RESUMO
Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton's tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.
Assuntos
Anticorpos Neutralizantes , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Linfoma , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Anticorpos Neutralizantes/uso terapêutico , Pessoa de Meia-Idade , Feminino , Antivirais/uso terapêutico , SARS-CoV-2/imunologia , Linfoma/tratamento farmacológico , Linfoma/complicações , COVID-19/imunologia , COVID-19/complicações , Ritonavir/uso terapêutico , Idoso , Estudos Prospectivos , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Resultado do Tratamento , Combinação de Medicamentos , Recidiva , Lopinavir/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêuticoAssuntos
Bevacizumab , Hemorragia Gastrointestinal , Humanos , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/etiologia , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Masculino , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Idoso , Hemostasia/efeitos dos fármacos , Linfoma/tratamento farmacológico , Linfoma/complicações , Feminino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVES: Epilepsy is a common comorbidity of brain tumors; however, little is known about the prevalence, onset time, semiology, and risk factors of seizures in primary CNS lymphoma (PCNSL). Our objectives were to determine the prevalence of epilepsy in PCNSL, to identify factors associated with epilepsy, and to investigate the prognostic significance of seizures in PCNSL. METHODS: We performed an observational, retrospective single-center study at a tertiary neuro-oncology center (2011-2023) including immunocompetent patients with PCNSL and no history of seizures. We collected clinical, imaging, and treatment data; seizure status over the course of PCNSL; and oncological and seizure outcome. The primary outcome was to determine the prevalence of epilepsy. Furthermore, we aimed to identify clinical, radiologic, and treatment-related factors associated with epilepsy. Univariate analyses were conducted using the χ2 test for categorical variables and unpaired t test for continuous variables. Predictors identified in the unadjusted analysis were included in backward stepwise logistic regression models. RESULTS: We included 330 patients, 157 (47.6%) were male, median age at diagnosis was 68 years, and the median Karnofsky Performance Status score was 60. Eighty-three (25.2%) patients had at least 1 seizure from initial diagnosis to the last follow-up, 40 (12.1%) as the onset symptom, 16 (4.8%) during first line of treatment, 27 (8.2%) at tumor progression and 6 (1.8%) while in remission. Focal aware seizures were the most frequent seizure type, occurring in 43 (51.8%) patients. Seizure freedom under antiseizure medication was observed in 97.6% patients. Cortical contact (odds ratio [OR] 8.6, 95% CI 4.2-15.5, p < 0.001) and a higher proliferation index (OR 5.7, 95% CI 1.3-26.2, p = 0.02) were identified as independent risk factors of epilepsy. Patients with PCNSL and epilepsy had a significantly shorter progression-free survival (median progression-free survival 9.6 vs 14.1 months, adjusted hazard ratio 1.4, 95% CI 1.0-1.9, p = 0.03), but not a significantly shorter overall survival (17 vs 44.1 months, log-rank test, p = 0.09). DISCUSSION: Epilepsy affects a quarter of patients with PCNSL, with half experiencing it at the time of initial presentation and potentially serving as a marker of disease progression. Further research is necessary to assess the broader applicability of these findings because they are subject to the constraints of a retrospective design and tertiary center setting.
