Aug 2026· Progress in Biomedical Engineering· 0 citations
Medicine
TL;DR
By embedding measurement into the therapeutic design loop and prioritizing long-term safety and developmental outcomes alongside efficacy, next-generation engineered cell therapies may evolve toward adaptable, precision-guided systems capable of improving both survival and quality of life for children.
Abstract
Pediatric solid tumors continue to pose a major therapeutic challenge, with survival gains lagging behind those achieved in pediatric hematologic malignancies. While traditional approaches have focused on dose escalation and intensification of systemic therapies to improve survival, this strategy is often limited by significant short- and long-term morbidity from intensive multimodal treatment. Because children have developing organs and decades of life ahead, therapeutic strategies must balance durable tumor control with preservation of neurodevelopment, organ function, and quality of life. Immunotherapy has generated significant interest as an alternative to dose escalation; however, clinical translation in pediatric solid tumors has been limited by antigen heterogeneity, tumor plasticity, immune-cold or immune-excluded phenotypes, and a profoundly immunosuppressive tumor microenvironment. Bioengineered cellular therapies, particularly chimeric antigen receptor (CAR) T cells and CAR-modified natural killer (CAR NK) cells, provide a modular platform to address these barriers through synthetic receptor design, multi-antigen targeting, controlled activation, and improved trafficking to anatomically restricted sites such as the brain. However, engineering advances alone are unlikely to achieve durable benefit without parallel integration of quantitative in vivo monitoring capable of reporting biodistribution, persistence, and functional engagement. Non-invasive imaging and measurement-enabled approaches can provide mechanistic insight into therapeutic performance, discriminate between delivery failure and functional dysfunction, and support rational iteration of construct design, dosing, and route of administration. In this perspective, we review the current status of CAR T and CAR NK therapies in pediatric solid malignancies, outline key biological and engineering challenges, and propose a pediatric-centered development framework that integrates controllable cell engineering with quantitative, non-invasive assessment of in vivo behavior. By embedding measurement into the therapeutic design loop and prioritizing long-term safety and developmental outcomes alongside efficacy, next-generation engineered cell therapies may evolve toward adaptable, precision-guided systems capable of improving both survival and quality of life for children.
Breast cancer is one of the most common malignancies worldwide and remains a leading cause of cancer-related mortality. Over the past decades, advances in multimodal treatment have significantly improved patient survival. However, disease recurrence, metastatic progression, and therapeutic resistance continue to limit long-term outcomes, underscoring the need for more effective therapies. Among emerging immunotherapeutic approaches, chimeric antigen receptor T (CAR-T) cell therapy has attracted considerable attention. CAR-T therapy has achieved remarkable success in hematologic malignancies, prompting its investigation in breast cancer. However, translating this success to solid tumors remains challenging because of fundamental biological differences between hematologic and solid malignancies. Major barriers include antigen heterogeneity, limited tumor trafficking and infiltration, an immunosuppressive tumor microenvironment, and therapy-related toxicities. Numerous preclinical and clinical studies are currently evaluating CAR-T cell therapy in solid tumors, including breast cancer. These efforts incorporate next-generation CAR designs and novel engineering strategies with the goal of reproducing the clinical success achieved in hematologic malignancies. Although the available clinical evidence is still largely limited to early-phase trials, current findings suggest that CAR-T therapy in breast cancer is feasible and generally well tolerated. Most reported adverse events have been low-grade inflammatory toxicities, whereas severe neurotoxicity and dose-limiting toxicities have been infrequent. Despite this favorable safety profile, clinical responses remain modest, with stable disease representing the most common outcome and durable objective responses being uncommon. These findings underscore the need to overcome the major biological barriers that continue to limit CAR-T cell therapy in solid tumors. This review summarizes recent advances in CAR-T cell engineering, discusses the major target antigens investigated to date, provides a comprehensive overview of the available clinical evidence, and examines the key biological and clinical challenges that must be addressed to improve future therapeutic outcomes.
Ahmad Farajzadeh, Mahmoud Mahmoudi, Soroush Yazdani et al.· International Immunopharmaco...· 0 citations
The biological mechanisms underlying resistance to CAR-T therapy in solid tumors are examined and emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity are critically evaluated.
Wei Cheng, Mei-Lan Liu, Yu-Hua Diao et al.· Cancer Biome and Targeted Th...· 0 citations
Brain cancer remains a major global health challenge due to its high morbidity and mortality. Current standard therapies are often limited by incomplete tumor resection, systemic toxicity, and the inability to effectively penetrate the blood-brain barrier (BBB), which restricts drug delivery to the tumor site. These challenges underscore the urgent need for innovative therapeutic strategies that can overcome these barriers and improve treatment outcomes. Biological materials encompass a diverse range of molecules, from small peptides to monoclonal antibodies, either derived from living organisms or synthetically synthesized. Unlike traditional therapies, biologics provide a more targeted approach, including specific tumor targeting, immune system modulation, and regenerating damaged cells. Although biologics offer significant promise for brain cancer treatment, major challenges associated with blood-brain and tumour barriers continue to limit their translation, and comprehensive reviews bridging therapeutic advances with delivery technologies remain scarce. While individual biologic classes have been extensively studied, a unified assessment of these modalities and their delivery optimization is still needed. This review addresses the current gap by critically examining recent advances in biologic therapies and evaluating emerging invasive and non-invasive delivery strategies to enhance their therapeutic efficacy in brain cancer.
