Biomarker Research最新文献

Multiple myeloma (MM) is a blood cancer characterized by the clonal evolution of plasma cells. In 2022, there were an estimated 118 000 MM cases and 121 000 deaths worldwide. The treatment landscape of MM has undergone a dramatic transformation in recent decades, shifting from conventional chemotherapy to more targeted approaches. In order to overcome intrinsic and acquired resistance mechanisms that frequently restrict the efficacy of single-agent therapies, drug combination strategies have been developed to simultaneously target multiple pathogenetic pathways. Building on the success of immunomodulatory agents, CRBN E3 ligase modulators (CELMoDs), iberdomide (CC-220) and mezigdomide (CC-92480), have been designed as promising and more selective agents. CELMoDs demonstrate a 10-20 times higher binding capacity and they promote a more profound and rapid breakdown of Ikaros and Aiolos compared to traditional immunomodulatory agents. According to the National Cancer Institute Surveillance Program, the median survival for fit patients is greater than ten years, and the 5-year survival for the general MM patient population in the US approaches 60%. Despite these encouraging numbers, MM is still an incurable disease, and the majority of patients eventually relapse and require additional lines of therapy. Combining CELMoDs with cellular therapies significantly improves the response rate in MM patients. In this paper, based on the literature presented at the Annual Meeting of the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), the International Myeloma Society (IMS), and the European Hematology Association (EHA) in the 2020-2025 timeframe, we explore the rationale and emerging evidence of combining CELMoDs with immunotherapies, and their use as a bridge to transplant or as post-ASCT maintenance therapy in MM.

The conversion of leukemic blasts into antigen-presenting dendritic cells of leukemic origin (DC_leu) by GM-CSF and PGE1 has demonstrated preclinical efficacy in eliciting leukaemia-specific immune responses, offering a promising immunotherapeutic strategy for relapsed/refractory AML. We report on a 65-year-old patient with AML refractory to multiple treatment lines, including two allogeneic stem cell transplantations, who received individualized experimental treatment with intravenous GM-CSF and PGE1 and no additional anti-leukaemic therapy. Based on preceding ex-vivo treatment of patient´s blood with GM-CSF/PGE1 that showed immune activation and blast lysis, we hypothesized that intravenous administration of the compounds to the patient would promote in-vivo antileukaemic immune reactions and potentially induce clinical response. Eight treatment cycles were administered, and extensive immune monitoring was performed. The treatment was well tolerated and resulted in sustained clinical stabilization over four months. Immune monitoring showed generation of mature DC_leu, activation of leukaemia-directed effector and memory cells (including IFN-γ-producing and degranulating T and NK cells), downregulation of immune checkpoint (PD-1/CTLA-4) expressing T cells and blasts, and a reduction in regulatory B- and T cells. This case illustrates the feasibility and tolerability of GM-CSF + PGE1 therapy and its potential to modulate anti-leukaemic immunity in a patient with highly refractory AML.

Background: The low response rate of anti-PD-1 monoclonal antibodies (mAbs) in hepatocellular carcinoma (HCC) requires the development of combination immunotherapy strategies to improve their efficacy. This study aimed to use LAG-3-targeted PET imaging to monitor the efficacy of anti-PD-1 mAb, a stimulator of interferon genes (STING) agonist, and anti-LAG-3 mAb, both individually and in combination. Furthermore, we evaluated the potential of a triple immunotherapy regimen (anti-PD-1 mAb, STING agonist, and anti-LAG-3 mAb) to improve HCC treatment.

Methods: The LAG-3 inhibitor C25 based on a cyclic peptide was chelated with NOTA, radiolabeled with [⁶⁸Ga]GaCl₃. The resulting [⁶⁸Ga]Ga-NOTA-C25 underwent in vivo PET imaging and ex vivo biodistribution examination in Hepa1-6 tumor-bearing mice. [⁶⁸Ga]Ga-NOTA-C25 PET was used to monitor the efficacy of monotherapy and dual immunotherapy with anti-PD-1 monoclonal antibody (mAb) and STING agonists. The tumor uptake of [⁶⁸Ga]Ga-NOTA-C25, tumor response, and survival rates were measured following different treatments. The therapeutic efficacy, molecular mechanisms, and safety of triple immunotherapy were validated using histopathological analysis and flow cytometry.

