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Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Loncastuximab tesirine (Lonca), an antibody conjugate targeting CD19, has demonstrated significant clinical benefit in R/R DLBCL in a global phase 2 LOTIS-2 study. In the China bridging pivotal phase 2 OL-ADCT-402-001 study, eligible patients aged ≥18 years with R/R DLBCL who had failed ≥ 2 lines of systemic therapies were enrolled and treated with Lonca every 3 week with 150 µg/kg for 2 cycles; then 75 µg/kg for subsequent cycles (up to 1 year). The primary endpoint was overall response rate (ORR) assessed by independent review committee. Primary analyses for efficacy and safety were performed on the patients who received at least one treatment and had at least 6 months of follow-up following an initial documented response. As of data-cutoff, 64 patients received Lonca (median: 4.0 cycles [range: 1 to 17]). The median number of prior lines of therapies was 3.0 (range: 2 to 12). The ORR was 51.6% (95% CI: 38.7% to 64.2%), and the complete response rate was 23.4%. Hematological events accounted for the majority of the most common (≥15%) Grade ≥3 treatment-emergent adverse events (TEAEs), in which increased gamma glutamyltransferase (25.0%), and hypokalaemia (18.8%) also were reported. Serious TEAEs were reported in 35 of 64 patients with 4 fatal TEAEs. In conclusion, Lonca monotherapy demonstrated clinically meaningful efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL, which was consistent with the results of the LOTIS-2 study in Caucasian patients.

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INTRODUCTION: The current treatment regimens for Hodgkin's lymphoma (HL) are associated with high incidences of adverse events. PURPOSE: This study aimed to compare the efficacy and safety of doxorubicin + bleomycin + vincristine + dacarbazine (ABVD) and standard bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (BEACOPP) chemotherapy in the treatment of advanced stage HL. METHODS: This multicenter, randomized, parallel, open, positive control noninferiority trial was conducted from 2016 to 2019 and comprised 93 subjects who were randomized in a 1:1 ratio between the treatment (BEACOPP; n = 44) and control (ABVD; n = 49) groups. RESULTS: The primary efficacy endpoint of this trial was the objective response rate (ORR) after eight cycles of chemotherapy, which was 100.00% (36/36) in the treatment group and 95.74% (45/49) in the control group. The incidence of adverse reactions was 100% in both groups. Significant differences (P < 0.05) in the incidences of grade 3 (39/44 [88.64%] vs. 23/49 [46.94%]) and grade 4 (27/44 [61.36%] vs. 8/49 [16.94%]) adverse events were observed between the treatment and control groups, respectively. However, most of these reactions were manageable, with no serious consequences, and were reversible after discontinuation of the treatment. CONCLUSION: Both regimens had a similar ORR and were associated with a high number of adverse events. The ABVD regimen was better tolerated and safer than the standard BEACOPP regimen. This study indicates that the standard BEACOPP regimen may be considered as a treatment option for patients with advanced HL.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Ciclofosfamida , Dacarbazina , Doxorrubicina , Etopósido , Enfermedad de Hodgkin , Prednisona , Procarbazina , Vincristina , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Bleomicina/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Vincristina/efectos adversos , Vincristina/uso terapéutico , Vincristina/administración & dosificación , Masculino , Procarbazina/administración & dosificación , Procarbazina/efectos adversos , Procarbazina/uso terapéutico , Adulto , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Femenino , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/uso terapéutico , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prednisona/uso terapéutico , Dacarbazina/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/uso terapéutico , Persona de Mediana Edad , Adulto Joven , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/uso terapéutico , Adolescente , Estadificación de Neoplasias , Resultado del Tratamiento

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Hyperthermia therapy is considered an effective anticancer strategy. However, high temperature can trigger an excessive inflammatory response, leading to tumor self-protection, immunosuppression, metastasis, and recurrence. To address this issue, we reported a multifunctional photothermal nanoplatform to achieve mild hyperthermia photothermal therapy (mild PTT) based on cisplatin (DDP) and a ferrocene metal-organic framework (MOF-Fc) nanocomposite, which can specifically enhance ferroptosis-triggered oxidative stress levels and synchronously amplify mild hyperthermia PTT-mediated anticancer responses. Both in vitro and in vivo antineoplastic results verify the superiority of mild PTT with DDP/MOF-Fc@HA. The combination of DDP and MOF-Fc exhibits Fenton catalytic activity and glutathione depletion capacity, magnifying mild hyperthermia effects via the radical oxygen species (ROS)-adenosine triphosphate (ATP)-HSP silencing pathway, with important implications for clinical hyperthermia therapy.

