Search Results (57)

Young women who have survived cancer may have lost their fertility due to cytotoxic treatments like chemotherapy or irradiation. So far, oocyte or ovarian tissue cryopreservation are well-known and well-used opportunities for fertility preservation prior cytotoxic therapies. However, these methods are not possible in certain cases, like those with a high risk of ovarian metastasis or prepubertal girls. Therefore, new medical and biotechnological options are also being sought to help this patient group to fulfill their desire to have their own biological children. The investigation described here focuses on the possibility of in vitro follicle maturing. To this point, a long-term temperature and pH-controlled bioreactor system is developed that can supply a whole ovary with oxygen and nutrients over several days and offers the possibility of hormone administration or the delivery of other drugs. This bioreactor was then tested with mature bovine ovaries. After appropriate cannulation, antithrombotic vascular perfusion, and antibiotic pretreatment, the ovaries were cultured for up to 9 days without any contamination or suffering major vital cell damage. The controlled application of oocyte stimulation hormones (human menopausal gonadotropin; hMG) also enabled successful in vitro follicle growth and maturation. From a technical point of view, there is still optimization potential for this bioreactor system, but in principle, it has been demonstrated that long-term ovary cultivation and in vitro maturation of follicles are possible, which opens up further potential for these and other applications. Full article

Background/Objectives: Eosinophilic myocarditis (EM) is a rare, life-threatening inflammatory cardiomyopathy driven by eosinophil cytotoxicity and extracellular trap formation. Interleukin-5 (IL-5) inhibition may disrupt this pathogenic cascade. We reviewed contemporary evidence on IL-5 blockade in EM and contextualized it with an illustrative case. Methods: We searched PubMed through May 2025 for reports of EM treated with mepolizumab or benralizumab. Inclusion criteria were consistent with prior cohorts: acute cardiac symptoms with biomarker elevation plus abnormalities on transthoracic echocardiography and/or cardiac magnetic resonance imaging (CMR), along with documented IL-5-targeted therapy. We extracted clinical, imaging, biopsy, treatment-timing, and outcome data and included one institutional case. Results: Twenty-one episodes were analyzed (median age, 45 years; 10 men). Underlying conditions included eosinophilic granulomatosis with polyangiitis (10 cases; 48%), hypereosinophilic syndrome (5 cases; 24%), drug reaction with eosinophilia and systemic symptoms (DRESS, 3 cases; 14%), and eosinophilic asthma (3 cases; 14%). Treatments involved mepolizumab in 17 cases (81%) and benralizumab in 4 (19%); 4 patients received “early-start” therapy within 14 days of EM diagnosis. Among the 11 episodes with reported left ventricular ejection fraction (LVEF) at baseline and follow-up, the median baseline LVEF was 40% (range, 30–62), with 10 of 11 (91%) <50%. On follow-up, all 11 patients improved: 4 normalized (≥50%) and 7 improved to 40–49%. CMR (n = 18) demonstrated late gadolinium enhancement in 14 cases (78%), edema in 9 (50%), and intracardiac thrombus in 4 (22%). Endomyocardial biopsy confirmed eosinophilic infiltration in 13 of 15 cases (87%). Outcomes included one death (fulminant DRESS), one recovery following veno-arterial extracorporeal membrane oxygenation, and one successful heart transplantation. Illustrative case: A 24-year-old man on a steroid taper received mepolizumab 300 mg on Day 4. His LVEF improved from 47% to 59% by Day 15, accompanied by biomarker decline and successful steroid tapering. Conclusions: Across published cases and our institutional experience, IL-5–targeted therapy appears safe, steroid-sparing, and associated with rapid ventricular recovery, particularly when initiated early. Although limited, these findings support the need for prospective trials to define the optimal agent, dosing, timing, and integration with standard immunosuppression and anticoagulation. Full article

Cutaneous metastases from breast carcinoma represent a debilitating complication of advanced disease progression, significantly impacting patients’ quality of life. Electrochemotherapy (ECT), which combines cytotoxic drugs such as bleomycin or cisplatin with electric pulses to enhance cellular permeability, has shown promising efficacy as a local treatment for these lesions. Objectives: This literature review examines the principles of ECT, its mechanisms of action and the clinical outcomes in patients with primary breast cancer. Across clinical series, patient-level ORR typically ranges from ~70–90% and CR up to ~58% at 6–12 weeks, with lower rates in larger (>3 cm) or deeper lesions. ECT is safe, well tolerated, and potentially synergistic with other systemic therapies. However, its efficacy is influenced by factors such as lesion size, tumor receptor status, and prior radiotherapy. Optimizing patient selection, standardizing treatment protocols, and developing combination approaches with immunotherapy or targeted therapies represent key future directions to improve clinical outcomes. Full article

