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Although multiple myeloma (MM) responds well to immunotherapeutic treatment, certain portions of MM are still unresponsive or relapse after immunotherapy. Other immune molecules are needed for the immunotherapy of MM. Here, we revealed that leukocyte immunoglobulin-like receptor B4 (LILRB4) was highly expressed in multiple myeloma cell lines and patient samples and that the expression of LILRB4 was adversely correlated with the overall survival of MM patients. Knockdown of LILRB4 efficiently delayed the growth of MM cells both in vitro and in vivo. Mechanistically, IKZF1 transactivated LILRB4 expression to trigger the downstream of STAT3-PFKFB1 pathways to support MM cell proliferation. Blockade of LILRB4 signaling by blocking antibodies can effectively inhibit MM progression. Our data show that targeting LILRB4 is potentially an additional therapeutic strategy for the immunotherapeutic treatment of MM.
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Mieloma Múltiple , Receptores Inmunológicos , Factor de Transcripción STAT3 , Transducción de Señal , Mieloma Múltiple/patología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/genética , Humanos , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Ratones , Proliferación Celular , Factor de Transcripción Ikaros/metabolismo , Factor de Transcripción Ikaros/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Femenino , Regulación Neoplásica de la Expresión Génica , MasculinoRESUMEN
Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.
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Linfocitos T CD8-positivos , Movimiento Celular , Ratones Endogámicos C57BL , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Humanos , Receptores CXCR3/metabolismo , Cadenas beta de Integrinas/metabolismo , Médula Ósea/inmunología , Médula Ósea/patología , Médula Ósea/metabolismo , Intestinos/inmunología , Intestinos/patología , Ratones , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Línea Celular Tumoral , Ratones NoqueadosRESUMEN
This registration study assessed clinical outcomes of TQ-B3525, the dual phosphatidylinositol-3-kinase (PI3K) α/δ inhibitor, in relapsed and/or refractory follicular lymphoma (R/R FL). This phase II study (ClinicalTrials.gov NCT04324879. Registered March 27, 2020) comprised run-in stage and stage 2. R/R FL patients after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Based on results (ORR, 88.0%; duration of response [DOR], 11.8 months; progression-free survival [PFS], 12.0 months) in 25 patients at run-in stage, second stage study was initiated and included 82 patients for efficacy/safety analysis. Patients received prior-line (median, 3) therapies, with 56.1% refractory to previous last therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3-93.1%), with 28 (34.2%) complete responses. Disease control rate was 95.1% due to 7 (8.5%) stable diseases. Median time to response was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. with median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months. Median overall survival (OS) was not reached by cutoff date; 24-month OS rate was estimated as 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events were observed in 63 (76.8%) cases, with neutropenia (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. TQ-B3525 showed favorable efficacy and safety for R/R FL patients after ≥2 lines prior therapies.
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Linfoma Folicular , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/genética , Supervivencia sin Progresión , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéuticoRESUMEN
BACKGROUND: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. METHODS: In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. RESULTS: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. CONCLUSIONS: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.
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Anticuerpos Monoclonales Humanizados , Antígenos CD19 , Síndrome de Liberación de Citoquinas , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Femenino , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Adulto , Antígenos CD19/inmunología , Estudios Retrospectivos , Persona de Mediana Edad , Adolescente , Adulto Joven , Síndrome de Liberación de Citoquinas/etiología , Receptores Quiméricos de Antígenos/inmunología , Niño , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológicoRESUMEN
The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.