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BACKGROUND: Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. METHODS: Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. RESULTS: Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. CONCLUSIONS: Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/etiología , Enfermedad de Hodgkin/patología , Gemcitabina , Oxaliplatino/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Trasplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento

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This study aimed to explore the distribution, characteristics and prognostic value of baseline peripheral blood lymphocyte subsets in patients with extranodal NK/T-cell lymphoma (NKTCL). We conducted this cross-sectional study of 205 newly-diagnosed NKTCL patients receiving first-line chemotherapy and radiation at our institute between 2010 and 2020. Baseline peripheral blood lymphocytes were detected using flow cytometry, and the clinical value was analyzed. Compared with healthy controls, patients with NKTCL presented with a distinct peripheral immunity with higher levels of cytotoxic CD8+ T cells (33.230 ± 12.090% vs. 27.060 ± 4.010%, p < 0.001) and NKT cells (7.697 ± 7.219% vs. 3.550 ± 2.088%, p < 0.001) but lower proportions of suppressive regulatory T cells (Treg, 2.999 ± 1.949% vs. 3.420 ± 1.051%, p = 0.003) and CD4+ helper T cells (Th, 33.084 ± 11.361% vs. 37.650 ± 3.153%, p < 0.001). Peripheral lymphocytes were differentially distributed according to age, stage, and primary site in patients with NKTCL. The proportion of Th cells/lymphocytes was associated with tumor burden reflected by stage (p = 0.037), serum lactate dehydrogenase (p = 0.0420), primary tumor invasion (p = 0.025), and prognostic index for NK/T-cell lymphoma (PINK) score (p = 0.041). Furthermore, elevated proportions of T cells (58.9% vs. 76.4%, p = 0.005), Th cells (56.3% vs. 68.8%, p = 0.047), or Treg cells (49.5% vs. 68.9%, p = 0.040) were associated with inferior 5-year progression-free survivals (PFS) via univariable survival analysis. Multivariate cox regression revealed elevated Th cells as an independent predictor for unfavorable PFS (HR = 2.333, 95% CI, 1.030-5.288, p = 0.042) in NKTCL. These results suggested the proportion of Th cells positively correlated with tumor burden and was a potential non-invasive biomarker for inferior survival for patients with NKTCL.

Asunto(s)

Linfoma Extranodal de Células NK-T , Humanos , Pronóstico , Citometría de Flujo , Estudios Transversales , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfocitos T Colaboradores-Inductores , Linfocitos/patología

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Anti-programmed cell death-1 (anti-PD-1) therapies have shown a favorable efficacy and good tolerance for relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). However, there are limited data on long-term outcomes among patients with r/r cHL who achieve an objective response to anti-PD-1 therapies. A total of 260 responders from four, phase 2 clinical trials were included in this study. The median age was 32 years with a male/female ratio of 1.3:1. After a median follow-up period of 31.1 months, 116 (44.6%) responders experienced disease progression and 18 (6.9%) died. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 55.1% and 89.7% overall. Patients with partial remission (PR) had inferior outcomes compared with those who achieved complete remission (3-year PFS, 29.5% vs. 72.3%, P < 0.001; 3-year OS, 81.5% vs. 94.4%, P = 0.017). Moreover, the survival outcome was inferior for patients with refractory disease compared with those with relapsed disease. Multivariate Cox regression analysis showed PR and refractory disease were independent risk factors for PFS. In conclusion, PR and refractory disease have a negative impact on the survival benefit of anti-PD-1 therapeutics in patients with r/r cHL, which highlights the need for multimodal treatment strategies.

