research efforts. Herein, we present an overview landscape We analyze active 203 focusing on discuss limitations their translation, highlight emerging approaches to address these challenges. In addition, review select studies that show promise improve future prospects.

Language: Английский

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State of the art in CAR-based therapy: In vivo CAR production as a revolution in cell-based cancer treatment

Cellular Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Chimeric antigen receptor (CAR) therapy has successfully treated relapsed/refractory hematological cancers. This strategy can effectively target tumor cells. However, despite positive outcomes in clinical applications, challenges remain to overcome. These hurdles pertain the production of drugs, solid resistance, and side effects related treatment. Some cases have been missed during drug preparation due manufacturing issues, prolonged times, high costs. mainly arise from vitro process, so reevaluating this process could minimize number patients. The immune cells are traditionally collected sent laboratory; after several steps, modified express CAR gene before being injected back into patient's body. During vivo method, is introduced inside allows for treatment begin sooner, avoiding potential failures associated In review, we will elaborate on using CAR, examine benefits approach, ultimately present available solutions incorporating practice.

Language: Английский

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Scarless circular mRNA-based CAR-T cell therapy elicits superior anti-tumor efficacy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Abstract Messenger RNA (mRNA)-based transient expression of CAR shows optimal safety profiles and provides promising opportunities to address existing challenges viral vector-based CAR-T therapies meet emerging medical needs in noncancerous indications. However, linear mRNAs are intrinsically unstable thus just achieve compromised efficacy. Here, we engineered a permuted intron exon (PIE) platform synthesize scarless circular mRNA (cmRNA) for potent long-lasting cmRNA significantly increased amount duration anti-CD19 on human T cells. cmRNA-based cells elicit superior anti-tumor efficacy over counterparts, demonstrated by parallel lines evidence including vitro specific cell-killing, cytokine release, transcriptomics patterns, vivo tumor elimination survival benefit. We found that efficiently eliminated target provide antitumor These results suggested could be unleashing full potential technologies cell therapies.

Language: Английский

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Unlocking the Gates: Therapeutic Agents for Noninvasive Drug Delivery Across the Blood-Brain Barrier

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 26, 2024

The blood-brain barrier (BBB) is a highly selective network of various cell types that acts as filter between the blood and brain parenchyma. Because this, BBB remains major obstacle for drug delivery to central nervous system (CNS). In recent years, there has been focus on developing modifiable platforms, such monoclonal antibodies (mAbs), nanobodies (Nbs), peptides, nanoparticles, both therapeutic agents carriers targeted treat cancers diseases. Methods bypassing can be invasive or noninvasive. Invasive techniques, transient disruption using low pulse electrical fields intracerebroventricular infusion, lack specificity have numerous safety concerns. this review, we will noninvasive transport mechanisms offer high levels biocompatibility, personalization, are regarded generally safer than their counterparts. Modifiable platforms designed noninvasively traverse through one more following pathways: passive diffusion physio-pathologically disrupted BBB, adsorptive-mediated transcytosis, receptor-mediated shuttle-mediated somatic gene transfer. Through understanding pathways, new applications, including Chimeric Antigen Receptors T-cell (CAR-T) therapy, approaches across emerging.

Language: Английский

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Better, Faster, Stronger: Accelerating mRNA‐Based Immunotherapies With Nanocarriers

Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology, Journal Year: 2024, Volume and Issue: 16(6)

Published: Nov. 1, 2024

ABSTRACT Messenger ribonucleic acid (mRNA) therapeutics are attracting attention as promising tools in cancer immunotherapy due to their ability leverage the vivo expression of all known protein sequences. Even small amounts mRNA can have a powerful effect on vaccines by promoting synthesis tumor‐specific antigens (TSA) or tumor‐associated (TAA) antigen‐presenting cells (APC). These then presented T cells, eliciting strong antitumor immune stimulation. The potential be further enhanced expressing immunomodulatory agents, such cytokines, antibodies, and chimeric antigen receptors (CAR), enhancing tumor immunity. Recent research also explores mRNA‐encoded death inducers microenvironment (TME) modulators. Despite its promise, clinical translation mRNA‐based anticancer strategies faces challenges, including inefficient targeted delivery vivo, failure endosomal escape, inadequate intracellular release, resulting poor transfection efficiencies. Inspired approval lipid nanoparticle‐loaded against coronavirus disease 2019 (COVID‐19) encouraging outcomes therapies trials, innovative nonviral nanotechnology systems been engineered. aim advance immunotherapies from application. This review summarizes recent preclinical progress polymeric nanomedicines for delivering therapeutics, cytokines antibody‐based immunotherapies, vaccines, CAR therapies. It addresses advanced direct oncolysis TME reprogramming highlights key challenges translating these use, exploring future perspectives, role artificial intelligence machine learning development.

