Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma

Blood Cancer Journal, Journal Year: 2024, Volume and Issue: 14(1)

Published: May 27, 2024

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), there is limited data regarding impact tocilizumab (TCZ) corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate prognostic these immunosuppressants recipients BCMA- or GPRC5D-directed CAR T cells relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial investigational autologous products at a single institution from March 2017-March 2023. primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete (CRR), (OS). In total, 101 (91% anti-BCMA 9% anti-GPRC5D cells) were analyzed. Within 30 days post-infusion, 34% received CCS 49% TCZ CRS/ICANS management. At median follow-up 27.4 months, no significant difference PFS observed between non-CCS groups (log-rank p = 0.35) non-TCZ 0.69). ORR, CRR, OS also comparable evaluated groups. our multivariable model, administering with/without did not independently influence (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among MM, timely appropriate use mitigating immune-mediated toxicities does appear antitumor activity long-term outcomes therapy.

Language: Английский

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Soluble B‐cell maturation antigen in multiple myeloma

American Journal of Hematology, Journal Year: 2024, Volume and Issue: 99(4), P. 727 - 738

Published: Jan. 25, 2024

B-cell maturation antigen (BCMA) has emerged as a promising immunotherapeutic target in multiple myeloma (MM) management, with the successive approval of antibody-drug conjugates, bispecific antibodies, and chimeric receptor T-cell therapies directed to this membrane receptor. Soluble BCMA (sBCMA), truncated version produced through gamma-secretase cleavage, can be quantified serum/plasma samples from patients MM via electrochemiluminescence, fluorescence, or enzyme-linked immunosorbent assays, well mass spectrometry-based proteomics. Besides its short serum half-life independence kidney function, sBCMA represents reliable convenient tool for monitoring nonsecretory oligosecretory disease. Numerous studies have suggested potential utility bioanalyte risk stratification premalignant plasma cell disorders, diagnosis prognostication MM, response evaluation following anti-myeloma therapies. In short, might "Swiss army knife" laboratory testing, but is it ready prime time?

Language: Английский

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Ectopic expression of NKG7 enhances CAR-T function and improves the therapeutic efficacy in liquid and solid tumors

Pharmacological Research, Journal Year: 2024, Volume and Issue: unknown, P. 107506 - 107506

Published: Nov. 1, 2024

Language: Английский

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Dual CARM1- and IKZF3-targeting: a novel approach to multiple myeloma therapy Synergy between CARM1 inhibition and IMiDs

Deleted Journal, Journal Year: 2025, Volume and Issue: 33(1), P. 200952 - 200952

Published: Feb. 20, 2025

Advancements in the treatment of multiple myeloma (MM) have resulted an improvement survival rate. However, there continues to be urgent need for improved therapies. The protein arginine methyltransferase, CARM1 (coactivator associated methyltransferase 1), is emerging as a potential cancer therapy target and inhibitors been developed. MM cell lines are particularly dependent on survival. Here, we show that targeting through small molecule inhibition potentiates activity immunomodulatory drugs (IMiDs) line models MM. This likely occurs synergistic Aiolos (IKZF3) MYC expression. Rational design new molecule, 074, which consists inhibitor linked IMiD pomalidomide, was carried out with this agent led more potent killing cells than either or single agents. Importantly, 074 able override resistance. Taken together, our results demonstrate dual CARM1/IKZF3-targeting agents represent promising novel therapeutic strategy IMiD-resistant disease.

Language: Английский

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Applications and prospects of molecularly targeted drugs combined with CAR-T cell therapy to treat multiple myeloma

Best Practice & Research Clinical Haematology, Journal Year: 2025, Volume and Issue: unknown, P. 101633 - 101633

Published: May 1, 2025

Language: Английский

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GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells

Oncotarget, Journal Year: 2024, Volume and Issue: 15(1), P. 159 - 174

Published: March 5, 2024

GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) recommended 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as single agent at killing multiple myeloma cells than had previously been observed tumor cell types. interacted proteasome inhibitors greater additive fashion to kill alone it killed inhibitor-resistant similar extent. The drug combination bortezomib activated ATM, the AMPK PERK inactivated ULK1, mTORC1, eIF2α, NFκB Hippo pathway. increased ATG13 S318 phosphorylation expression Beclin1, ATG5, BAK BIM, reduced levels BCL-XL MCL1. enhance autophagosome formation autophagic flux, knock down AMPKα, Beclin1 or ATG5 significantly both autophagy killing. Knock BIM HDACs1/2/3 beyond that required autophagy. This associated acetylation methylation histone H3. Combined caused activation ATM inactivation HDAC also enhanced phosphorylation, those BCL-XL. Collectively, our present studies support performing additional