Assuntos
Neoplasias do Sistema Nervoso Central , Epilepsia , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Fatores de Risco , Prevalência , Prognóstico , Epilepsia/epidemiologia , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/complicações , Linfoma/epidemiologia , Linfoma/complicações , Adulto , Idoso de 80 Anos ou maisRESUMO
Introduction: NK cells can mediate tumor cell killing by natural cytotoxicity and by antibody-dependent cell-mediated cytotoxicity (ADCC), an anti-tumor mechanism mediated through the IgG Fc receptor CD16A (FcγRIIIA). CD16A polymorphisms conferring increased affinity for IgG positively correlate with clinical outcomes during monoclonal antibody therapy for lymphoma, linking increased binding affinity with increased therapeutic potential via ADCC. We have previously reported on the FcγR fusion CD64/16A consisting of the extracellular region of CD64 (FcγRI), a high-affinity Fc receptor normally expressed by myeloid cells, and the transmembrane/cytoplasmic regions of CD16A, to create a highly potent and novel activating fusion receptor. Here, we evaluate the therapeutic potential of engineered induced pluripotent stem cell (iPSC)-derived NK (iNK) cells expressing CD64/16A as an "off-the-shelf", antibody-armed cellular therapy product with multi-antigen targeting potential. Methods: iNK cells were generated from iPSCs engineered to express CD64/16A and an interleukin (IL)-15/IL-15Rα fusion (IL-15RF) protein for cytokine independence. iNK cells and peripheral blood NK cells were expanded using irradiated K562-mbIL21-41BBL feeder cells to examine in in vitro and in vivo assays using the Raji lymphoma cell line. ADCC was evaluated in real-time by IncuCyte assays and using a xenograft mouse model with high circulating levels of human IgG. Results: Our data show that CD64/16A expressing iNK cells can mediate potent anti-tumor activity against human B cell lymphoma. In particular, (i) under suboptimal conditions, including low antibody concentrations and low effector-to-target ratios, iNK-CD64/16A cells mediate ADCC, (ii) iNK-CD64/16A cells can be pre-loaded with tumor-targeting antibodies (arming) to elicit ADCC, (iii) armed iNK-CD64/16A cells can be repurposed with additional antibodies to target new tumor antigens, and (iv) cryopreserved, armed iNK-CD64/16A are capable of sustained ADCC in a tumor xenograft model under saturating levels of human IgG. Discussion: iNK-CD64/16A cells allow for a flexible use of antibodies (antibody arming and antibody targeting), and an "off-the-shelf" platform for multi-antigen recognition to overcome limitations of adoptive cell therapies expressing fixed antigen receptors leading to cancer relapse due to antigen escape variants.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Antígenos de Neoplasias , Células-Tronco Pluripotentes Induzidas , Células Matadoras Naturais , Linfoma , Receptores de IgG , Ensaios Antitumorais Modelo de Xenoenxerto , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Receptores de IgG/genética , Humanos , Animais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Linfoma/terapia , Linfoma/imunologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/imunologia , Antígenos de Neoplasias/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linhagem Celular Tumoral , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/genética , Camundongos SCIDRESUMO
Relapsed and/or refractory (R/R) primary central nervous system lymphoma (PCNSL) has a poor prognosis. A 57-year-old man diagnosed with PCNSL achieved a complete response by high-dose methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The disease was not cured, so he was treated with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel after the third relapse. However, the disease relapsed again 28 days after CAR T-cell therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was attempted as curative therapy after bridging with second ASCT and tirabrutinib monotherapy. Although a temporary response was achieved, the disease relapsed 98 days after allo-HSCT. While receiving tirabrutinib for relapse after allo-HSCT, the patient developed acute respiratory failure due to transplant-related toxicity and post-transplant thrombotic microangiopathy. He died 175 days after allo-HSCT. Although various treatments for PCNSL have been investigated in recent years, the treatment strategy for R/R PCNSL has not been established. Further studies are warranted to improve the outcomes of patients with R/R PCNSL.
Assuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Recidiva , Transplante Homólogo , Humanos , Neoplasias do Sistema Nervoso Central/terapia , Antígenos CD19/imunologia , Pessoa de Meia-Idade , Masculino , Linfoma/terapia , Receptores de Antígenos QuiméricosRESUMO
Background: Autologous stem cell transplantation (ASCT) is a potentially curative strategy for relapse or refractory(r/r) aggressive lymphoma. However, a proportion of lymphoma patients who are at high risk of mobilization failure fail to mobilize stem cells and cannot proceed to ASCT. The aim of this study is to explore the efficacy and safety of Etoposide combined with Cytarabine (EA) plus G-CSF mobilization in poor mobilizers (PMs) with r/r aggressive lymphoma. Methods: This retrospective study analyzed the outcomes of chemo-mobilization based on EA (Etoposide 0.1 g/m2, qd d1~3; AraC 0.5 g/m2, q12h d1~3) in 98 patients with r/r aggressive lymphoma. Of these, 39 patients met the criteria for predicted PMs as proposed by the Gruppo Italiano Trapianto di Midollo Osseo working group. Results: Of the 39 PMs, 38(97.4%) patents harvested adequate mobilization (≥2×106 CD34+ cells/kg), while 31(79.5%) patients achieved optimal mobilization (≥5×106 CD34+ cells/kg). Overall, the mean number of CD34+ cells/kg collected was 17.99(range: 1.08~83.07) ×106 with an average of 1.4 apheresis sessions, and the number was 15.86(range: 0.37~83.07) ×106 for the first apheresis, respectively. A single apheresis procedure was sufficient to reach the target yield of adequate mobilization in 35(89.7%) PMs, while 76.9% of PMs achieved optimal collection within two apheresis sessions. We observed acceptable hematological toxicity and antibiotic usage exposure in 26 patients with a mean duration of 3.6 days. No grade 4 infection or mobilization-related mortality was recorded. Most patients underwent ASCT and achieved successful hematopoietic recovery with prompt engraftment duration, except for one NK/T-cell lymphoma patient who succumbed to severe septicemia after receiving conditioning chemotherapy. Conclusion: Our findings indicate that EA plus G-CSF is an effective and tolerable CD34+ stem cell mobilization strategy for patients with r/r lymphoma, including those predicted to be PMs. This regimen could be an option for patients with r/r lymphoma, particularly those undergoing mobilization for salvage ASCT therapy.
