Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy

Published: April 16, 2025

Abstract Adoptive T cell therapy (ACT) using chimeric antigen receptor (CAR) engineered cells is currently being explored in multiple cancer types beyond leukemia/lymphoma. A key step CAR-T manufacturing the activation and expansion of cells, which facilitates viral transduction, however, may hamper fitness reduce vivo persistence. We developed “T-Expand” for expansion, comprising dextran-based nanoparticles (NPs) conjugated with anti-CD3 anti-CD28 antibodies. The NPs triggered robust polyclonal human efficiency range commercial microbeads (Dynabeads™). Engineered presence T-Expand, CD19 CAR exhibited enhanced proliferative capacity, cytotoxicity persistence vitro , furthermore, showed superior anti-lymphoma activity mouse models resulting complete tumor clearance at one fourth dose. Importantly, T-Expand biocompatible no observed toxicity, circumventing removal steps after compared to Dynabeads TM . As a platform, simplifies process while enhancing functionality, thereby holding promise increasing clinical efficacy therapy. Graphical abstract/Cover figure: Illustration T-Expands ex

Language: Английский

---

IL-4 exerts beneficial anti-tumor effect dependent on a short-range manner

Cytokine, Journal Year: 2025, Volume and Issue: 191, P. 156950 - 156950

Published: April 26, 2025

---

The Potential Use of Digital Twin Technology for Advancing CAR-T Cell Therapy

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(5), P. 321 - 321

Published: April 30, 2025

CAR-T cell therapy is a personalized immunotherapy that has shown promising results in treating hematologic cancers. However, its therapeutic efficacy solid cancers often limited by tumor evasion mechanisms, resistance pathways, and an immunosuppressive microenvironment. These challenges highlight the need for advanced predictive models to better capture intricate interactions between cells tumors enhance their potential. Digital Twins represent transformative approach optimizing providing virtual representation of therapy-tumor trajectory using high-dimensional patient data. In this review, we first define outline fundamental steps development. We then explore critical parameters required designing CAR-T-specific Twins. examine published case studies demonstrating few applications addressing key therapy, including impact on clinical trials manufacturing processes. Finally, discuss limitations associated with integrating into therapy. As Twin technology continues evolve, potential through precision modeling real-time adaptation could redefine landscape cancer treatment.

Language: Английский

---

A new paradigm for cancer immunotherapy: Orchestrating type 1 and type 2 immunity for curative response

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 31, 2024

The immune system serves a vital function in safeguarding the body against external pathogens and eradicating cancerous cells. Depending on nature of encountered, orchestrates distinct immunological strategies: type 1 immunity primarily targets intracellular pathogens, including viruses certain bacteria; 2 is adept at combating parasites within mucosal tissues dermis; while 3 instrumental clearance extracellular fungi bacteria.1 Nevertheless, mechanisms by which influences cancer initiation, progression, therapeutic intervention remain partially elucidated. Traditionally, has been regarded as foremost defence cancers, current immunotherapeutic approaches checkpoint blockade (ICB)2 chimeric antigen receptor T-cell (CAR-T) therapy3 are crafted to activate or enhance responses cancer. Despite clinical success, curative response 1-centric immunotherapies limited, frequently resulting low patient rate high relapse with diminished durability response. CAR-T therapy targeting CD19 exhibited exceptional initial rates various malignancies derived from B-cell lineages; however, remains formidable challenge. To elucidate underlying factors contributing relapse, we conducted comprehensive single-cell multi-omics analysis over one million pre-infusion cells sourced 82 pediatric patients B-acute lymphoblastic leukaemia (B-ALL) six healthy donors.4 were participants two pioneering global trials for B-ALL (NCT01626495 NCT02906371), follow-up duration extending beyond ten years. While some experienced years post-treatment, others achieved remarkable long-term cancer-free survival, enduring up eight years, thereby being considered cured their malignancy. Clustering revealed that cell products who demonstrated significantly higher proportion characterized signatures (type cells); conversely, no noteworthy differences observed exhibiting signatures.4 Furthermore, preclinical experiments indicated proliferative capacity surpassed more than tenfold, indicative superior memory characteristics signs exhaustion.4 In recurrent model, effectively mitigated relapse.4 These findings underscore pivotal previously underappreciated role fostering sustained efficacy haematologic (Figure 1A). Compared hematologic malignancies, solid tumours pose an even challenge immunotherapy due intricate immunosuppressive tumour microenvironments (TME). quality functionality CD8+ T cells—the principal cytotoxic effectors—are crucial determinants success interventions tumours. However, prolonged exposure TME drives towards exhaustion, leading effector functions compromised persistence.5 Notably, cytokine interferon-γ associated induction exhaustion selective depletion tumour-specific cells,6 suggesting excessive may paradoxically undermine antitumor efficacy.7 Given regulatory modulating hypothesized could alleviate test this hypothesis, engineered fusion protein combining IL-4 Fc fragment (Fc–IL-4) assessed its effects tumor-infiltrating cells8 1B). Remarkably, Fc–IL-4 selectively enriched terminally exhausted (PD-1+TIM-3+TCF-1− TTE) cells, augmenting cytotoxicity functions. Mechanistically, acted directly TTE elevated expression α (IL-4Rα) compared progenitors, activating signal transducer activator transcription 6 (STAT6) mammalian target rapamycin (mTOR) signalling pathways. This activation profoundly enhanced glycolytic metabolism upregulated suite enzymes, particularly lactate dehydrogenase A (LDHA), revitalizing these Subsequently, potential immunotherapies, ICB, across models. results combination therapies robust multiple syngeneic xenograft models elicited effects. For instance, administration alongside OT1 complete (100%) YUMM1.7-OVA melanoma model. MC38-HER2 colon HER2-CAR-T resulted 87% eradication. Raji lymphoma pairing CD19-CAR-T led 75% clearance. ICB MC38 all mice achieving resistance subsequent rechallenge, underscoring long-lasting memory. As representative factor, not only revitalizes but also complements immunity-centric strategies, facilitating durable We found that, another immunity, interleukin-10 (IL-10)–Fc can through metabolic reprogramming.9 Additionally, CAR be metabolically optimized engineering them secrete IL-10, metastases.10 IL-10-secreting anti-CD19 currently tested several ongoing first-in-human investigator-initiated treatment relapsed refractory diffuse large 2A). Collectively, Fc–IL-4, advance therapies, centric immunity. investigation synergy opens new paradigm clinic 2B). Li Tang acknowledges grant support Swiss National Science Foundation (315230_204202, IZLCZ0_206035 CRSII5_205930) EPFL. All schematics created BioRender.com. co-founder, shareholder, advisor Leman Biotech. interests reviewed managed remaining authors declare competing interests.

