Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory–like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC. 

CAR memory–like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer

<ns3:p><ns3:bold>Background:</ns3:bold> Invasive ductal carcinoma (IDC) is the most common type of breast cancer (BC) worldwide. Nowadays, due to its heterogeneity and high capacity for metastasis, it is necessary to discover novel diagnostic and prognostic biomarkers. Therefore, this study aimed to identify novel candidate prognostic genes for IDC using an integrated bioinformatics approach. <ns3:bold>Methods:</ns3:bold> Three expression profile data sets were obtained from GEO (GSE29044, GSE3229, and GSE21422), from which differentially expressed genes (DEGs) were extracted for comparative transcriptome analysis of experimental groups (IDC versus control). Next, STRING was utilized to construct a protein interaction network with the shared DEGs, and MCODE and cytoHubba were used to identify the hub genes, which were then characterized using functional enrichment analysis in DAVID and KEGG. Finally, using the Kaplan-Meier tracer database, we determined the correlation between the expression of hub genes and overall survival in BC. <ns3:bold>Results:</ns3:bold> We identified seven hub genes (Kinesin-like protein KIF23 [KIF23], abnormal spindle-like microcephaly [ASPM]-associated protein [ASPMAP], Aurora kinase A [AURKA], Rac GTPase-activating protein 1 [RACGAP1], centromere protein F [CENPF], hyaluronan-mediated motility receptor [HMMR], and protein regulator of cytokinesis 1 [PRC1]), which were abundant in microtubule binding and tubulin binding, pathways linked to fundamental cellular structures including the mitotic spindle, spindle, microtubule, and spindle pole. The role of these genes in the pathophysiology of IDC is not yet well characterized; however, they have been associated with other common types of BC, modulating pathways such as Wnt/β-catenin, the epithelial-to-mesenchymal transition (EMT) process, chromosomal instability (CIN), PI3K/AKT/mTOR, and BRCA1 and BRCA2, playing an important role in its progression and being associated with a poor prognosis, thus representing a way to improve our understanding of the process of tumorigenesis and the underlying molecular events of IDC. <ns3:bold>Conclusions</ns3:bold>: Genes identified may lead to the discovery of new prognostic targets for IDC.</ns3:p> 

pdf/identification-of-prognostic-biomarkers-of-invasive-ductal-2yvyk2cj51.pdf

Identification of prognostic biomarkers of invasive ductal carcinoma by an integrated bioinformatics approach

CD38 and B-cell maturation antigens (BCMAs) are prevalently expressed on neoplastic plasma cells in multiple myeloma (MM), making them ideal therapeutic targets. Anti-CD38 monoclonal antibodies, such as approved daratumumab and isatuximab, are currently the milestone in MM treatment because they induce plasma cell apoptosis and kill through several mechanisms, including antibody-dependent cellular cytotoxicity or phagocytosis. BCMA is considered an excellent target in MM, and three different therapeutic strategies are either already available in clinical practice or under investigation: antibody–drug conjugates, such as belantamab-mafodotin; bispecific T cell engagers; and chimeric antigen receptor-modified T cell therapies. Despite the impressive clinical efficacy of these new strategies in the treatment of newly diagnosed or multi-refractory MM patients, several mechanisms of resistance have already been described, including antigen downregulation, the impairment of antibody-dependent cell cytotoxicity and phagocytosis, T- and natural killer cell senescence, and exhaustion. In this review, we summarize the current knowledge on the mechanisms of action and resistance of anti-CD38 and anti-BCMA agents and their clinical efficacy and safety.

/pdf/innovative-anti-cd38-and-anti-bcma-targeted-therapies-in-3077kxs0.pdf

Innovative Anti-CD38 and Anti-BCMA Targeted Therapies in Multiple Myeloma: Mechanisms of Action and Resistance

ABSTRACT Introduction CAR-T therapies for relapsed or refractory (r/r) T-cell lymphoblastic leukemia/lymphoma (T-LL/L) faces challenges, with most clinical studies conducted in small, dispersed cohorts and often reviewed alongside preclinical studies. This review focuses exclusively on clinical studies, evaluating CAR constructs, safety and efficacy. Methods A systematic review was conducted of databases, clinical trial registries, and abstracts from conferences (June 2014 to June 2024). Preclinical studies and studies lacking clinical details were excluded. Data on patient demographics, CAR-T characteristics, response rates, survival, and adverse events were analyzed. Results Eleven CAR-T constructs targeting CD7 and two targeting CD5 were identified. Complete remission (CR/CRi) rates ranged from 55% to 100%, exceeding 80% in most studies. Relapse, often in extramedullary sites, ranged from 7% to 66%. Cytokine release syndrome and neurotoxicity were generally manageable. GVHD incidence varied (none to 60%), primarily in allogeneic CAR-T recipients. Infections contributed to 6–38% of treatment-related mortality. Conclusions CAR-T therapy achieves high response rates in r/r T-LL/L and may serve as a bridge to allogeneic transplantation. However, the short follow-up and the duration of responses remain concerns, and challenges endure, including GVHD, immune recovery and infection control. Standardized reporting is crucial to optimize therapy outcomes and safety in future trials. Registration PROSPERO (CRD420251024662).