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Proteínas de la Ataxia Telangiectasia Mutada , Daño del ADN , N-Metiltransferasa de Histona-Lisina , Leucemia Mieloide Aguda , Proteína de la Leucemia Mieloide-Linfoide , Transducción de Señal , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Daño del ADN/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Transducción de Señal/genética , Animales , Ratones , Línea Celular Tumoral , Metiltransferasas/metabolismo , Metiltransferasas/genética , Proteína de Unión a CREB/metabolismo , Proteína de Unión a CREB/genética , Reordenamiento Génico , Histonas/metabolismo , Histonas/genética , Fosforilación , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , AcetilaciónRESUMEN
INTRODUCTION: Chimeric antigen receptor (CAR) T cell therapy has markedly improved the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). The relative positioning of tumor lesions in lymphoma varies among patients, manifesting as either aggregation (clumped together) or dissemination (spread throughout the body). Prognostic significance of factors indicating the relative positioning of tumor lesions in CAR T cell therapy remains underexplored. For aggregation, prior research proposed the tumor volume surface ratio (TVSR), linking it to prognosis in chemotherapy. Regarding dissemination, indicators such as disease stage or extranodal involvement, commonly used in clinical practice, have not demonstrated prognostic significance in CAR T cell therapy. This study aims to analyze current indicators of tumor aggregation or dissemination and introduce a novel indicator to assess the prognostic value of tumor lesions' relative positioning in DLBCL patients undergoing CAR T cell therapy. METHODS: This retrospective study included 42 patients receiving CAR T cell therapy. Lesion image information was obtained from the last PET/CT scan prior to CAR T cell infusion, including total metabolic tumor volume, total tumor surface, diameter of lymphoma masses, and the sites of tumor lesions. We evaluated TVSR and bulky disease as descriptors of tumor aggregation. We refined existing indicators, stage III&IV and >1 site extranodal involvement, to distill a new indicator, termed 'extra stage', to better represent tumor dissemination. The study examined the prognostic significance of tumor aggregation and dissemination. RESULTS: Our findings indicate that TVSR, while prognostically valuable in chemotherapy, lacks practical prognostic value in CAR T cell therapy. Conversely, bulky disease emerged as an optimal prognostic indicator of tumor aggregation. Both bulky disease and extra stage were associated with poor prognosis and exhibiting synergistic prognostic impact in CAR T cell therapy. CONCLUSIONS: Overall, the relative positioning of tumor lesions significantly influences the prognosis of patients with DLBCL receiving CAR T cell therapy. The ideal scenario involves tumors with minimal dissemination and no aggregation.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Retrospectivos , Pronóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor ß (TGF-ß)-Smad3 signaling with TGF-ß inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-ß inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.
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The quiescence and activation of adult stem cells are regulated by many kinds of molecular mechanisms, and RNA alternative splicing participates in regulating many cellular processes. However, the relationship between stem cell quiescence and activation regulation and gene alternative splicing has yet to be studied. In this study, we aimed to elucidate the regulation of stem cell quiescence and activation by RNA alternative splicing. The upregulated genes in activated mouse neural stem cells (NSCs), muscle stem cells, and hematopoietic stem cells were collected for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The genes from three tissue stem cells underwent Venn analysis. The mouse NSCs were used for quiescence and reactivation induction. The immunostaining of cell-specific markers was performed to identify cell properties. The reverse transcription-polymerase chain reaction and western blotting were used to detect the gene expression and protein expression, respectively. We found that the upregulated genes in activated stem cells from three tissues were all enriched in RNA splicing-related biological processes; the upregulated RNA splicing-related genes in activated stem cells displayed tissue differences; mouse NSCs were successfully induced into quiescence and reactivation in vitro without losing differentiation potential; serine and arginine-rich splicing factor 3 (Srsf3) was highly expressed in the activated mouse NSCs, and the overexpression of SRSF3 protein promoted the activation of quiescent mouse NSCs and increased the neural cell production. Our data indicate that the alternative splicing change may underline the transition of quiescence and activation of stem cells. The manipulation of the splicing factor may benefit tissue repair by promoting the activation of quiescent stem cells.
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Arginina , Células-Madre Neurales , Animales , Ratones , Células-Madre Neurales/metabolismo , ARN/metabolismo , Factores de Empalme de ARN/metabolismo , SerinaRESUMEN
Chimeric antigen receptor (CAR)-positive cell therapy, specifically with anti-CD19 CAR-T (CAR19-T) cells, achieves a high complete response during tumor treatment for hematological malignancies. Large-scale production and application of CAR-T therapy can be achieved by developing efficient and low-cost enrichment methods for CAR-T cells, expansion monitoring in vivo, and overcoming tumor escape. Here, novel CAR-specific binding aptamers (CAR-ap) to traceless sort CAR-positive cells and obtain a high positive rate of CAR19-T cells is identified. Additionally, CAR-ap-enriched CAR19-T cells exhibit similar antitumor capacity as CAR-ab (anti-CAR antibody)-enriched CAR-T cells. Moreover, CAR-ap accurately monitors the expansion of CAR19-T cells in vivo and predicts the prognosis of CAR-T treatment. Essentially, a novel class of stable CAR-ap-based bispecific circular aptamers (CAR-bc-ap) is constructed by linking CAR-ap with a tumor surface antigen (TSA): protein tyrosine kinase 7 (PTK7) binding aptamer Sgc8. These CAR-bc-aps significantly enhance antitumor cytotoxicity with a loss of target antigens by retargeting CAR-T cells to the tumor in vitro and in vivo. Overall, novel CAR-aptamers are screened for traceless enrichment, monitoring of CAR-positive cells, and overcoming tumor cell immune escape. This provides a low-cost and high-throughput approach for CAR-positive cell-based immunotherapy.