Language: Английский

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Minimally modified off-the-shelf allogeneic CAR T cells

Deleted Journal, Journal Year: 2024, Volume and Issue: 32(3), P. 200851 - 200851

Published: Aug. 1, 2024

T cells modified with synthetic chimeric antigen receptors (CARs) have been enormously successful in treating hematological malignancies, and multiple products are now approved for use patients relapsed/refractory leukemia, lymphoma, myeloma. However, on-demand manufacturing of an autologous engineered cell product creates considerable financial, logistical, availability challenges to the widespread implementation therapy. To complicate matters, aggressive disease may require bridging therapy while undergoes release testing, quality function CAR be variable between following courses For these reasons, off-the-shelf strategies using alternative allogeneic sources ex vivo engineering including healthy donor cells, pluripotent stem cell-derived cells1Michaels Y.S. Durland L.J. Zandstra P.W. Engineering Cell Development Next Generation Stem Cell-Derived Immunotherapies.GEN Biotechnol. 2023; 2: 106-119https://doi.org/10.1089/genbio.2023.0008Crossref PubMed Google Scholar, natural killer (NK) cells2Marin D. Li Y. Basar R. Rafei H. Daher M. Dou J. Mohanty V. Dede Nieto Uprety N. et al.Safety, efficacy determinants response CD19-specific CAR-NK CD19+ B tumors: a phase 1/2 trial.Nat. Med. 2024; 30: 772-784https://doi.org/10.1038/s41591-023-02785-8Crossref Scopus (43) direct engineering3Short L. Holt R.A. Cullis P.R. Evgin Direct engineering.Trends Pharmacol. Sci. 45: 406-418https://doi.org/10.1016/j.tips.2024.03.004Abstract Full Text PDF (1) Scholar being explored preclinically clinically. Using therapeutic αβ two challenges: native receptor (TCR) can cause graft versus host (GVHD), conversely, (2) alloreactive NK quickly reject cells. address former, components TCR complex such as α constant (TRAC) gene disrupted by clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator-like effector nucleases (TALENs), locus repurposed express CAR.4van der Stegen S.J.C. Lindenbergh P.L. Petrovic R.M. Xie Diop M.P. Alexeeva Shi Mansilla-Soto Hamieh Eyquem al.Generation T-cell-receptor-negative CD8αβ-positive from T-cell-derived induced cells.Nat. Biomed. Eng. 2022; 6: 1284-1297https://doi.org/10.1038/s41551-022-00915-0Crossref (34) latter problem mismatched human leukocyte (HLA), deletion β2 microglobulin (B2M) class II-transactivator (CIITA) genes stealth that fail HLA I II respectively.5Jo S. Das Williams A. Chretien A.S. Pagliardini T. Le Roy Fernandez J.P. Clerre Jahangiri B. Chion-Sotinel I. al.Endowing universal T-cell immune-evasive properties TALEN-gene editing.Nat. Commun. 13: 3453https://doi.org/10.1038/s41467-022-30896-2Crossref (48) Since HLA-negative targeted overexpression minimally polymorphic HLA-E molecules engage NKG2A inhibitory on compensate this problem.6Wang Iriguchi Waseda Ueda Xu Minagawa Ishikawa Yano Ishi hypoimmunogenic genetically 2021; 5: 429-440https://doi.org/10.1038/s41551-021-00730-zCrossref (79) An strategy involves targeting either deleting CD52 concurrently anti-CD52 antibody alemtuzumab7Poirot Philip Schiffer-Mannioui C. Derniame Potrel P. Bas Lemaire Galetto al.Multiplex Genome-Edited Manufacturing Platform "Off-the-Shelf" Adoptive Immunotherapies.Cancer Res. 2015; 75: 3853-3864https://doi.org/10.1158/0008-5472.Can-14-3321Crossref expressing alloimmune defense recognizes activation marker 4-1BB.8Mo F. Watanabe McKenna M.K. Hicks M.J. Srinivasan Gomes-Silva Atilla E. Smith Ataca Ma al.Engineered resist immune rejection.Nat. 39: 56-63https://doi.org/10.1038/s41587-020-0601-5Crossref (76) These approaches deplete globally some selectively (Figure 1 left). In recent issue Molecular Therapy Oncology, Quach al. astutely leveraged biology CD30 (also known TNFRSF8), combined expansion antigen-specific bypass multiplexed genetic modifications required prevent rejection GVHD associated therapies.9Quach D.H. Ganesh H.R. Briones Y.D. Nouraee Hadidi Y.F. Sharma Rooney C.M. Rejection resistant CD30.CAR-modified Epstein-Barr virus-specific platform CD30(+) lymphoma.Mol. Ther. Oncol. 