CAR-T cell therapy in T-Cell lymphoblastic leukemia/lymphoma: where do we stand now?

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 109/L (Rho = 0.639, p &lt; 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients. 

Use of Eltrombopag to Improve Thrombocytopenia and Tranfusion Requirement in Anti-CD19 CAR-T Cell-Treated Patients

ASPM overexpression enhances cellular proliferation and migration and predicts worse prognosis for papillary renal cell carcinoma

S187: updated phase 1/2 data of safety and efficacy of ct103a, fully human bcma-directed car t cells, in relapsed/refractory multiple myeloma

Background: Background: CD19 Chimeric Antigen Receptor T cell(CAR-T)therapy has been successfully used to treat refractory/relapse B-cell lymphoma (r/r B-NHL). However,the risk was significantly increased due to gastrointestinal bleeding of CAR-T cell therapy for gastrointestinal (GI) lymphoma. Aims: Aims: To explored the risk factors of GI bleeding and the efficacy of CAR-T cell therapy for GI lymphoma . Methods: Methods: From May 2019 to December 2021,26 patients with r/r B-NHL involvement of the GI tract were enrolled. The male/female ratio was 1.8:1, with a median age of 40.5 years (range, 19-69 years).The diagnosis included diffuse large B-cell lymphoma (DLBCL) (n=21) and Burkitt lymphoma (n=5). All patients were in advanced stage (stage III-IV), and received a median of 7 lines of prior treatment.The disease status was progressive disease (PD)in all patients who failed to multi-line therapies.The median International Prognostic Index (IPI) was 3 (range, 1-4).Most patients (16/26,61.5%) received bridging therapy before CAR T cell infusion.The most common site of involvement was the colonic(10/26,38.5%), followed by small

https://doi.org/10.1097/01.hs9.0000847688.01787.13

P1206: gastrointestinal bleeding significantly reduced the efficacy and survival of cd19 car-t cell therapy in patients with gastrointestinal tract involvement of refractory/relapsed b-cell lymphoma

Background: Background: The prognosis of refractory/relapsed T-cell lymphoma is extremely poor, especially for the patients who failed to allogeneic hematopoietic stem cell transplantation(allo-HSCT). Aims: Aims: For r/r T-cell lymphoma, a clinical trial using CD7 chimeric antigen receptor T-cell(CD7 CAR-T) has been registered, and the safety and efficacy will be evaluated. Methods: Methods: From August 2017 to January 2022, 10 patients were enrolled. The median age was 32(19-72) years old. The diagnosis included T cell lymphoblastic lymphoma(T-LBL,n=8) ,hepatosplenic T-cell lymphoma(HSTL,n=1)and monomorphic epitheliotropic intestinal T-cell lymphoma(MEITL,n=1). The disease status was progressive disease (PD)in all patients who failed to multi-line therapies, including allo-HSCT (7/10,70%), local irradiation (2/10,20%) .Three patients(3/10, 30%)had central nervous system involvement.In order to further reduce the tumor burden, all patients were treated with bridging therapy before CAR-T cell infusion. Before the trial, the expression of CD7 antigen in tumor tissue was positive confirmed by pathology. Patients received FC regimen (fludarabine and cyclophosphamide) before CAR-T cells infusion. The kinetics and function of CAR-T cells was monitored by quantitative PCR and flow cytometry. The efficacy was evaluated by PET-CT as well as bone marrow puncture every 3 month after CAR-T infusion.

P1236: efficacy and toxicity for cd7 chimeric antigen receptor t-cell therapy in patients with relapsed/refractory t-cell lymphoma

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Papers

ASPM overexpression enhances cellular proliferation and migration and predicts worse prognosis for papillary renal cell carcinoma

S187: updated phase 1/2 data of safety and efficacy of ct103a, fully human bcma-directed car t cells, in relapsed/refractory multiple myeloma

P1206: gastrointestinal bleeding significantly reduced the efficacy and survival of cd19 car-t cell therapy in patients with gastrointestinal tract involvement of refractory/relapsed b-cell lymphoma

P1236: efficacy and toxicity for cd7 chimeric antigen receptor t-cell therapy in patients with relapsed/refractory t-cell lymphoma