Current and future immunotherapeutic approaches in pancreatic cancer treatment

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: June 4, 2024

Abstract Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type tumor have remained grim long time. Currently, it extremely challenging to prevent or detect early enough effective treatment because patients rarely exhibit symptoms there are no reliable indicators detection. Most advanced spreading that difficult treat, treatments like chemotherapy radiotherapy can only slightly prolong their life by few months. Immunotherapy has revolutionized pancreatic cancer, yet its effectiveness limited tumor's immunosuppressive hard-to-reach microenvironment. First, article explains microenvironment highlights wide range immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered chimeric antigen [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced cells, immune checkpoint inhibitors, immunomodulators, vaccines, strategies targeting myeloid in context contemporary knowledge future trends. Lastly, discusses main challenges ahead immunotherapy.

Language: Английский

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Enhancement of anti‐sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2‐targeted CAR

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 1, 2025

Abstract Background Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, represent a group of malignancies that significantly contribute to cancer‐related morbidity mortality in children young adults. These cancers share common challenges, high rates metastasis, recurrence or treatment resistance, leading 5‐year survival rate approximately 20% for patients with advanced disease stages. Despite the critical need, therapeutic advancements have been limited over past three decades. The advent chimeric antigen receptor (CAR)‐based immunotherapies offers promising avenue novel treatments. However, CAR‐T cells faced significant challenges success treating solid tumours due issues such as poor tumour infiltration, immunosuppressive microenvironments off‐target effects. In contrast, adaptation CAR technology natural killer (NK) has demonstrated potential both haematological tumours, suggesting new strategy paediatric sarcomas. Methods This study developed validated CAR‐NK cell therapy targeting ephrin type‐A receptor‐2 (EphA2) antigen, which is highly expressed various Results expression was successfully detected on surface NK post‐electroporation, indicating successful transfection. Significantly, EphA2‐specific enhanced cytotoxic activity against several lines vitro, those compared unmodified cells. Transient messenger RNA (mRNA) transfection safe approach genetic engineering, further chemical modifications mRNA enhancing stability temporal EphA2‐CAR cells, thereby promoting prolonged protein expression. Additionally, vivo EphA2‐CAR‐NK showed anti‐cancer rhabdomyosarcoma osteosarcoma mouse models. Conclusions provides foundational basis clinical evaluation EphA2‐targeted across spectrum anti‐tumour effects observed vitro/vivo suggests improved outcomes hard‐to‐cure Key points Addressing unmet needs Sarcomas. sarcoma, exhibit lack progress decades necessitates innovative approaches. Advancing immunotherapy Natural modified receptors (CARs) overcome limitations particularly tumours. are associated targeting, reduced effects, safety profiles. EphA2 target. EphA2, overexpressed multiple identified viable target CAR‐based its role progression angiogenesis. Innovations mRNA‐based engineering. demonstrates feasibility transient engineer expression, offering non‐integrative safer alternative viral transduction. Enhancements through modifications, can optimise Preclinical efficacy superior cytotoxicity vitro demonstrate models osteosarcoma. Clinical translation potential. findings establish strong preclinical rationale immunotherapeutic option Future research directions: Combining immune checkpoint inhibitors other immunomodulatory agents could enhance durability. Advanced mimicking human needed refine this approach.

Language: Английский

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CAR-T Cell Therapy: From the Shop to Cancer Therapy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15688 - 15688

Published: Oct. 28, 2023

Cancer is a worldwide health problem. Nevertheless, new technologies in the immunotherapy field have emerged. Chimeric antigen receptor (CAR) technology novel biological form to treat cancer; CAR-T cell genetic engineering has positively revolutionized cancer immunotherapy. In this paper, we review latest developments treatment. We present structure of different generations and variants cells including TRUCK (T redirected for universal cytokine killing. explain approaches manufactured ex vivo vivo. Moreover, describe limitations areas opportunity current challenges treating hematological solid using as well its constraints approaches. summarize other immune that been CAR technology, such natural killer (NK), macrophages (M), dendritic (DC). conclude potential not only but chronic diseases.

Language: Английский

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Advancing Autoimmune Rheumatic Disease Treatment: CAR-T Cell Therapies - Evidence, Safety, and Future Directions

Seminars in Arthritis and Rheumatism, Journal Year: 2024, Volume and Issue: 67, P. 152479 - 152479

Published: May 24, 2024

Despite advancements in managing autoimmune rheumatic diseases (ARDs) with existing treatments, many patients still encounter challenges such as inadequate responses, difficulty maintaining remission, and side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has now emerged a promising option cases of refractory ARDs.

