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Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma.Signal Transduction and Targeted Therapy Jan 2024Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T...
Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Interleukin-15; Cell Line, Tumor; T-Lymphocytes; Receptors, Fc
PubMed: 38212320
DOI: 10.1038/s41392-023-01702-2 -
Life Science Alliance Sep 2023Among glucocorticoids (GCs), dexamethasone (Dex) is widely used in treatment of multiple myelomas. However, despite a definite benefit, all patients relapse. Moreover,...
Among glucocorticoids (GCs), dexamethasone (Dex) is widely used in treatment of multiple myelomas. However, despite a definite benefit, all patients relapse. Moreover, the molecular basis of glucocorticoid efficacy remains elusive. To determine genomic response to Dex in myeloma cells, we generated bulk and single-cell multi-omics data and high-resolution contact maps of active enhancers and target genes. We show that a minority of glucocorticoid receptor-binding sites are associated with enhancer activity gains, increased interaction loops, and transcriptional activity. We identified and characterized a predominant enhancer enriched in cohesin (RAD21) and more accessible upon Dex exposure. Analysis of four gene-specific networks revealed the importance of the CTCF-cohesin couple and the synchronization of regulatory sequence openings for efficient transcription in response to Dex. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity, in particular, lineage-specific genes. As consequences, -encoding BIM critical for Dex-induced apoptosis and protective from chemotherapy-induced apoptosis are rather up-regulated in different cells. In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.
Topics: Humans; Dexamethasone; Multiple Myeloma; Neoplasm Recurrence, Local; Glucocorticoids; Apoptosis; Receptors, Glucocorticoid
PubMed: 37524526
DOI: 10.26508/lsa.202302195 -
Pathology Oncology Research : POR 2023Multiple myeloma (MM) is a hematologic disorder characterized by the accumulation of malignant plasma cells in the bone marrow. Genetic and environmental factors are... (Review)
Review
Multiple myeloma (MM) is a hematologic disorder characterized by the accumulation of malignant plasma cells in the bone marrow. Genetic and environmental factors are contributed to the etiology of MM. Notably, studies have shown that obesity increases the risk of MM and worsens outcomes for MM patients. Adipokines play an important role in mediating the close association between MM and metabolic derangements. In this review, we summarize the epidemiologic studies to show that the risk of MM is increased in obese. Accumulating clinical evidence suggests that adipokines could display a correlation with MM. and studies have shown that adipokines are linked to MM, including roles in the biological behavior of MM cells, cancer-associated bone loss, the progression of MM, and drug resistance. Current and potential therapeutic strategies targeted to adipokines are discussed, proposing that adipokines can guide early patient diagnosis and treatment.
Topics: Humans; Multiple Myeloma; Adipokines; Risk Factors; Obesity
PubMed: 37637774
DOI: 10.3389/pore.2023.1611338 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2023Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor... (Review)
Review
Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.
Topics: Humans; Multiple Myeloma; Agammaglobulinemia; Immunologic Deficiency Syndromes; Immunization, Passive; Antibodies
PubMed: 37353432
DOI: 10.1016/j.clml.2023.05.008 -
Clinical and Translational Science Jan 2024Multiple myeloma (MM) remains incurable despite improvements in treatment options. B-cell maturation antigen (BCMA) is predominantly expressed in B-lineage cells and... (Review)
Review
Multiple myeloma (MM) remains incurable despite improvements in treatment options. B-cell maturation antigen (BCMA) is predominantly expressed in B-lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLI ) is the first T-cell redirecting bispecific antibody approved for patients with MM. Targeting both CD3 receptor complex on T cells and BCMA on myeloma cells, teclistamab leads to T-cell activation and subsequent lysis of BCMA+ cells. The recommended dose of teclistamab is 1.5 mg/kg subcutaneous weekly after two step-up doses of 0.06 and 0.3 mg/kg, which was selected after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Exposure-response analyses of efficacy and safety data were also used to confirm the teclistamab dose. Teclistamab resulted in a high rate of deep and durable responses (63% overall response, 45.5% complete response or better, with 22 months median duration of response) in patients with triple-exposed relapsed/refractory MM. Common adverse reactions included cytokine release syndrome, hematologic abnormalities, and infections. Teclistamab is currently being investigated as monotherapy as well as combination therapy across different MM indications.
Topics: Humans; Translational Science, Biomedical; B-Cell Maturation Antigen; Multiple Myeloma; Antibodies, Bispecific; Antineoplastic Agents; CD3 Complex
PubMed: 38266057
DOI: 10.1111/cts.13717 -
Haematologica Dec 2023Multiple Myeloma (MM) is a plasma cell neoplasm originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in...