Assuntos
Citarabina , Etoposídeo , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Linfoma , Humanos , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Masculino , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Adulto , Pessoa de Meia-Idade , Linfoma/terapia , Linfoma/mortalidade , Linfoma/tratamento farmacológico , Estudos Retrospectivos , Idoso , Adulto Jovem , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva , Resultado do Tratamento , AdolescenteRESUMO
Biomarkers for immune checkpoint inhibitors (ICIs) response and resistance include PD-L1 expression and other environmental factors, among which the gut microbiome (GM) is gaining increasing interest especially in lymphomas. To explore the potential role of GM in this clinical issue, feces of 30 relapsed/refractory lymphoma (Hodgkin and primary mediastinal B-cell lymphoma) patients undergoing ICIs were collected from start to end of treatment (EoT). GM was profiled through Illumina, that is, 16S rRNA sequencing, and subsequently processed through a bioinformatics pipeline. The overall response rate to ICIs was 30.5%, with no association between patients clinical characteristics and response/survival outcomes. Regarding GM, responder patients showed a peculiar significant enrichment of Lachnospira, while non-responder ones showed higher presence of Enterobacteriaceae (at baseline and maintained till EoT). Recognizing patient-related factors that may influence response to ICIs is becoming critical to optimize the treatment pathway of heavily pretreated, young patients with a potentially long-life expectancy. These preliminary results indicate potential early GM signatures of ICIs response in lymphoma, which could pave the way for future research to improve patients prognosis with new adjuvant strategies.
Assuntos
Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Linfoma/tratamento farmacológico , Linfoma/microbiologia , Adulto Jovem , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: The hyperinflammatory condition and lymphoproliferation due to Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) affect the detection of lymphomas by 18F-FDG PET/CT. We aimed to improve the diagnostic capabilities of 18F-FDG PET/CT by combining laboratory parameters. METHODS: This retrospective study involved 46 patients diagnosed with EBV-positive HLH, who underwent 18F-FDG PET/CT before beginning chemotherapy within a 4-year timeframe. These patients were categorized into two groups: EBV-associated HLH (EBV-HLH) (n = 31) and EBV-positive lymphoma-associated HLH (EBV + LA-HLH) (n = 15). We employed multivariable logistic regression and regression tree analysis to develop diagnostic models and assessed their efficacy in diagnosis and prognosis. RESULTS: A nomogram combining the SUVmax ratio, copies of plasma EBV-DNA, and IFN-γ reached 100% sensitivity and 81.8% specificity, with an AUC of 0.926 (95%CI, 0.779-0.988). Importantly, this nomogram also demonstrated predictive power for mortality in EBV-HLH patients, with a hazard ratio of 4.2 (95%CI, 1.1-16.5). The high-risk EBV-HLH patients identified by the nomogram had a similarly unfavorable prognosis as patients with lymphoma. CONCLUSIONS: The study found that while 18F-FDG PET/CT alone has limitations in differentiating between lymphoma and EBV-HLH in patients with active EBV infection, the integration of a nomogram significantly improves the diagnostic accuracy and also exhibits a strong association with prognostic outcomes.