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Receptores Quiméricos de Antígenos , Escape del Tumor , Linfocitos T , Inmunoterapia Adoptiva/métodos , InmunoterapiaRESUMEN
BACKGROUND: Little was known on infection and mortality rates, still less the risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant in B-cell lymphoma patients following CD19 targeted chimeric antigen receptor T cell (CAR-T). AIMS: We performed a retrospective multicenter study and analyzed the details of relapsed/refractory (R/R) B-cell lymphoma patients who received CD19 targeted CAR-T heretofore in five cellular immunotherapy centers in China during the omicron wave. MATERIALS & METHODS: One hundred fifty-four patients were enrolled in this study. RESULTS: Among them, 52 patients (33.8%) were uninfected, 74 patients (48.1) had ambulatory mild disease (including nine patients of asymptomatic infection), 22 patients (14.3%) had moderate disease and six patients (3.9%) had severe disease when data collected up. Three patients with severe disease died from COVID-19, the death rate was 1.9% for all enrolled patients, and 2.9% for infected patients. We also found that patients over 60 years old or with diabetes mellitus (DM) tend to develop severe disease (p = 0.0057 and p = 0.0497, respectively). Patients had CAR-T infusion within 6 months also tend to have severe disease (p = 0.0011). In multivariate logistic regression model, CAR-T infusion within 6 months (relative risk (RR) 40.92; confidence interval (CI) 4.03-415.89; p = 0.002) were associated with significantly higher risk of severe disease. CONCLUSION: Through this study, we conclude that the outcome for B-cell lymphoma patients following CD19 targeted CAR-T therapy when facing omicron infection was improved, but aggressive precautionary measures were particularly crucial for patients with high risk factors.
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COVID-19 , Linfoma de Células B , Receptores Quiméricos de Antígenos , Humanos , Persona de Mediana Edad , SARS-CoV-2 , Linfocitos T , COVID-19/epidemiología , COVID-19/terapia , COVID-19/etiología , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19 , Factores de Riesgo , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%-30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.
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Leucemia Mieloide Aguda , Proteína p53 Supresora de Tumor , Animales , Ratones , Humanos , Proteína p53 Supresora de Tumor/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutación , Pronóstico , Resultado del Tratamiento , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/uso terapéuticoRESUMEN
CD19 CAR-T (chimeric antigen receptor-T) cell immunotherapy achieves a remission rate of approximately 70% in recurrent and refractory lymphoma treatment. However, the loss or reduction of CD19 antigen on the surface of lymphoma cells results in the escape of tumor cells from the immune killing of CD19 CAR-T cells (CAR19-T). Therefore, novel therapeutic strategies are urgently required. In this study, an anti-CD79b/CD3 bispecific antibody (BV28-OKT3) was constructed and combined with CAR19-T cells for B-cell lymphoma treatment. When the CD19 antigen was lost or reduced, BV28-OKT3 redirected CAR19-T cells to CD79b+ CD19- lymphoma cells; therefore, BV28-OKT3 overcomes the escape of CD79b+ CD19- lymphoma cells by the killing action of CAR19-T cells in vitro and in vivo. Furthermore, BV28-OKT3 triggered the antitumor function of CAR- T cells in the infusion product and boosted the antitumor immune response of bystander T cells, markedly improving the cytotoxicity of CAR19-T cells to lymphoma cells in vitro and in vivo. In addition, BV28-OKT3 elicited the cytotoxicity of donor-derived T cells toward lymphoma cells in vitro, which depended on the presence of tumor cells. Therefore, our findings provide a new clinical treatment strategy for recurrent and refractory B-cell lymphoma by combining CD79b/CD3 BsAb with CAR19-T cells.