Multiple Myeloma (MM) is a plasma cell neoplasm originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of MM and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% penetrance that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the IL6Myc tumors resemble aggressive MM by RNA and protein expression. We also found that IL6Myc tumors accumulated fusions and missense mutations in genes that overlap significantly with human myeloma, indicating that the mouse is good model for studying disease etiology. Lastly, we derived cell lines from IL6Myc tumors that express cell surface markers typical of MM and readily engraft into mice, home to the bone marrow, and induce osteolytic disease. The cell lines may be useful in developing immunotherapies directed against BAFF-R and TACI, though not BCMA, and may also be a good model for studying dexamethasone resistance. These data indicate that the IL6Myc model is useful for studying development of aggressive MM and for developing new treatments against such forms of the disease.
Topics: Mice; Humans; Animals; Multiple Myeloma; Bone Marrow
PubMed: 37439384
DOI: 10.3324/haematol.2022.282538 -
Blood Mar 2024A major hurdle in adoptive T-cell therapy is cell exhaustion and failure to maintain antitumor responses. Here, we introduce an induced pluripotent stem cell (iPSC)...
A major hurdle in adoptive T-cell therapy is cell exhaustion and failure to maintain antitumor responses. Here, we introduce an induced pluripotent stem cell (iPSC) strategy for reprogramming and revitalizing precursor exhausted B-cell maturation antigen (BCMA)-specific T cells to effectively target multiple myeloma (MM). Heteroclitic BCMA72-80 (YLMFLLRKI)-specific CD8+ memory cytotoxic T lymphocytes (CTL) were epigenetically reprogrammed to a pluripotent state, developed into hematopoietic progenitor cells (CD34+ CD43+/CD14- CD235a-), differentiated into the T-cell lineage and evaluated for their polyfunctional activities against MM. The final T-cell products demonstrated (1) mature CD8αβ+ memory phenotype, (2) high expression of activation or costimulatory molecules (CD38, CD28, and 41BB), (3) no expression of immune checkpoint and senescence markers (CTLA4, PD1, LAG3, and TIM3; CD57), and (4) robust proliferation and polyfunctional immune responses to MM. The BCMA-specific iPSC-T cells possessed a single T-cell receptor clonotype with cognate BCMA peptide recognition and specificity for targeting MM. RNA sequencing analyses revealed distinct genome-wide shifts and a distinctive transcriptional profile in selected iPSC clones, which can develop CD8αβ+ memory T cells. This includes a repertoire of gene regulators promoting T-cell lineage development, memory CTL activation, and immune response regulation (LCK, IL7R, 4-1BB, TRAIL, GZMB, FOXF1, and ITGA1). This study highlights the potential application of iPSC technology to an adaptive T-cell therapy protocol and identifies specific transcriptional patterns that could serve as a biomarker for selection of suitable iPSC clones for the successful development of antigen-specific CD8αβ+ memory T cells to improve the outcome in patients with MM.
Topics: Humans; Multiple Myeloma; Induced Pluripotent Stem Cells; B-Cell Maturation Antigen; T-Lymphocytes, Cytotoxic; Antineoplastic Agents; CD8 Antigens
PubMed: 37890146
DOI: 10.1182/blood.2023020528 -
Biomedicine & Pharmacotherapy =... Dec 2023Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) has been approved for treating multiple myeloma (MM). Some clinical studies...
Enhanced antitumor efficacy, proliferative capacity, and alleviation of T cell exhaustion by fifth-generation chimeric antigen receptor T cells targeting B cell maturation antigen in multiple myeloma.
Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) has been approved for treating multiple myeloma (MM). Some clinical studies reported suboptimal outcomes, including reduced cytotoxicity of CAR-T cells and tumor evasion through increased expression of programmed death-ligand 1 (PD-L1). To enhance CAR-T cell efficiency and overcome PD-L1-mediated T cell suppression, we developed anti-BCMA-CAR5-T cells equipped with three costimulatory domains and the ability to secrete anti-PD-L1 single-chain variable fragment (scFv) blockade molecules. Anti-BCMA-CAR4-T cells contained a fully human anti-BCMA scFv and three intracellular domains (CD28, 4-1BB, and CD27) joined with CD3ζ. Anti-BCMA-CAR5-T cells were generated by fusing anti-BCMA-CAR4 with anti-PD-L1 scFv. Both anti-BCMA-CAR4-T and anti-BCMA-CAR5-T cells demonstrated comparable antitumor activity against parental MM cells. However, at an effector-to-target ratio of 1:2, only anti-BCMA-CAR5-T cells maintained cytolytic activity against PD-L1 high MM cells, unlike anti-BCMA-CAR4 T cells. Anti-BCMA-CAR5-T cells were specifically activated by BCMA-expressing target cells, resulting in increased CAR-T cell proliferation, release of cytolytic mediators, and pro-inflammatory cytokines. Anti-BCMA-CAR5-T cells demonstrated specific cytotoxicity against BCMA-expressing target cells, leading to decreased target cell numbers, increased CAR-T cell numbers, and preserved CAR expression during antigenic re-stimulation. Interestingly, only anti-BCMA-CAR5-T cells showed reduced PD-1 receptor levels, which correlated with decreased PD-L1 expression on target cells. We successfully generated anti-BCMA-CAR5-T cells capable of secreting anti-PD-L1 scFv. These cells exhibited superior antitumor efficiency, proliferative capacity, and alleviated T-cell exhaustion against MM cells. Further investigation into the antitumor efficacy of anti-BCMA-CAR5-T cells is warranted in ex vivo and clinical research settings.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; B7-H1 Antigen; T-Cell Exhaustion; Cell Line, Tumor; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 37844355
DOI: 10.1016/j.biopha.2023.115691 -
Blood Cancer Discovery Sep 2023The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics...
UNLABELLED
The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus
plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality. SIGNIFICANCE
This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337.
Topics: Humans; Receptors, Chimeric Antigen; Prognosis; Multiple Myeloma; Immunotherapy, Adoptive; Neoplasm, Residual; Neoplasms, Plasma Cell
PubMed: 37486974
DOI: 10.1158/2643-3230.BCD-23-0044 -
JAMA Network Open Nov 2023Cancer treatment can result in burdensome toxic effects that profoundly affect patient quality of life. In seeking to emphasize the efficacy of tested treatments,...
IMPORTANCE
Cancer treatment can result in burdensome toxic effects that profoundly affect patient quality of life. In seeking to emphasize the efficacy of tested treatments, clinical trial reports may use subjective or minimizing terms to describe adverse events (AEs).
OBJECTIVE
To evaluate patterns of AE reporting in multiple myeloma (MM) randomized clinical trials (RCTs) published between 2015 and early 2023.
DESIGN, SETTING, AND PARTICIPANTS
For this cohort study, the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched to assess the prevalence of minimizing terms in MM RCTs published between January 1, 2015, and March 1, 2023. Minimizing terms were defined as subjective terms used to favorably describe the safety profile of the intervention. The terms searched included convenient, manageable, acceptable, expected, well-tolerated, tolerable, favorable, and safe. Final data analysis was performed on July 21, 2023.
MAIN OUTCOMES AND MEASURES
The primary outcome was the occurrence of at least 1 minimizing term in an article. Univariate logistic regression analyses were performed to evaluate the association between the presence of at least 1 minimizing term and the actual incidence of grade 3 or 4 AEs, serious AEs, or grade 5 AEs.
RESULTS
Of the 65 RCTs included, 56 (86%) used minimizing terms when describing treatment-emergent AEs. The most frequently used minimizing terms were well-tolerated or tolerable in 29 trials (45%), manageable in 18 (28%), and acceptable in 16 (25%). Grade 3 or 4 AE rate in the examined RCTs ranged from 23% to 94%, with a median of 75% (IQR, 59%-82%). A univariate regression analysis demonstrated no association between the use of minimizing terms and grade 3 or 4 AE rates (odds ratio [OR], 1.35 [95% CI, 0.88-2.10] per 10% AE rate increase; P = .17) or grade 5 AE rates (OR, 3.16 [95% CI, 0.27-12.7] per 10% AE rate increase; P = .45).
CONCLUSIONS AND RELEVANCE
These findings suggest that trial investigators and sponsors regularly use minimizing terms to describe toxic effects in MM trials, and use of this terminology may not reflect actual AE rates in these studies. Instead of using these terms, trial investigators should highlight event rates and patient-reported outcomes, to allow clinicians and patients to better evaluate the true tolerability of AEs.
Topics: Humans; Multiple Myeloma; Randomized Controlled Trials as Topic; Cohort Studies
PubMed: 37948080
DOI: 10.1001/jamanetworkopen.2023.42195