Assuntos
Infecções por Vírus Epstein-Barr , Fluordesoxiglucose F18 , Linfo-Histiocitose Hemofagocítica , Nomogramas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Feminino , Masculino , Linfo-Histiocitose Hemofagocítica/diagnóstico por imagem , Linfo-Histiocitose Hemofagocítica/virologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Adulto , Idoso , Compostos Radiofarmacêuticos , Herpesvirus Humano 4/isolamento & purificação , Prognóstico , Linfoma/diagnóstico por imagem , Linfoma/virologiaRESUMO
We present here the K9 lymphoma assay, a novel 31-gene targeted next-generation sequencing panel designed for genomic profiling of canine lymphoid neoplasms. Addressing the growing demand for advanced diagnostics in veterinary oncology, this assay enables sensitive identification of known and actionable mutations specific to canine lymphomas, while evaluating its prognostic potential to facilitate diagnosis and prognosis. Our analysis, spanning several B- and T-cell lymphoma histotypes, unveiled distinct mutational landscapes distinguishing tumors derived from immature versus mature lymphocytes. Clustering analysis revealed a shared genetic origin between diffuse large B-cell lymphoma and marginal zone lymphoma, aligning with findings in human lymphomas, with TRAF3 emerging as the most frequently mutated gene across B-cell lymphoma subtypes. Significantly, TP53 mutations demonstrated universal adverse prognostic implications across B-cell lymphomas. Additionally, SETD2 mutations contributed to shorter time-to-progression, underscoring the role of epigenetic dysregulation in B-cell tumors. In T-cell lymphomas, SATB1 and FBXW7 were frequently mutated, warranting further investigation in larger cohorts. Our findings advocate for tailored therapeutic approaches based on the genetic profile, impacting treatment decisions and outcomes in canine lymphoma management. This study provides pivotal insights bridging veterinary and human oncology, paving the way for comprehensive genomic diagnostics and therapeutic strategies in comparative oncology.
Assuntos
Doenças do Cão , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Cães , Animais , Doenças do Cão/genética , Doenças do Cão/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Prognóstico , Linfoma/genética , Linfoma/veterinária , Linfoma/diagnóstico , Linfoma/patologia , Linfoma de Células T/genética , Linfoma de Células T/veterinária , Linfoma de Células T/patologia , Linfoma de Células T/diagnósticoRESUMO
BACKGROUND: Autologous stem cell transplantation (ASCT) is a pivotal treatment for lymphoma patients. The BeEAM regimen (Bendamustine, Etoposide, Cytarabine, Melphalan) traditionally relies on cryopreservation, whereas the CEM regimen (Carboplatin, Etoposide, Melphalan) has been optimized for short-duration administration without the need for cryopreservation. This study rigorously compares the clinical and safety profiles of the BeEAM and CEM regimens. METHODS: A controlled, randomized clinical trial was conducted with 58 lymphoma patients undergoing ASCT at the International Medical Center (IMC) in Cairo, Egypt. Patients were randomly assigned to either the BeEAM (n = 29) or CEM (n = 29) regimen, with an 18-month follow-up period. Clinical and safety outcomes were meticulously compared, focusing on time to engraftment for neutrophils and platelets, side effects, length of hospitalization, transplant-related mortality (TRM), and survival rates. RESULTS: The findings demonstrate a significant advantage for the CEM regimen. Neutrophil recovery was markedly faster in the CEM group, averaging 8.5 days compared to 14.5 days in the BeEAM group (p < 0.0001). Platelet recovery was similarly expedited, with 11 days in the CEM group versus 23 days in the BeEAM group (p < 0.0001). Hospitalization duration was substantially shorter for CEM patients, averaging 18.5 days compared to 30 days for those on BeEAM (p < 0.0001). Furthermore, overall survival (OS) was significantly higher in the CEM group at 96.55% (95% CI: 84.91-99.44%) compared to 79.31% (95% CI: 63.11-89.75%) in the BeEAM group (p = 0.049). Progression-free survival (PFS) was also notably superior in the CEM group, at 86.21% (95% CI: 86.14-86.28%) versus 62.07% (95% CI: 61.94-62.20%) in the BeEAM group (p = 0.036). CONCLUSION: The CEM regimen might demonstrate superiority over the BeEAM regimen, with faster neutrophil and platelet recovery, reduced hospitalization time, and significantly improved overall and progression-free survival rates. Future studies with longer duration and larger sample sizes are warranted. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under the registration number NCT05813132 ( https://clinicaltrials.gov/ct2/show/NCT05813132 ). (The first submitted registration date: is March 16, 2023).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina , Carboplatina , Citarabina , Etoposídeo , Transplante de Células-Tronco Hematopoéticas , Linfoma , Melfalan , Condicionamento Pré-Transplante , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Masculino , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Adulto , Linfoma/terapia , Linfoma/mortalidade , Linfoma/tratamento farmacológico , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Adulto Jovem , Adolescente , Resultado do TratamentoRESUMO
Left ventricular dysfunction in dogs after the administration of doxorubicin (DOX) has been extensively examined. However, the effects of DOX on right ventricular (RV) function remain unknown. Therefore, the present study investigated whether the chemotherapy treatment with DOX decreases RV function. Twelve dogs (five with multicentric lymphoma, four with hemangiosarcoma, two with thyroid cancer, and one with lung adenocarcinoma) that received at least two doses of DOX were prospectively enrolled. Echocardiography and the measurement of troponin I were performed prior to each administration of DOX and approximately one month after the last administration. Right ventricular function was assessed by the RV fractional area change and RV Tei index. Two (n=4), three (n=3), four (n=3), and five (n=2) doses of DOX were administered. While no significant differences were observed in the RV fractional area change, the RV Tei index was significantly impaired after two doses of DOX. Troponin I level significantly increased after four doses. Cumulative doses of DOX correlated with the RV Tei index (r=0.77, P<0.001). The present results demonstrated that the chemotherapy treatment with DOX decreased RV function in a dose-dependent manner in dogs.