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Anticuerpos Biespecíficos , Linfoma de Células B , Linfoma , Humanos , Linfocitos T , Antígenos CD19 , Muromonab-CD3 , Linfoma/tratamiento farmacológico , Inmunoterapia Adoptiva/métodosRESUMEN
BACKGROUND: The hypomethylating agent decitabine is the standard therapy for intermediate or high risk myelodysplastic syndrome (MDS). METHODS: In this trial, 191 adult patients with intermediate/high risk MDS (IPSS score ≥ 0.5) randomly received decitabine using a standard regimen (20 mg/m2 /day for 5 consecutive days; n = 94) or an extended regimen with lower daily dose (12 mg/m2 /day for 8 consecutive days; n = 97) every 4 weeks, for a total of 4 cycles. RESULTS: The median follow-up was 14 months (range 2-36). The primary end point of overall response rate in the intent-to-treat analysis was 41.5% and 38.1% in the standard and extended dosing arms, respectively (p = 0.660). Complete remission and marrow complete remission also did not differ between the two arms. Cytopenia was the most frequent adverse event (76.4%). The median duration of neutropenia per cycle did not differ between the two arms during the first two cycles, but significantly shorter in the extended dosing arm in the third cycle (8.5 vs. 15.5 days, p = 0.049) and in the fourth cycle (8 vs. 14 days, p = 0.294). CONCLUSION: The 5-day 20-mg/m2 /day and 8-day 12-mg/m2 /day decitabine regimens have similar efficacy and safety in patients with intermediate or high risk MDS.
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Síndromes Mielodisplásicos , Neutropenia , Adulto , Humanos , Decitabina , Azacitidina/efectos adversos , Resultado del Tratamiento , Síndromes Mielodisplásicos/tratamiento farmacológico , Neutropenia/inducido químicamenteRESUMEN
It has been reported that arsenic trioxide (ATO) regulates lymphoma cell cycle, apoptosis, autophagy and mitochondrial activity, while it synergizes with other cytotoxic agents. In addition, ATO targets anaplastic lymphoma kinase (ALK)-fusion oncoprotein to repress anaplastic large cell lymphoma (ALCL). The current study aimed to investigate the efficacy and safety of ATO plus etoposide, solumedrol, high-dose cytarabine and cisplatin (ESHAP) chemotherapy compared with ESHAP chemotherapy alone in patients with relapsed or refractory (R/R) ALK+ ALCL. A total of 24 patients with R/R ALK+ ALCL were enrolled in the present study. Among them, 11 patients were treated with ATO plus ESHAP, while the remaining 13 patients received ESHAP chemotherapy alone. Subsequently, treatment response, event-free survival (EFS), overall survival (OS) and adverse event (AEs) rates were recorded. Both complete response (72.7% vs. 53.8%; P=0.423) and objective response (81.8% vs. 69.2%; P=0.649) rates were higher in the ATO plus ESHAP group compared with the ESHAP group. However, statistical significance was not reached. In addition, EFS was significantly prolonged (P=0.047), while OS was not significantly increased (P=0.261) in the ATO plus ESHAP group compared with the ESHAP group. More specifically, the 3-year accumulating EFS and OS rates were 59.7 and 77.1% in the ATO plus ESHAP group, respectively, and 13.8 and 59.8% in the ESHAP group, respectively. The majority of AEs, such as thrombocytopenia (81.8% vs. 46.2%; P=0.105), fever (81.8% vs. 46.2%; P=0.105) and dyspnea (36.4% vs. 15.4%; P=0.182), were more prevalent in the ATO plus ESHAP group compared with the ESHAP group. However, no statistical significance was observed. In conclusion, the current study indicated that ATO plus ESHAP chemotherapy could exert a superior efficacy compared with ESHAP chemotherapy alone in patients with R/R ALK+ ALCL.