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Enfermedad de Hodgkin , Humanos , Femenino , Masculino , Adulto , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad Crónica , Progresión de la Enfermedad , Terapia Combinada , Tolerancia Inmunológica

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Abnormal epigenetic regulation is identified to correlate with cancer progression and renders tumor refractory and resistant to reactive oxygen species (ROS)-based anti-tumor actions. To address it, a sequential ubiquitination and phosphorylation epigenetics modulation strategy is developed and exemplified by the well-established Fe-metal-organic framework (Fe-MOF)-based chemodynamic therapy (CDT) nanoplatforms that load the 26S proteasome inhibitor (i.e., MG132). The encapsulated MG132 can blockade 26S proteasome, terminate ubiquitination, and further inhibit transcription factor phosphorylation (e.g., NF-κB p65), which can boost pro-apoptotic or misfolded protein accumulations, disrupt tumor homeostasis, and down-regulate driving genes expression of metastatic colorectal cancer (mCRC). Contributed by them, Fe-MOF-unlocked CDT is magnified to considerably elevate ROS content for repulsing mCRC, especially after combining with macrophage membrane coating-enabled tropism accumulation. Systematic experiments reveal the mechanism and signaling pathway of such a sequential ubiquitination and phosphorylation epigenetics modulation and explain how it could blockade ubiquitination and phosphorylation to liberate the therapy resistance to ROS and activate NF-κB-related acute immune responses. This unprecedented sequential epigenetics modulation lays a solid foundation to magnify oxidative stress and can serve as a general method to enhance other ROS-based anti-tumor methods.

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Neoplasias Colorrectales , FN-kappa B , Humanos , Fosforilación , FN-kappa B/genética , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Epigénesis Genética , Ubiquitinación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética

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OBJECTIVES: The advanced extra-nodal NK/T-cell lymphoma (ENKTL) is highly aggressive and lacks effective treatment with a poor prognosis. This study aimed to investigate the effectiveness and safety of autologous hematopoietic stem cell transplantation (ASCT) in CR1. METHODS: Forty of 121 patients with advanced ENKTL from four Chinese hospitals between January 2006 to December 2021 who achieved first complete remission (CR1) and received at least 4 cycles chemotherapy, were enrolled for analysis. Twenty patients received ASCT as up-front consolidation therapy (Group A), and 20 patients only received chemotherapy (Group B). Clinical features, treatment and follow-up information were collected. RESULTS: With a median follow-up of 27 months (range, 4-188 months), the 2-year overall survival (OS) in Group A, 61% (95% CI 37%-85%), was better than that in Group B, 26% (95% CI 2%-50%), p = .018. The 2-year progression-free survival (PFS) was 56% (95% CI 32%-80%) in Group A, 26% (95% CI 2%-50%) in Group B, p = .026. III-IV grade hematological toxicity was the most common adverse event. No treatment-related deaths were observed in both groups. CONCLUSION: Up-front ASCT could improve survival of advanced ENKTL patients in first complete remission, but need be confirmed by a prospective clinical trial.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Linfoma Extranodal de Células NK-T , Linfoma de Células T Periférico , Células T Asesinas Naturales , Humanos , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pronóstico , Linfoma de Células T Periférico/etiología

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Circulating tumor DNA (ctDNA) carries tumor-specific genetic and epigenetic variations. To identify extranodal natural killer/T cell lymphoma (ENKTL)-specific methylation markers and establish a diagnostic and prognosis prediction model for ENKTL, we describe the ENKTL-specific ctDNA methylation patterns by analyzing the methylation profiles of ENKTL plasma samples. We construct a diagnostic prediction model based on ctDNA methylation markers with both high specificity and sensitivity and close relevance to tumor staging and therapeutic response. Subsequently, we built a prognostic prediction model showing excellent performance, and its predictive accuracy is significantly better than the Ann Arbor staging and prognostic index of natural killer lymphoma (PINK) risk system. Notably, we further establish a PINK-C risk grading system to select individualized treatment for patients with different prognostic risks. In conclusion, these results suggest that ctDNA methylation markers are of great value in diagnosis, monitoring, and prognosis, which might have implications for clinical decision-making of patients with ENKTL.

