The CAR macrophage cells, a novel generation of chimeric antigen-based approach against solid tumors

Biomarker Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: Nov. 28, 2023

Abstract Today, adoptive cell therapy has many successes in cancer therapy, and this subject is brilliant using chimeric antigen receptor T cells. The CAR with its FDA-approved drugs, could treat several types of hematological malignancies thus be very attractive for treating solid cancer. Unfortunately, the cannot functional cancers due to unique features. This treatment method harmful adverse effects that limit their applications, so novel treatments must use new cells like NK cells, NKT macrophage Among these innate features, are more tumor seem a better candidate prior methods. have vital roles microenvironment and, direct effect, can eliminate efficiently. In addition, being part immune system, attended sites. With high infiltration, modulations effective. review investigates last achievements CAR-macrophage future immunotherapy method.

Language: Английский

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Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 2, 2023

Advancements in chimeric antigen receptor engineered T-cell (CAR-T) therapy have revolutionized treatment for several cancer types over the past decade. Despite this success, obstacles including high price tag, manufacturing complexity, and treatment-associated toxicities limited broad application of therapy. Chimeric natural killer cell (CAR-NK) offers a potential opportunity simpler more affordable “off-the-shelf” treatment, likely with fewer toxicities. Unlike CAR-T, CAR-NK therapies are still early development, few clinical trials yet reported. Given challenges experienced through development CAR-T therapies, review explores what lessons we can apply to build better therapies. In particular, explore importance optimizing immunochemical properties CAR construct, understanding factors leading product persistence, enhancing trafficking transferred cells tumor, ensuring metabolic fitness product, strategies avoid tumor escape loss. We also trogocytosis, an important emerging challenge that equally applies cells. Finally, discuss how these limitations already being addressed future directions may be possible.

Language: Английский

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CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 26, 2024

Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces significant hurdles, including T-cell inhibition mediated by the PD-1/PD-L1 axis. The effects of disrupting this pathway on T-cells are being actively explored and controversial outcomes have been reported. Here, we hypothesize that CAR-antigen affinity may be a key factor modulating susceptibility towards We systematically interrogate CAR-T cells targeting HER2 with either low (LA) or high (HA) in various preclinical models. Our results reveal an increased sensitivity LA to PD-L1-mediated when compared their HA counterparts using vitro models tumor lines supported lipid bilayers modified display varying PD-L1 densities. CRISPR/Cas9-mediated knockout (KO) PD-1 enhances cytokine secretion polyfunctionality antitumor effect vivo downregulation gene signatures related exhaustion. By contrast, features remain unaffected following KO. This behavior holds true CD28 ICOS but not 4-1BB co-stimulated cells, which less sensitive albeit LA. findings inform therapies involving disruption tailored particular effective treatment tumors.

Language: Английский

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Encoding and display technologies for combinatorial libraries in drug discovery: The coming of age from biology to therapy

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3362 - 3384

Published: April 10, 2024

Drug discovery is a sophisticated process that incorporates scientific innovations and cutting-edge technologies. Compared to traditional bioactivity-based screening methods, encoding display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments promising tools pharmaceutical hit due their high efficiency, throughput, resource minimization. This review systematically summarizes the development history, typology, prospective applications of displayed technologies, including phage display, ribosomal mRNA yeast cell one-bead one-compound, DNA-encoded, peptide nucleic acid-encoded, new peptide-encoded examples preclinical clinical translation. We discuss progress novel targeted therapeutic agents, covering spectrum small-molecule inhibitors nonpeptidic macrocycles linear, monocyclic, bicyclic peptides, in addition antibodies. also address pending challenges future prospects drug discovery, size libraries, advantages disadvantages technology, translational potential, market space. intended establish comprehensive high-throughput strategy researchers developers.

Language: Английский

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Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: March 15, 2023

Abstract Cancer immunotherapies utilizing genetically engineered T cells have emerged as powerful personalized therapeutic agents showing dramatic preclinical and clinical results, particularly in hematological malignancies. Ectopically expressed chimeric antigen receptors (CARs) reprogram immune to target eliminate cancer. However, CAR cell therapy's success depends on the balance between effective anti-tumor activity minimizing harmful side effects. To improve therapy outcomes mitigate associated toxicities, scientists from different fields are cooperating developing next-generation products using latest molecular biology synthetic tools technologies. The immunotherapy field is rapidly evolving, with new approaches strategies being reported at a fast pace. This comprehensive literature review aims provide an up-to-date overview of developments controlling for improved safety, efficacy, flexibility.

Language: Английский

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Coengineering specificity, safety, and function into T cells for cancer immunotherapy

Immunological Reviews, Journal Year: 2023, Volume and Issue: 320(1), P. 166 - 198

Published: Aug. 7, 2023

Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a cell receptor (TCR) or chimeric antigen (CAR), have demonstrated clinical efficacy for proportion patients cancer-types. The field ACT has been driven forward by the success CD19-CAR therapy against various advanced B-cell malignancies, curative responses some leukemia patients. However, relapse remains problematic, in particular lymphoma. Moreover, variety reasons, relative limited non-hematological solid tumors. Indeed, addition pre-infusion challenges lymphocyte collection manufacturing, failure can be attributed several biological processes post-transfer including, (i) inefficient trafficking, infiltration, expansion retention, (ii) chronic exposure coupled with insufficient costimulation resulting exhaustion, (iii) range barriers microenvironment (TME) mediated both suppressive immune infiltrate, (iv) heterogeneity loss, down-regulation presentation machinery, (v) gain intrinsic mechanisms resistance such as apoptosis, (vi) forms toxicity other adverse events Affinity-optimized TCRs improve function innovative CAR designs well gene-modification strategies used coengineer specificity, safety, into cells. Coengineering designed not only directly support transferred cells, but also block TME harness endogenous innate adaptive immunity. Here, we review selection remarkable coengineering strategies, tools, receptors, gene-cargo, that developed recent years augment control ACT, more which are advancing clinic.