Language: Английский

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Antigen escape in CAR-T cell therapy: Mechanisms and overcoming strategies

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 178, P. 117252 - 117252

Published: Aug. 3, 2024

Chimeric antigen receptor T (CAR-T) cell therapy has shown promise in treating hematological malignancies and certain solid tumors. However, its efficacy is often hindered by negative relapses resulting from escape. This review firstly elucidates the mechanisms underlying escape during CAR-T therapy, including enrichment of pre-existing target-negative tumor clones, gene mutations or alternative splicing, deficits processing, redistribution, lineage switch, epitope masking, trogocytosis-mediated loss. Furthermore, we summarize various strategies to overcome escape, evaluate their advantages limitations, propose future research directions. Thus, aim provide valuable insights enhance effectiveness therapy.

Language: Английский

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Next-Generation Immunotherapy: Advancing Clinical Applications in Cancer Treatment

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(21), P. 6537 - 6537

Published: Oct. 30, 2024

Next-generation immunotherapies have revolutionized cancer treatment, offering hope for patients with hard-to-treat tumors. This review focuses on the clinical applications and advancements of key immune-based therapies, including immune checkpoint inhibitors, CAR-T cell therapy, new vaccines designed to harness system combat malignancies. A prime example is success pembrolizumab in treatment advanced melanoma, underscoring transformative impact these therapies. Combination treatments, integrating immunotherapy chemotherapy, radiation, targeted are demonstrating synergistic benefits improving patient outcomes. also explores evolving role personalized immunotherapy, guided by biomarkers, genomic data, tumor environment, better target individual Although significant progress has been made, challenges such as resistance, side effects, high costs persist. Technological innovations, nanotechnology artificial intelligence, explored future enablers The evaluates trials, breakthroughs, emerging immune-modulating agents delivery systems that hold great promise enhancing efficacy, reducing toxicity, expanding access immunotherapy. In conclusion, this highlights ongoing reshaping care, strategies poised overcome current further extend therapeutic reach.

Language: Английский

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Basic Concepts and Indications of CAR T Cells

Hämostaseologie, Journal Year: 2025, Volume and Issue: 45(01), P. 014 - 023

Published: Feb. 1, 2025

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer immunotherapy, particularly for hematological malignancies. This personalized approach is based on genetically engineering cells derived from the patient to target antigens expressed—among others—on malignant cells. Nowadays they offer new hope where conventional therapies, such as chemotherapy and radiation, have often failed. Since first FDA approval in 2017, CAR rapidly expanded, proving highly effective against previously refractory diseases with otherwise a dismal outcome. Despite its promise, continues face significant challenges, including complex manufacturing, management of toxicities, resistance mechanisms that impact long-term efficacy, limited access well high costs, which continue shape ongoing research clinical applications. review aims provide an overview therapy, fundamental concepts, applications, current future directions

Language: Английский

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Strategies to Overcome Antigen Heterogeneity in CAR-T Cell Therapy

Cells, Journal Year: 2025, Volume and Issue: 14(5), P. 320 - 320

Published: Feb. 20, 2025

Chimeric antigen receptor (CAR) gene-modified T-cell therapy has achieved significant success in the treatment of hematological malignancies. However, this not yet made breakthroughs solid tumors and still faces issues resistance relapse cancers. A major reason for these problems is antigenic heterogeneity tumor tissues. This review outlines encountered CAR-T cell corresponding strategies to address it. These include using combination increase abundance target antigens, optimizing structure CARs enhance sensitivity low-density developing multi-targeted cells, reprogramming TME activate endogenous immunity. approaches offer new directions overcoming therapy.

Language: Английский

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Advancements in Personalized CAR-T Therapy: Comprehensive Overview of Biomarkers and Therapeutic Targets in Hematological Malignancies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7743 - 7743

Published: July 15, 2024

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel anticancer using autologous or allogeneic T-cells. To date, six CAR-T therapies for specific B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphomas (NHL), and multiple myeloma (MM) have been approved by the Food Drug Administration (FDA). Significant barriers to effectiveness of include cytokine release syndrome (CRS), neurotoxicity in case Allogeneic Stem Cell Transplantation (Allo-SCT) graft-versus-host-disease (GVHD), escape, modest antitumor activity, restricted trafficking, limited persistence, immunosuppressive microenvironment, senescence exhaustion CAR-Ts. Furthermore, cancer drug resistance remains major problem clinical practice. therapy, combination with checkpoint blockades bispecific engagers (BiTEs) other drugs, appears be an appealing strategy. Many these agents shown impressive results, combining efficacy tolerability. Biomarkers like extracellular vesicles (EVs), cell-free DNA (cfDNA), circulating tumor (ctDNA) miRNAs may play important role toxicity, relapse assessment, prediction, can implicated applications establishing safe efficacious personalized medicine. However, further research required fully comprehend particular side effects immunomodulation, ascertain best order this medication conventional chemotherapy targeted therapies, find reliable predictive biomarkers.

Language: Английский

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CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy

Cancer Gene Therapy, Journal Year: 2024, Volume and Issue: 31(8), P. 1124 - 1134

Published: April 12, 2024

Language: Английский

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