Yu-Ran Feng, Yuxue Cao, Maria Kavallaris et al.· Advances in Materials· 0 citations
Cell therapy has reshaped the treatment landscape for some hematological malignancies, but its role in urological tumors remains limited and uneven. Early studies in bladder cancer, renal cell carcinoma and prostate cancer suggest that cell therapy can redirect recognition of tumor-associated antigens, enhance cytotoxic effector function and reactivate endogenous antitumor immunity. However, current cell therapies have not yet achieved satisfactory durable responses in most patients. Durable remission depends on more than target recognition: tumor cells must express accessible antigens, and infused cells must enter lesions and maintain their activity within them. More importantly, immune activation must be strong enough to control tumors but sufficiently restrained to avoid systemic toxicity. Therefore, this review evaluates the factors influencing cell therapy from the perspectives of target selection, tumor accessibility, cellular persistence and activation control. It also compares different cell-therapy platforms in light of current clinical evidence and discusses the mechanisms that limit therapeutic efficacy. Finally, it proposes translational priorities and remaining challenges for the further development of cell therapy in urological tumors.
Ju Li, Huan Yang· Biochimica et biophysica act...· 0 citations
Editorial on the research topic Next-Generation Treatment for Pediatric Cancer: Advancing Immunotherapy through Combinations. Cancer remains one of the leading causes of disease-related mortality among children and adolescents. Despite advances in treatments, outcomes for many pediatric tumors remain limited, particularly in patients with high-risk, relapsed, or refractory disease. Standard therapies, including surgery, chemotherapy, radiotherapy, and stem cell transplantation, are frequently associated with severe long-term toxicities and secondary malignancies. Resistance and relapse remain major clinical challenges. Recent progress in cancer immunotherapy has revolutionized adult oncology, and remarkable clinical advances have been observed in several pediatric cancers. However, comparable benefits in most solid tumors remain limited. Among molecular targets, anaplastic lymphoma kinase (ALK) has emerged as a critical driver of tumorigenesis in several pediatric malignancies, including anaplastic large cell lymphoma (ALCL), neuroblastoma and inflammatory myofibroblastic tumor. While ALK tyrosine kinase inhibitors have demonstrated clinical benefit, the emergence of resistance highlights the need for alternative or complementary strategies. ALK can act as an oncoantigen, as shown by spontaneous ALK-specific humoral and T-cell responses in patients with ALK-positive ALCL, and ALK-directed immunotherapies have been developed and have shown efficacy in preclinical models of ALK-positive tumors, including ALCL and neuroblastoma. Therefore, ALK-directed immunotherapies represent biologically rational and promising approaches that may, if proven safe and effective in clinical trials, address resistance and improve long-term disease control. In this review, we will discuss ALK-specific immunotherapies, including ALK vaccines, ALK CAR-T and other cellular therapies, as well as ALK-targeting antibodies with a particular focus on pediatric ALK-positive tumors.
Monica Maccagno, Roberta Tagliero, Roberto Chiarle et al.· Frontiers in Immunology· 0 citations
ABSTRACT Cellular therapies representa promising area of immunotherapy for advanced cancers,therapies including T cell receptor (TCR) therapies, chimeric antigen receptor (CAR) T cell therapies, tumor-infiltrating lymphocyte (TIL) therapies, and natural killer (NK) cell therapies.Sarcomas pose unique challenges due to their molecular complexity and immunosuppressive tumor microenvironment (TME). TCRtherapiesargeting antigens likeNY-ESO-1, MAGE-A4, and PRAME have shown efficacy, highlighted by the FDA’s accelerated approval of afamitresgene autoleucel targeting MAGE-A4 for synovial sarcoma.CAR-T cell therapies targeting HER2, GD2, and B7-H3, along with TIL, and NK cell therapies are also under investigation.However, many are in early stages of clinical development, and their effectiveness may vary by sarcoma subtype. Overcoming challenges such as immunosuppressive TME, antigen escape, lack of T-cell persistence, and off-target toxicities is crucial to improving outcomes for sarcoma patients. This review summarizes the evolution of cellular therapies,ongoing research, challenges, and future directions in this field.
C. Wannaphut, P. Thirasastr, J. Livingston et al.· Human Vaccines & Immunothera...· 0 citations