Results: [⁶⁸Ga]Ga-NOTA-C25 PET imaging effectively and noninvasively detected LAG-3⁺ tumor-infiltrating lymphocytes (TILs) in Hepa1-6 tumor-bearing mice. In mice treated with anti-PD-1 mAb, STING agonist, or a combination immunotherapy, [⁶⁸Ga]Ga-NOTA-C25 PET revealed significantly increased LAG-3⁺ TIL levels. At the treatment endpoint, the combination of the STING agonist with the anti-PD-1 mAb resulted in a significantly higher uptake (1.35 ± 0.191%ID/g) compared to the control group (0.402 ± 0.017%ID/g), the anti-PD-1 mAb group (0.647 ± 0.037%ID/g), and the STING agonist group (0.874 ± 0.089%ID/g). Uptake of [⁶⁸Ga]Ga-NOTA-C25 was positively correlated with tumor therapeutic effects and survival rates. Triple immunotherapy with anti-PD-1 mAb, a STING agonist, and anti-LAG-3 mAb further enhanced efficacy compared to any dual immunotherapy regimen, and treatment efficacy was linearly associated with [⁶⁸Ga]Ga-NOTA-C25 tumor uptake.

Conclusions: Anti-PD-1 mAb and STING agonists have shown notable synergy in upregulating LAG-3 expression on TILs in HCC, which can be successfully tracked by [⁶⁸Ga]Ga-NOTA-C25 PET imaging. Furthermore, integration of a triple immunotherapy regimen comprising an anti-PD-1 mAb, STING agonist, and anti-LAG-3 mAb demonstrated a significant improvement in therapeutic efficacy over dual immunotherapy approaches.

Background: Early identification of high-risk individuals is crucial for optimizing cancer screening, particularly when considering expensive and invasive methods such as multi-omics technologies and endoscopic procedures. However, developing a robust, practical multi-cancer risk prediction model that integrates diverse, multi-scale data and with proper validation remains a significant challenge.

Methods: We initialized the FuSion study by recruiting 42,666 participants from Taizhou, China, with a discovery cohort (n = 16,340) and an independent validation cohort (n = 26,308) after exclusion criteria. We integrated multi-scale data from 54 blood-derived biomarkers and 26 epidemiological exposures to develop a risk prediction model for five common cancers, including lung, esophageal, liver, gastric, and colorectal cancer. Employing five supervised machine learning approaches, we used a LASSO-based feature selection strategy to identify the most informative predictors. The model was trained and internally validated in the discovery cohort, externally applied in the validation cohort, and further evaluated through a prospective clinical follow-up to assess cancer events via clinical examinations.

Results: The final model comprising four key biomarkers along with age, sex, and smoking intensity, achieving an AUROC of 0.767 (95% CI: 0.723-0.814) for five-year risk prediction. High-risk individuals (17.19% of the cohort) accounted for 50.42% of incident cancer cases, with a 15.19-fold increased risk compared to the low-risk group. During follow-up of 2,863 high-risk subjects, 9.64% were newly diagnosed with cancer or precancerous lesions. Notably, cancer detection in the high-risk group was 5.02 times higher than in the low-risk group and 1.74 times higher than in the intermediate-risk group. In particular, the incidence of esophageal cancers in the high-risk group was 16.84 times that of the low-risk group.

Conclusions: This is the first population-based prospective study in a large Chinese cohort that leverage multi-scale data including biomarkers for multi-cancer risk prediction. Our effective risk stratification model not only enhances early cancer detection but also lays the foundation for the targeted application of advanced screening methods, including but not limited to multi-omics technologies and endoscopy. These findings support precision prevention strategies and the optimal allocation of healthcare resources.