Background: Breast cancer continues to pose a significant global health challenge despite advances in early detection and targeted therapies. The development of novel chemotherapeutic agents remains crucial, particularly those with selective cytotoxicity toward specific breast cancer subtypes. Methods: A series of ten hybrid indolyl-methylidene phenylsulfonylhydrazones and one bis-indole derivative were designed, synthesized, and structurally characterized using NMR and high-resolution mass spectrometry (HRMS). Prior to synthesis, in silico screening was performed to assess drug likeness and ADME-related properties. Single-crystal X-ray diffraction was conducted for compound 3e. The cytotoxic potential of the synthesized compounds was evaluated using the MTT assay against MCF-7 (ER-α⁺) and MDA-MB-231 (triple-negative) breast cancer cell lines. Additionally, quantitative structure–activity relationship (QSAR) analysis was conducted to identify key structural features contributing to activity. Results: Most compounds exhibited selective cytotoxicity against MCF-7 cells. Notably, compound 3b demonstrated the highest potency with an IC₅₀ of 4.0 μM and a selectivity index (SI) of 20.975. Compound 3f showed strong activity against MDA-MB-231 cells (IC₅₀ = 4.7 μM). QSAR analysis revealed that the presence of a non-substituted phenyl ring and specific indolyl substituents (5-methoxy, 1-acetyl, 5-chloro) significantly contributed to enhanced cytotoxic activity and ligand efficiency. Conclusion: The synthesized phenylsulfonylhydrazone hybrids exhibit promising and selective cytotoxicity, particularly against ER-α⁺ breast cancer cells. Structural insights from QSAR analysis provide a valuable foundation for the further optimization of this scaffold as a potential source of selective anticancer agents. Full article

CAR-T cell therapy represents a breakthrough in cancer treatment, yet its implementation in developing countries remains challenging due to technical and infrastructural barriers. This study aimed to establish clinical-scale CAR-T production in Kazakhstan, a country with no prior experience in advanced cell and gene therapies. We implemented a complete CAR-T manufacturing pipeline, including in-house lentiviral vector (LV) production and automated CAR-T cell processing using the CliniMACS Prodigy system. Two anti-CD19 CAR LVs were used, one modeled after FDA-approved Kymriah (4-1BB costimulation) and another replicating Yescarta (CD28 costimulation). The vector produced locally achieved functional titers of 1.5 × 10¹⁰ TU/mL after concentration. Twelve clinical-scale CAR-T products were manufactured, exhibiting a memory-skewed T-cell phenotype. Functional assessments revealed that CD28-based CAR-T cells produced significantly higher Th1 cytokines (IFN-γ, TNF-α, IL-2; p < 0.05) than 4-1BB-based cells, though both demonstrated comparable cytotoxicity against CD19+ targets. These findings demonstrate the feasibility of establishing CAR-T production in resource-limited settings using a decentralized manufacturing framework. This work provides a scalable model of CAR-T therapy production in developing regions, suitable for clinical implementation using the hospital exemption framework. Critical gaps in access to advanced immunotherapies, including CAR-T, in the Central Eurasia region are addressed. Full article

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radiotherapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cytotoxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types. Full article

Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition and expression of the immune checkpoints programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) in RRP. We analyzed tissue samples from 30 patients treated at a tertiary care center between 2009 and 2021, including paired samples from individual patients collected at different time points. Immunohistochemical staining was performed for CD4, CD8, CTLA-4, FoxP3, and PD-L1 and correlated with disease severity and previous adjuvant therapies. Overall disease burden and intervention-free survival were not associated with the abundance of CD4⁺, CD8⁺, or FoxP3⁺ T cells, nor with immune checkpoint expression. However, patients with aggressive disease exhibited a higher intralesional FoxP3/CD4 T-cell ratio. Prior intralesional cidofovir treatment was associated with reduced CD4⁺ T-cell infiltration. These findings suggest that a locally immunosuppressive microenvironment, reflected by an elevated FoxP3/CD4 ratio, contributes to disease severity in RRP. Consistent CTLA-4 expression across all evaluated samples supports further investigation of anti-CTLA-4 therapy, either alone or in combination with other checkpoint inhibitors. Full article