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Background: Waldenström macroglobulinemia (WM) is a rare subtype of B-cell lymphoma. Rituximab-based combination therapy and Bruton's tyrosine kinase (BTK) inhibitors have greatly improved the prognosis of WM. Despite the high response rate and good tolerance of BTK inhibitors in treatment of WM, a proportion of patients still experience disease progression. Case presentation: We report a 55-year-old man with relapsed WM. The patient achieved partial remission after six courses of CHOP chemotherapy and multiple plasma exchanges in initial treatment. He was admitted to the hospital with abdominal distension, and was diagnosed with relapsed WM and subsequently started on zanubrutinib. Disease progression and histological transformation occurred during treatment. We performed liquid biopsies on transformed plasma, tumor tissue and ascites at the same time and found high consistency between ascites and tissues. Moreover, we detected resistance mutations of BTK inhibitors (BTK, PLCG2) in ascites that were not detected in plasma or tissue. Eventually, the patient died during the 15-month follow-up after relapse. Conclusion: We describe a rare case of WM transformation to DLCBCL treated with chemoimmunotherapy and BTK inhibition. We analyzed tumor DNA obtained at different anatomic sites and circulating tumor DNA (ctDNA) derived from plasma and ascites specimens, with apparent significant temporal and spatial heterogeneity. The case specifically highlights the clinical value of ctDNA of ascites supernatant from WM patients, which is a more convenient and relatively noninvasive method compared with traditional invasive tissue biopsy.
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ADN Tumoral Circulante , Linfoma de Células B , Macroglobulinemia de Waldenström , Humanos , Masculino , Persona de Mediana Edad , Ascitis , ADN Tumoral Circulante/genética , Progresión de la Enfermedad , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/genética , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.
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Inmunoterapia Adoptiva , Linfoma no Hodgkin , Receptores Quiméricos de Antígenos , Humanos , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19 , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Consenso , Inmunoterapia Adoptiva/efectos adversos , Linfoma no Hodgkin/terapiaRESUMEN
ABSTRACT: Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells' productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.
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Neoplasias Hematológicas , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Inmunoterapia Adoptiva , Neoplasias Hematológicas/terapia , Resultado del TratamientoRESUMEN
Interphase fluorescence in situ hybridization (iFISH) has been well established in the preliminary prognostic evaluation of multiple myeloma (MM). However, the chromosomal aberrations in patients with systemic light-chain amyloidosis, notably in patients with coexistent MM, have been rarely investigated. This study aimed to evaluate the effect of iFISH aberrations on the prognosis of systemic light-chain amyloidosis (AL) with and without concurrent MM. The iFISH results and clinical characteristics of 142 patients with systemic light-chain amyloidosis were analyzed, and survival analysis was conducted. Among the 142 patients, 80 patients had AL amyloidosis alone, and the other 62 patients had concurrent MM. The incidence rate of 13q deletion, t(4;14), was higher in AL amyloidosis patients with concurrent MM than that of primary AL amyloidosis patients (27.4% vs. 12.5%, and 12.9% vs. 5.0%, respectively), and the incidence rate of t(11;14) in primary AL amyloidosis patients was higher than that in AL amyloidosis patients with concurrent MM (15.0% vs. 9.7%). Moreover, the two groups had the similar incidence rates of 1q21 gain (53.8% and 56.5%, respectively). The result of the survival analysis suggested that patients with t(11;14) and 1q21 gain had a shorter median overall survival (OS) and progression-free survival (PFS), irrespective of the presence or absence of MM, and patients with AL amyloidosis and concurrent MM carrying t(11;14) had the poorest prognosis, with a median OS time of 8.1 months.
RESUMEN
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising form of adoptive T-cell immunotherapy for selected hematologic malignancies including leukemia, lymphoma and multiple myeloma. China has become the country with the largest number of registered CAR T-cell trials. Despite the remarkable clinical outcomes achieved with CAR Tcell therapy, challenges such as disease relapse, the process of manufacturing the CAR T cells and safety have limited the therapeutic efficacy of CAR T cells in hematologic malignancies. In this period of innovation, several clinical trials have reported the design of CAR directed at new targets in hematologic malignancies. In this review, we comprehensively summarize the contemporary landscape and clinical development of CAR T-cell therapy in China. In addition, we present strategies for further improving the clinical utility of CAR T-cell therapy, such as increasing the efficacy and response duration, in hematologic malignancies.