Background: Infants diagnosed with B cell acute lymphoblastic leukemia (B-ALL) and t(4;11) chromosomal rearrangement display poor therapeutic response, associated to the low expression of B lymphocyte factor HDAC7. This study was conceived to identify a therapeutic strategy for t(4;11) B-ALL that restores optimal HDAC7 expression.

Methods: A multiomics approach in a large infant pro-B-ALL cohort was employed to identify HDAC7's repression mechanism. These data, combined with cell culture assays in a variety of pro-B-ALL cell lines with differential HDAC7 levels, led us to define a novel combination therapy. Murine leukemia models and ex vivo assays using patient-derived xenografts (PDX) were employed to assess the benefits of this therapy when incorporated to glucocorticoid-based chemotherapy.

Results: Our data demonstrates that HDAC7 is epigenetically silenced by EZH2 and KMT2A::AFF1 fusion protein. Remarkably, the Menin-1 inhibitor MI-538 restores HDAC7 expression, and the effect is enhanced by class I HDAC inhibitor chidamide. This treatment drives leukemic pro-B cells towards a more differentiated state and impairs aberrant proliferation in an HDAC7-dependent manner. This newly identified therapy increases glucocorticoid sensitivity of PDX cells ex vivo, by repressing RUNX2 transcription factor. Finally, combining MI-538 and chidamide with standard chemotherapy reduces PDX cells engraftment in vivo and delays relapse.

Conclusions: The combined therapy proposed, based on Menin-1 inhibition, improves t(4;11) B-ALL cells' response to standard therapy, an effect partially mediated by HDAC7 induction. Therefore, this novel therapy opens a new field for personalized treatments in high-risk leukemia, especially for infants presenting low expression of HDAC7 B cell factor.

Selective RET inhibitors such as pralsetinib have become the standard of care for patients with RET fusion-positive non-small cell lung cancer (NSCLC). Serial analysis of circulating tumor DNA (ctDNA) has proven effective in monitoring disease control/progression and therapeutic response in NSCLC. In this prospective study, we analyzed longitudinal ctDNA profiles (at baseline, week 8, and at progression) in Chinese patients with advanced RET fusion-positive NSCLC treated with pralsetinib (NCT03037385), utilizing allele frequency-based, cfDNA quantity-normalized, and methylation-based metrics. Associations between ctDNA dynamics, tumor response, and genomic alterations were assessed. A total of 21 patients were enrolled. Baseline PIK3CA co-mutations were associated with inferior progression-free survival (PFS; 3.0 vs. 12.4 months, P < 0.001). Superior PFS was observed in patients with lower baseline ctDNA levels across all metrics: allele frequency-based (HR = 0.24; 95% confidence interval [CI], 0.07-0.80; P = 0.012), cfDNA quantity-normalized (HR = 0.20; 95% CI, 0.05-0.71; P = 0.006), and methylation-based (HR = 0.09; 95% CI, 0.01-0.85; P = 0.010). Early ctDNA clearance at the first radiographic assessment was also associated with prolonged PFS (median PFS not reached vs. 4.8 months; P = 0.002) and enhanced disease control (71.4% vs. 0%). Moreover, three distinct ctDNA dynamic profiles-clearance-rebound, reduction-rebound, and sustained clearance-were associated with different progression patterns (systemic progression, new extrathoracic lesions, new intracranial/intrathoracic lesions). No evidence of histologic transformation was identified at the time of progression. KRAS G12R and other non-canonical alterations emerged in ctDNA-rebound samples. Molecular progression preceded radiographic progression by a mean interval of 2.2 months. These findings suggest that ctDNA-based surveillance using multiple metrics, enables early forecasting of tumor response and progression in RET fusion-positive NSCLC. Early ctDNA clearance and dynamic profiles provide non-invasive biomarkers for early intervention, warranting further validation with ctDNA-guided strategies.