Assuntos
Antibióticos Antineoplásicos , Doenças do Cão , Doxorrubicina , Ecocardiografia , Troponina I , Animais , Cães , Doxorrubicina/administração & dosagem , Doenças do Cão/tratamento farmacológico , Masculino , Feminino , Antibióticos Antineoplásicos/uso terapêutico , Troponina I/sangue , Ecocardiografia/veterinária , Função Ventricular Direita/efeitos dos fármacos , Disfunção Ventricular Direita/veterinária , Disfunção Ventricular Direita/tratamento farmacológico , Linfoma/veterinária , Linfoma/tratamento farmacológico , Estudos Prospectivos , Hemangiossarcoma/veterinária , Hemangiossarcoma/tratamento farmacológicoRESUMO
BACKGROUND: Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation. METHODS: We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice. RESULTS: Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer. CONCLUSION: Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.
Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Interleucina-15 , Animais , Camundongos , Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Humanos , Modelos Animais de Doenças , Linhagem Celular Tumoral , Feminino , Subunidade alfa de Receptor de Interleucina-15 , Receptores de Antígenos Quiméricos/imunologia , Linfoma/terapia , Linfoma/imunologia , Camundongos Endogâmicos BALB C , Linfócitos T/imunologia , Linfócitos T/transplanteRESUMO
BACKGROUND: Dogs with lymphoma that fail cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (CHOP) before completion of their protocol are commonly thought to have poor long-term outcome, but no previous studies have evaluated the effect of early relapse on progression-free interval (PFI) or overall survival time (OST) for patients undergoing rescue chemotherapy. OBJECTIVE: Correlate rescue treatment outcomes in dogs with multicentric lymphoma with outcomes after 1st-line CHOP chemotherapy. METHODS: Data were collected from 6 previous retrospective or prospective studies in 187 dogs with multicentric lymphoma that received 1st-line CHOP chemotherapy and then received either lomustine (CCNU), L-asparaginase and prednisone (LAP), or rabacfosadine (RAB, Tanovea), with or without prednisone or L-asparaginase. RESULTS: The PFI after initiation of CHOP chemotherapy was significantly associated with response rate postprogression, PFI, and postrescue survival time (ST) for both rescue protocols. Immunophenotype (B- vs T-cell) was not significantly associated with response, PFI or OST for LAP but was significantly associated with response and PFI for RAB. CONCLUSION: Dogs that experience short PFI during or after 1st-line CHOP chemotherapy had lower response rates to rescue treatment, with shorter PFI and ST. Immunophenotype did not significantly affect outcome with LAP but was associated with PFI for RAB.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doenças do Cão , Doxorrubicina , Linfoma , Prednisona , Vincristina , Animais , Cães , Doenças do Cão/tratamento farmacológico , Vincristina/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisona/uso terapêutico , Prednisona/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Masculino , Linfoma/veterinária , Linfoma/tratamento farmacológico , Asparaginase/uso terapêutico , Resultado do Tratamento , Estudos Retrospectivos , Lomustina/uso terapêutico , Progressão da Doença , Estudos Prospectivos , Alanina/análogos & derivados , PurinasRESUMO
Lymphoid tumor patients often exhibit resistance to standard therapies or experience relapse post-remission. Relapse is driven by Tumor Initiating Cells (TICs), a subset of tumor cells capable of regrowing the tumor and highly resistant to therapy. Growing cells in 3D gels is a method to discern tumorigenic cells because it strongly correlates with tumorigenicity. The finding that TICs, rather than differentiated tumor cells, grow in 3D gels offers a unique opportunity to unveil TIC-specific signaling pathways and therapeutic targets common to various cancer types. Here, we show that culturing lymphoid cells in 3D gels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and promotes the growth of primary non-tumor lymphoid cells in 3D gels. A subset of lymphoma cells, characterized by an increased abundance of the antioxidant glutathione, escape ROS-induced lethality, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell growth in 3D gels and xenografts. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.