Clonal hematopoiesis (CH) is an age-related process in which hematopoietic stem/progenitor cells increase their fitness due to the acquisition of mutations that lead to a proliferative advantage and to clonal expansion. Its frequency increases with age, and it mostly affects people older than 70 years. The most mutated genes in CH are epigenetic regulators, DNA damage response genes, and splicing factors, which are all involved in the development of myeloid neoplasia. Some risk factors, including age, smoking, and prior cytotoxic therapy, increase the risk of developing CH or increase the fitness of CH. Various types of CH have been observed, associated or not with cytopenias or monocytosis. CH represents a risk factor for many pathological conditions and particularly for hematologic malignancies. A better understanding of the risks related to CH has triggered the development of research, translational, and clinical programs for the monitoring, prevention, and treatment of CH. Full article

Background/Objectives: Myeloid neoplasms are the most common secondary blood cancer in B-cell non-Hodgkin lymphoma (BNHL) patients treated with cytotoxic therapies. We aimed to characterize the genetic and clinicopathologic features of myeloid neoplasms arising after B-cell non-Hodgkin lymphoma (MN-BNHL) by comparing their features with myeloid neoplasms developing after solid cancer (MN-SC). Methods: We retrospectively analyzed the clinicopathologic and genetic data of myeloid neoplasm patients diagnosed between 2008 and 2023, categorized as MN-BNHL or MN-SC. Further NGS analysis was performed on available bone marrow samples with missing genetic data. The genetic profiles of myeloid neoplasms between BNHL and solid cancer groups were compared. Results: Sixteen patients developed MN-BNHL. Among the 11 MN-BNHL patients undergoing NGS, all harbored tier 1 mutations. PPM1D mutations (PPM1Dms) were most frequent (73%), followed by DNMT3A (46%) and TP53 (36%). PPM1Dms were significantly more prevalent than in MN-SC (n = 21), where TP53 mutations were most common (64%) (p < 0.001). PPM1Dms often co-occurred with DNMT3A. They were associated with prior radioimmunotherapy (relative risk (RR): 3.3 and RR 3.57). MN-BNHL patients with PPM1Dms exhibited improved survival compared to those without (p = 0.0376), but this benefit was negated by the presence of TP53 mutations (p = 0.0049). Conclusions: PPM1Dms are a prominent genetic feature in MN-BNHL, suggesting a distinct role in its development compared to MN-SC. Further investigation is needed to elucidate the precise contribution of PPM1D and its interaction with other mutations in BNHL-related myeloid neoplasm development and prognosis. Full article

Despite notable progress in managing B-cell acute lymphoblastic leukemia (B-ALL) over recent decades, particularly in pediatric cohorts where the 5-year overall survival (OS) reaches 90%, outcomes for the 10–15% with relapsed and refractory disease remain unfavorable. This disparity is further accentuated in adults, where individuals over the age of 40 years undergoing aggressive multiagent chemotherapy continue to have lower survival rates. While the adoption of pediatric-inspired treatment protocols has enhanced complete remission (CR) rates among younger adults, 20–30% of these patients experience relapse, resulting in a subsequent 5-year OS rate of 40–50%. For relapsed B-ALL in adults, there is no universally accepted standard salvage therapy, and the median OS is short. The cornerstone of B-ALL treatment continues to be the utilization of combined cytotoxic chemotherapy regimens to maximize early and durable disease control. In this manuscript, we go beyond the multiagent chemotherapy medications developed prior to the 1980s and focus on the incorporation of antibody-based therapy for B-ALL with an eye on existing and upcoming approved indications for blinatumomab, inotuzumab ozogamicin, other monoclonal antibodies, and chimeric antigen receptor (CAR) T cell products in frontline and relapsed/refractory settings. In addition, we discuss emerging investigational therapies that harness the therapeutic vulnerabilities of the disease through targeting apoptosis, modifying epigenetics, and inhibiting the mTOR pathway. Full article

Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system capable of killing virus-infected cells and/or cancer cells. The commonly used NK cells for therapeutic applications include primary NK cells and immortalized NK cell lines. However, primary NK cell therapy faces limitations due to its restricted proliferation capacity and challenges in stable storage. Meanwhile, the immortalized NK-92 cell line requires irradiation prior to infusion, which reduces its cytotoxic activity, providing a ready-made alternative and overcoming these bottlenecks. Recent improvements in differentiation protocols for iPSC-derived NK cells have facilitated the clinical production of iPSC-NK cells. Moreover, iPSC-NK cells can be genetically modified to enhance tumor targeting and improve the expansion and persistence of iPSC-NK cells, thereby achieving more robust antitumor efficacy. This paper focuses on the differentiation-protocols efforts of iPSC-derived NK cells and the latest progress in iPSC-NK cell therapy. Additionally, we discuss the current challenges faced by iPSC-NK cells and provide an outlook on future applications and developments. Full article