Language: Английский

---

Vgamma1+ gammadelta T cell-derived IL-4 initiates CD8 T cell immunity

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

Published: Dec. 6, 2024

Abstract Dendritic cells (DC) are pivotal for initiating adaptive immunity, a process triggered by the activation of DC via pathogen products or damage. Here, we describe an additional layer to this process, essential when pathogen-derived signals alone cannot directly achieve full activation. Immunisation with sporozoites from Plasmodium leads CD8 T cell priming in complex response that is initiated collaboration between conventional type 1 (cDC1) and γδ cells. We unveil role Vγ1 + cells, as they supply IL-4 synergises CD4 cell-derived CD40L signal induce IL-12 production cDC1. Both then synergy these cytokines driving enhanced receptor expression expansion responding This study reveals key Vγl immunity . More broadly, it shows responses some pathogens require help innate-like pass initiation threshold further amplify underscored production.

Language: Английский

---

A preclinical study of allogeneic CD19 chimeric antigen receptor double‐negative T cells as an off‐the‐shelf immunotherapy drug against B‐cell malignancies

Clinical & Translational Immunology, Journal Year: 2024, Volume and Issue: 13(12)

Published: Jan. 1, 2024

Abstract Objectives To evaluate the manufacturability, efficacy and safety of allogeneic CD19 chimeric antigen receptor double‐negative T cells (CD19‐CAR‐DNTs) as an off‐the‐shelf therapeutic cell product. Methods A membrane proteome array was used to assess off‐target binding CD19‐CAR. DNTs derived from healthy donors were transduced with lentiviral vectors encoding The manufacture CD19‐CAR‐DNTs under GMP conditions, their surface molecule expression patterns characterised using flow cytometry. We investigated potential by evaluating cryopreserved in terms viability well cytotoxicity against various + target lines primary patient blasts vitro. evaluated persistence xenograft models vivo . Results GMP‐grade manufactured for use advance. maintain antitumor activity blasts. These significantly prolonged survival Raji‐Luc‐xenografted NOG mice. Multiple infusions can further augment efficacy. Remarkably, following a single infusion mice, rapidly got distributed among well‐perfused organs initially, progressively spread most tissues, peaking at Day 43. In toxicity studies, reduced tumor burden ameliorated tissue damage tumor‐bearing Critically, no immunotoxicity or graft versus host disease observed non‐tumor‐bearing Conclusions fulfil requirements product, offering promising new approach treatment haematological malignancies.

Language: Английский

---

Harnessing Type II Cytokines to Reinvigorate Exhausted T Cells for Durable Cancer Immunotherapy

Genomics Proteomics & Bioinformatics, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

Count of references: 10Cancer immunotherapy has made significant strides in developing immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR)-based cellular therapies recent years.Despite these advancements, the immunosuppressive nature tumor microenvironment (TME) its metabolic complexity continue to present substantial challenges.Within this hostile environment, tumor-infiltrating T cells often experience severe functional impairment reduced cytotoxic potential.One main barriers effective long-lasting control is cell exhaustiona state characterized by diminished effector functions, impaired proliferation, sustained expression inhibitory receptors like PD-1, TIM-3 LAG-3.Although CAR-T therapy revolutionized treatment hematological malignancies, relapse was constantly reported limited efficacy observed treating solid tumors, largely due TME rapid onset exhaustion.To better understand mechanisms behind responses, a large-scale single-cell multi-omics study profiled over one million pre-infusion CAR collected from 82 acute lymphoblastic leukemia patients, with clinical follow-up extending up 10 years [1].The analysis highlighted that elevated type II cytokine activity infusion products linked patients maintaining 8-year remission.At chromatin level, higher increased accessibility found at loci GATA3, while IFNG, STAT1, STAT4 TBX21 showed negligible differences.Remarkably, also identified small

Language: Английский

---