Language: Английский

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Progress on Phage Display Technology: Tailoring Antibodies for Cancer Immunotherapy

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1903 - 1903

Published: Sept. 9, 2023

The search for innovative anti-cancer drugs remains a challenge. Over the past three decades, antibodies have emerged as an essential asset in successful cancer therapy. major obstacle developing is need non-immunogenic against human antigens. This unique requirement highlights disadvantage to using traditional hybridoma technology and thus demands alternative approaches, such humanizing murine monoclonal antibodies. To overcome these hurdles, can be obtained directly from Phage Display libraries, groundbreaking tool antibody selection. These libraries consist of genetically engineered viruses, or phages, which exhibit fragments, scFv Fab on their capsid. innovation allows vitro selection novel molecules directed towards As foreseen when was first described, nowadays, several Display-derived entered clinical settings are undergoing evaluation. comprehensive review unveils remarkable progress this field possibilities clever strategies phage tailoring refinement aimed at increasingly specific targets. Moreover, use selected cutting-edge formats discussed, CAR (chimeric antigen receptor) T-cell therapy ADC (antibody drug conjugate), amplifying spectrum potential therapeutic avenues.

Language: Английский

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Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Dec. 9, 2023

Abstract Background Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific a CD19 membrane-distal epitope characterized by slow association (on) dissociation (off) rates. We hypothesized that novel scFv engages an alternative membrane-proximal independent of is faster on- off-rates could mitigate failure improve clinical efficacy. Methods developed autologous product with 4-1BB co-stimulation using humanized chicken antibody (h1218). This harbors on/off rates compared FMC63. tested h1218-CART19 in vitro vivo FMC63-CART19-resistant models. conducted first-in-human multi-center phase I trial test AT101 (clinical-grade h1218-CART19) relapsed or refractory (r/r) NHL. Results Preclinically, h1218- but not FMC63-CART19 were able effectively eradicate lymphomas expressing point mutations (L174V R163L) co-expressing FMC63-CAR19 as found relapsing after FMC63-CART19. Furthermore, exhibited enhanced killing malignancies Mechanistically, we had reduced activation-induced cell death (AICD) expansion owing off-rates. Based on these preclinical results, performed dose-escalation trial, testing three dose levels (DL) (the GMP version h1218) 3 + design. In 12 treated (7 DLBCL, FL, 1 MCL, MZL), showed promising safety profile 8.3% grade CRS ( n = 1) 4 ICANS 1). whole cohort, overall response rate was 91.7%, complete 75.0%, which improved 100% DL-2 -3. correlates CR aplasia. Conclusions novel, safe, potent recognizes domain fast significant efficacy Trial registration NCT05338931; Date: 2022–04-01.

Language: Английский

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Outsmarting trogocytosis to boost CAR NK/T cell therapy

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Nov. 16, 2023

Abstract Chimeric antigen receptor (CAR) NK and T cell therapy are promising immunotherapeutic approaches for the treatment of cancer. However, efficacy CAR NK/T is often hindered by various factors, including phenomenon trogocytosis, which involves bidirectional exchange membrane fragments between cells. In this review, we explore role trogocytosis in highlight potential strategies its modulation to improve therapeutic efficacy. We provide an in-depth analysis as it relates fate function cells, focusing on effects activation, cytotoxicity, presentation. discuss how can mediate transient loss cancer thereby negatively affecting effector Additionally, address fratricide trogocytosis-associated exhaustion, limit persistence effectiveness CAR-expressing Furthermore, impact functionality, acquisition target molecules signaling pathways. To overcome negative cellular immunotherapy, propose innovative modulate augment therapy. These encompass targeting trogocytosis-related molecules, engineering cells resist trogocytosis-induced exhaustion leveraging enhance By overcoming limitations imposed may be possible unleash full against The knowledge presented review will guide future research development, leading improved outcomes field immunotherapy.

Language: Английский

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Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 27, 2023

Chimeric antigen receptor (CAR) T cells are “living drugs” that specifically recognize their target through an antibody-derived binding domain resulting in cell activation, expansion, and destruction of cognate cells. The FDA/EMA approval CAR for the treatment B malignancies established therapy as emerging pillar modern immunotherapy. However, nearly every second patient undergoing is suffering from disease relapse within first two years which thought to be due downregulation or loss on cancer cells, along with decreased functional capacities known exhaustion. Antigen below activation threshold leaves silent, rendering ineffective. With application a growing number malignant diseases, particularly solid tumors, there need augmenting sensitivity present at low densities Here, we discuss upcoming strategies current challenges designing CARs recognition aiming finally therapeutic efficacy while reducing risk tumor relapse.

Language: Английский

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