Assuntos
Glutationa , Linfoma , Células-Tronco Neoplásicas , Espécies Reativas de Oxigênio , Animais , Humanos , Feminino , Linfoma/patologia , Linfoma/metabolismo , Linfoma/tratamento farmacológico , Glutationa/metabolismo , Camundongos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Masculino , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Carcinogênese/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismoRESUMO
Radiomics analysis of [18F]-fluorodeoxyglucose ([18F]-FDG) PET images could be leveraged for personalised cancer medicine. However, the inherent sensitivity of radiomic features to intensity discretisation and voxel interpolation complicates its clinical translation. In this work, we evaluated the robustness of tumour [18F]-FDG-PET radiomic features to 174 different variations in intensity resolution or voxel size, and determined whether implementing parameter range conditions or dependency corrections could improve their robustness. Using 485 patient images spanning three cancer types: non-small cell lung cancer (NSCLC), melanoma, and lymphoma, we observed features were more sensitive to intensity discretisation than voxel interpolation, especially texture features. In most of our investigations, the majority of non-robust features could be made robust by applying parameter range conditions. Correctable features, which were generally fewer than conditionally robust, showed systematic dependence on bin configuration or voxel size that could be minimised by applying corrections based on simple mathematical equations. Melanoma images exhibited limited robustness and correctability relative to NSCLC and lymphoma. Our study provides an in-depth characterisation of the sensitivity of [18F]-FDG-PET features to image processing variations and reinforces the need for careful selection of imaging biomarkers prior to any clinical application.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Fluordesoxiglucose F18 , Processamento de Imagem Assistida por Computador , Tomografia por Emissão de Pósitrons , Humanos , Tomografia por Emissão de Pósitrons/métodos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Processamento de Imagem Assistida por Computador/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Linfoma/diagnóstico por imagem , Linfoma/patologia , Compostos Radiofarmacêuticos , Melanoma/diagnóstico por imagem , Melanoma/patologia , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , RadiômicaRESUMO
BACKGROUND: Due to similar clinical manifestations and imaging signs, differential diagnosis of primary intestinal lymphoma (PIL) and Crohn's disease (CD) is a challenge in clinical practice. AIM: To investigate the ability of radiomics combined with machine learning methods to differentiate PIL from CD. METHODS: We collected contrast-enhanced computed tomography (CECT) and clinical data from 120 patients form center 1. A total of 944 features were extracted single-phase images of CECT scans. Using the last absolute shrinkage and selection operator model, the best predictive radiographic features and clinical indications were screened. Data from 54 patients were collected at center 2 as an external validation set to verify the robustness of the model. The area under the receiver operating characteristic curve, accuracy, sensitivity and specificity were used for evaluation. RESULTS: A total of five machine learning models were built to distinguish PIL from CD. Based on the results from the test group, most models performed well with a large area under the curve (AUC) (> 0.850) and high accuracy (> 0.900). The combined clinical and radiomics model (AUC = 1.000, accuracy = 1.000) was the best model among all models. CONCLUSION: Based on machine learning, a model combining clinical data with radiologic features was constructed that can effectively differentiate PIL from CD.
Assuntos
Doença de Crohn , Neoplasias Intestinais , Aprendizado de Máquina , Curva ROC , Tomografia Computadorizada por Raios X , Humanos , Doença de Crohn/diagnóstico por imagem , Feminino , Diagnóstico Diferencial , Masculino , Pessoa de Meia-Idade , Adulto , Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/patologia , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Linfoma/diagnóstico por imagem , Linfoma/patologia , Idoso , Sensibilidade e Especificidade , Meios de Contraste/administração & dosagem , Adulto Jovem , RadiômicaRESUMO
Gonadal dysfunction, the most frequent endocrine complication in both sexes after autologous hematopoietic cell transplant (HCT) could increase bone loss and sarcopenia, a disease characterized by reduced muscle strength and mass. Sarcopenia is associated with worse survival, lower remission rates, and progression-free survival in patients with lymphoma after HCT. Low bone mass affected approximately 20% of the transplanted patients within 2 years and harms quality of life. This study was conducted in a single center and identified a strong relationship with patients transplanted more recently by LEC (lomustine, etoposide, and cyclophosphamide) conditioning regimen with sarcopenia. Peripheral neuropathy and bone mass changes were also associated with sarcopenia as well, suggesting a relationship with muscle strength loss.