Background/Objectives: Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series: Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions: Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities. Full article

Glioblastoma (GBM) is an immunologically cold tumor, but several immunotherapy-based strategies show promise, including the administration of ex vivo expanded and activated cytotoxic gamma delta T cells. Cytotoxicity is partially mediated through interactions with natural killer group 2D ligands (NKG2DL) on tumor cells. We sought to determine whether the addition of the blood–brain barrier penetrant PARP inhibitor niraparib to the standard of care DNA alkylator temozolomide (TMZ) could upregulate NKG2DL, thereby improving immune cell recognition. Changes in viability were consistent with prior publications as there was a growth inhibitory effect of the combination of TMZ and niraparib. However, decreases in viability did not always correlate with changes in NKG2DL mRNA. ULBP1/Mult-1 mRNA was increased with the combination therapy in comparison to either drug alone in two of the three cell types tested, even though viability was consistently decreased. mRNA expression correlated with protein levels and ULBP1/MULT-1 cell surface protein was significantly increased with TMZ and niraparib treatment in four of the five cell types tested. Gamma delta T cell-mediated cytotoxicity at a 10:1 effector-to-target ratio was significantly increased upon pretreatment of cells derived from a GBM PDX with TMZ and niraparib in comparison to the control or either drug alone. Together, these data demonstrate that the combination of PARP inhibition, DNA alkylation, and gamma delta T cell therapy has the potential for the treatment of GBM. Full article

Allogeneic natural killer (NK) cell therapy has been effective in treating cancer. Many studies have tested NK cell therapy using human pluripotent stem cells (hPSCs). However, the impacts of the origin of PSC-NK cells on competence are unclear. In this study, several types of hPSCs, including human-induced PSCs (hiPSCs) generated from CD34+, CD3−CD56+, and CD56− cells in umbilical cord blood (UCB), three lines of human embryonic stem cells (hESCs, ES-1. ES-2 and ES-3) and MHC I knockout (B2M-KO)-ESCs were used to differentiate into NK cells and their capacities were analyzed. All PSC types could differentiate into NK cells. Among the iPSC-derived NK cells (iPSC-NKs) and ESC-derived NK cells (ES-NKs), 34+ iPSCs and ES-3 had a higher growth rate and cytotoxicity, respectively, ES-3 also showed better efficacy than 34+ iPSCs. B2M-KO was similar to the wild type. These results suggest that the screening for differentiation of PSCs into NK cells prior to selecting the PSC lines for the development of NK cell immunotherapy is an essential process for universal allotransplantation, including the chimeric antigen receptor (CAR). Full article

Glioblastoma multiforme (GBM) is a fast-growing and aggressive brain tumour, which remains largely resistant to treatment; the prognosis for patients is poor, with a median survival time of about 12–18 months, post diagnosis. In an effort to bring more efficacious treatments to patients, we targeted the down regulation of ITCH, an E3 ligase that is overexpressed in a variety of cancers, and which inhibits P73, a tumour suppressor gene. 6-O-glycolchitosan (GC) was used to deliver siRNA ITCH (GC60-siRNA-ITCH) and gemcitabine via the nose to brain route in CD-1 nude mice which had previously been implanted intracranially with U87-MG-luc2 cells. Prior to this in vivo study, an in vitro study established the synergistic effect of siRNA-ITCH in combination with a chemotherapy drug—gemcitabine. A downregulation of ITCH, an upregulation of p73 and enhanced apoptosis were observed in vitro in U87-MG cells, using qPCR, Western blot analysis, confocal laser scanning microscopy, flow cytometry and cytotoxicity assays. When GC60-siRNA-ITCH was combined with gemcitabine, there was a resultant decrease in cell proliferation in vitro. In CD1 mice, the administration of siRNA-ITCH (7 doses of 0.081 mg/kg) alone did not significantly affect animal survival (increasing mean survival from 29 to 33 days when compared to untreated animals), whereas intranasal gemcitabine had a significant effect on survival (increasing survival from 29 to 45 days when compared to untreated animals, p < 0.01). The most significant effect was seen with combination therapy (GC60-siRNA-ITCH plus gemcitabine), where survival increased by 89%, increasing from 29 to 54 days (p < 0.01). Our data demonstrate that siRNA chemosensitises brain tumours to gemcitabine and that the nose-to-brain delivery route may be a viable route for the treatment of intracranial tumours. Full article