Language: Английский

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Case report: Dual-targeted BCMA and CS1 CAR-T-cell immunotherapy in recurrent and refractory extramedullary multiple myeloma

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 30, 2024

The development of CAR-T-cell immunotherapy has notably elevated the efficacy treating multiple myeloma. Currently, a variety targets, including BCMA, CS1, CD38, FcRH5, and GPRC5D, are being investigated. Despite these significant advancements, challenges such as antigen escape, limited persistence CAR-T cells, intricate nature tumor microenvironment persist, leading to relapses following treatment.

Language: Английский

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Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 3, 2024

Background On April 18, 2024, the U.S. Food and Drug Administration officially required updating of “boxed warning” for T cell malignancies all chimeric antigen receptor (CAR-T) therapies. Given clinical significance these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world studies have been lacking newly marketed CAR-T products idecabtagene vicleucel (ide-cel) ciltacabtagene autoleucel (cilta-cel), which target B maturation antigen, especially regarding risk secondary malignancies. Therefore, we aimed to thoroughly analyze adverse events (AEs) information in FDA Adverse Event Reporting System (FAERS) database comprehensively understand risks ide-cel cilta-cel. Methods We extracted AE reports related cilta-cel from FAERS ( https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html .) January 1, 2019 December 31, 2023. Disproportionality analysis Bayesian were used identify signals across subgroups specific cases (including death malignancies). Weibull distribution was employed determine time onset. Results A total 695 848 included database. This identified 81 positive 74 Notably, comparisons with drug labels revealed “unexpected signals,” including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12–122.03) plasma myeloma (12.45; 8.18–18.95) ide-cel, increased serum ferritin (24.98; 8.0–77.58) large intestine perforation (18.57; 5.98–57.69) Both drugs showed higher incidence among male recipients patients aged ≥65 years, although female faced greater risk. Most AEs occurred at early stage administration. detected both drugs, primarily occurring one-year post-administration. Conclusion study provides foundation understanding profile therapy, particularly relation emergence Such insights are helpful decision-making safe effective utilization therapeutic agents.

Language: Английский

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Advances in adoptive cellular immunotherapy and therapeutic breakthroughs in multiple myeloma

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Oct. 28, 2024

Abstract The basic idea of modulating the immune system to better recognize and fight tumor cells has led successful introduction adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which patient's own are isolated subsequently expanded (ex vivo) reinfused, have also contributed significantly development a personalized strategy. Complementing this, unprecedented advances ACTs as chimeric antigen receptor (CAR)-T cell therapies their derivatives such CAR-NK, CAR-macrophages, CAR-γδT CAR-NKT further maximized therapeutic outcomes. Herein, we provide comprehensive overview multiple myeloma (MM) outline how they evolved from an experimental form mainstay standard clinical settings. Besides, insights into cytokine-induced killer (CIK) therapy, alternative ACT that (as CIK or CAR-CIK) enormous potential spectrum MM. We summarize results major preclinical studies therapy MM address current challenges (such cytokine release syndrome (CRS) neurotoxicity) limit its complete success cancer landscape.

Language: Английский

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The effects of anti-lung cancer in nude mice by a fully human single-chain antibody against associated antigen Ts7TMR between A549 cells and Trichinella spiralis

Artificial Cells Nanomedicine and Biotechnology, Journal Year: 2024, Volume and Issue: 52(1), P. 300 - 308

Published: May 16, 2024

Lung cancer is a dangerous disease that lacking in an ideal therapy. Here, we evaluated the anti-lung effect nude mice of fully human single-chain antibody (scFv) against associated antigen 7 transmembrane receptor (Ts7TMR), which also called G protein-coupled receptor, between A549 cells and Trichinella spiralis (T. spiralis). Our data showed anti-Ts7TMR scFv could inhibit lung growth dose-dependent manner, with tumour inhibition rate 59.1%. HE staining did not reveal any obvious tissue damage. Mechanistically, immunohistochemical revealed down-regulated expression PCNA VEGF tissues. Overall, this study found by suppressing cell proliferation angiogenesis, may provide new strategy for treating cancer.

Language: Английский

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