32200814https://doi.org/10.1016/j.omton.2024.200814Abstract virus (EBV)-specific (EBVSTs) expanded vitro peptides representing latent lytic (EBNA1, LMP1, LMP2, BZLF1) simultaneously reduces risk enables EBV-positive through TCR. is expressed not only Reed-Sternberg Hodgkin lymphoma anaplastic large lymphomas but also subsets activated cells,10van Weyden C.A. Pileri S.A. Feldman A.L. Whisstock Prince H.M. Understanding targeting: historical perspective providing insight into future directions.Blood Cancer 2017; 7: e603https://doi.org/10.1038/bcj.2017.85Crossref (0) they demonstrated multi-specificity toward CD30-positive targets CAR. Instead exploited expression mixed lymphocyte reactions (MLRs), EBVSTs inhibited thus resisted their killing. Given upregulated upon recognition, it was surprising transduced did undergo fratricide. authors showed binds cis, masking epitope surrounding right). The effectiveness approach will borne out ongoing clinical trial where manufactured EBV-seropositive donors (NCT04288726). study has already reported early positive outcomes, tolerable safety profile, and, seven evaluable patients, complete responses three partial responses.11Quach Ramos Lulla P.D. Thakkar S.G. Becerra-Dominguez Mehta Perconti al.Safety Efficacy Off-the-Shelf CD30.CAR-Modified Virus-Specific Cells Patients CD30-Positive Lymphoma.Blood. 138: 1763https://doi.org/10.1182/blood-2021-153421Crossref likely further improved combination vaccines12Tanaka Tashiro Omer Lapteva Ando Ngo Dotti G. Kinchington Leen A.M. al.Vaccination enhance proliferation (CAR)-modified cells.Clin. 23: 3499-3509https://doi.org/10.1158/1078-0432.CCR-16-2138Crossref (70) viral reactivation.13Lapteva Gilbert Diaconu Rollins L.A. Al-Sabbagh Naik Krance Tripic Hiregange Raghavan al.T-Cell Receptor Stimulation Enhances Expansion Function CD19 Chimeric Antigen Receptor-Expressing Cells.Clin. 2019; 25: 7340-7350https://doi.org/10.1158/1078-0432.CCR-18-3199Crossref (35) Of note, were detected peripheral blood there no evidence expansion.11Quach Although MLR cultures suggest eliminated, lack suggests levels kinetics across contribute rejection. When expresses high target antigen, subject fratricide other CAR-expressing example described CD7.14Gomes-Silva Lee Wagner D.L. Davis T.H. Rouce R.H. Bao Brenner Mamonkin CD7-edited CD7-specific malignancies.Blood. 130: 285-296https://doi.org/10.1182/blood-2017-01-761320Crossref (307) What physical allow good cis binding protection fratricide? location scFv length source hinge domain determine whether molecule enough flexibility bind conformation. It would interesting test CARs similar functionality specific construct used Protection dependent. Binding surface-expressed could potentially activate signaling both itself antigenic receptor. case, ligation promote signal transduction MAPK NFKB, which help survive proliferate.10van Delineation enable design cis-protective molecules. supported BC Foundation Fondation Léon Fredericq. L.E. Canadian Institute Health Research, Foundation, Michael Research BC, Terry Fox Institute. All declared potential conflicts interest.

Language: Английский

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Critical Considerations of mRNA-LNPs Technology for CAR-T Therapy: Components, Payloads and Emerging Horizons

Materials Chemistry Frontiers, Journal Year: 2024, Volume and Issue: 8(19), P. 3106 - 3135

Published: Jan. 1, 2024

The application and optimization of circRNA-LNP.

Language: Английский

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Perspective Chapter: Targeting the Myeloid Compartment – Innovative Immunotherapy Strategies for Malignant Brain Tumors

IntechOpen eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 13, 2024

This chapter explores the complex immune landscape of malignant brain tumors and potential immunotherapy in their treatment. It focuses on predominant role tumor-associated macrophages tumor microenvironment, including monocyte-derived macrophages, microglia, border-associated macrophages. We discuss results various trials, checkpoint blockade. While some approaches have shown promise, particularly metastases, many faced challenges improving patient outcomes, especially glioblastoma. The section highlights importance understanding diverse functions myeloid cells microenvironment proposes strategies for targeting these cells. Finally, we emphasize need more comprehensive research macrophage niche to develop effective immunotherapies tumors, potentially revolutionizing treatment this challenging field.

Language: Английский

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