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

Current Landscape and Future Directions in Cancer Immunotherapy: Therapies, Trials, and Challenges

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 821 - 821

Published: Feb. 27, 2025

Cancer remains a leading global health challenge, placing immense burdens on individuals and healthcare systems. Despite advancements in traditional treatments, significant limitations persist, including treatment resistance, severe side effects, disease recurrence. Immunotherapy has emerged as promising alternative, leveraging the immune system to target eliminate tumour cells. However, challenges such immunotherapy patient response variability, need for improved biomarkers limit its widespread success. This review provides comprehensive analysis of current landscape cancer immunotherapy, highlighting both FDA-approved therapies novel approaches clinical development. It explores checkpoint inhibitors, cell gene therapies, monoclonal antibodies, nanotechnology-driven strategies, offering insights into their mechanisms, efficacy, limitations. By integrating emerging research advancements, this underscores continued innovation optimise overcome existing barriers.

Language: Английский

The current socioeconomic and regulatory landscape of immune effector cell therapies

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Dec. 4, 2024

Immune cell effector therapies, including chimeric antigen receptor (CAR)-T cells, T-cell (TCR) T natural killer (NK) and macrophage-based represent a transformative approach to cancer treatment, harnessing the immune system target eradicate malignant cells. CAR-T therapy, most established among these, involves engineering cells express CARs specific antigens, showing remarkable efficacy in hematologic malignancies like leukemias, B-cell lymphomas, multiple myeloma. Similarly, TCR-modified which reprogram recognize intracellular tumor antigens presented by major histocompatibility complex (MHC) molecules, offer promise for range of solid tumors. NK-cell therapies leverage NK cells' innate cytotoxicity, providing an allogeneic that avoids some immune-related complications associated with T-cell-based therapies. Macrophage-based still early stages development, focus on reprogramming macrophages stimulate response against microenvironment. Despite their promise, socioeconomic regulatory challenges hinder accessibility scalability These treatments are costly, currently exceeding $400,000 per patient, creating significant disparities access based status geographic location. The high manufacturing costs stem from personalized, labor-intensive processes harvesting, modifying, expanding patients' Moreover, logistics delivering these limit reach, particularly low-resource settings. Regulatory pathways further complicate landscape. In United States., Food Drug Administrations' (FDA) accelerated approval cell-based facilitate innovation but do not address cost-related barriers. Europe, European Medicines Agency (EMA) offers adaptive pathways, yet decentralized reimbursement systems create uneven across member states. Additionally, differing standards quality control worldwide pose hurdles global harmonization access. To expand reach multipronged is needed-streamlined frameworks, policies reduce treatment costs, international collaborations standardize manufacturing. Addressing obstacles essential make life-saving accessible broader patient population worldwide. We present literature review current landscape barriers approved standard care therapy at various levels.

Language: Английский