Asunto(s)

ADN Tumoral Circulante , Linfoma Extranodal de Células NK-T , Humanos , Pronóstico , ADN Tumoral Circulante/uso terapéutico , Linfoma Extranodal de Células NK-T/diagnóstico , Linfoma Extranodal de Células NK-T/patología , Linfoma Extranodal de Células NK-T/terapia , Metilación , Estudios Retrospectivos , Células Asesinas Naturales

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This study reported 2-year efficacy and safety of relma-cel in Chinese patients with relapsed/refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL). In this phase 1 dose-escalating trial, patients received lymphodepleting chemotherapy for 3 days, followed by relma-cel as a single infusion in escalating dose levels (25 × 106, 50 × 106, 100 × 106, and 150 × 106 CAR-T cells). The endpoints included best objective response rate (ORR), best complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A total of 23 patients were enrolled, including 60.9% with diffuse large B-cell lymphoma and 26.1% with follicular lymphoma. Twenty patients were evaluable for efficacy, and the best ORR was 85.0% and the best CRR was 75.0%. With a median follow-up of 24.2 months, 6 patients died and 2 had progressive disease, the median DOR, PFS, and OS were all not reached. The 2-year PFS and OS rates were 60.0% and 70.0%, respectively. Any grade and grade ≥ 2 cytokine release syndrome occurred in 18.2% and 13.6% of patients, respectively. Only 1(4.5%) patient had grade 3 CRS lasting 13 days, which was resolved by tocilizumab. No grade ≥ 2 neurotoxicity events or treatment-related deaths occurred. Patients with R/R B-NHL treated with relma-cel achieved durable response with favorable safety profile.

Asunto(s)

Linfoma Folicular , Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Linfoma de Células B Grandes Difuso/terapia , Linfocitos T , Inmunoterapia Adoptiva/métodos , Antígenos CD19

RESUMEN

OBJECTIVE: We aimed to assess the association between induction chemotherapy (CT) response and survivals and to explore an induction CT response-adapted treatment strategy for localized extranodal NK/T-cell lymphoma (NKTCL) receiving first-line sequential CT and radiation (RT). METHODS: We retrospectively reviewed the data of patients with localized NKTCL receiving first-line CT+RT from 2010 to 2020 at two independent institutes (primary cohort, n = 203; validation cohort, n = 67). Responses after induction CT (initial response), RT (final response) and survivals were analyzed. RESULTS: Patients with initial complete remission (CR) had higher final CR rate than the others (99.1% vs. 78.7%, P < 0.001). Initial CR was associated with superior 5-year progression-free survival (PFS, 90.0% vs. 61.4% vs. 30.8%, P < 0.001) and overall survival (OS, 93.5% vs. 70.7% vs. 60.6%, P < 0.001), as compared to initial partial remission or non-response. Though majority of cases with initial non-CR achieved final CR after RT, they still had a tendency of shortened OS compared with initial CRs (86.9% vs. 90.6%, P = 0.063). Multivariate analysis demonstrated patients with initial non-CR had higher relapse (HR = 4.748, 95% CI, 2.396-9.407, P < 0.001) and death hazard (HR = 4.296, 95% CI, 1.802-10.24, P = 0.001). Furthermore, more intensive therapy of ≥6 total cycles of CT yielded significantly superior 5-year OS for patients with initial non-CR (76.7% vs. 54.7%, P = 0.026) rather than patients with initial CR. CONCLUSION: Deep remission from induction CT was associated with favorable survivals in localized NKTCL receiving CT+RT, and an induction CT response-adapted individualized treatment strategy might be recommended in clinical practice.

Asunto(s)

Linfoma Extranodal de Células NK-T , Linfoma de Células T Periférico , Humanos , Quimioterapia de Inducción , Estudios Retrospectivos , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/radioterapia , Sobrevida

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Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×105/kg, 1×106/kg and 3×106/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen. Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity. Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.

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Background: The optimal first-line treatment for extra-nodal NK/T-cell lymphoma (ENKTL) has not been well-defined. This study aimed to evaluate the efficacy and safety of pegaspargase, cyclophosphamide, vincristine, etoposide and prednisone (COEPL) regimen combined with radiotherapy for patients with newly diagnosed ENKTL. Methods: Our study is a prospective, open-label clinical trial. Patients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. For patients with stage I/II nasal ENKTL, treatment included 2 cycles of induction COEPL regimen followed by concurrent chemoradiotherapy, then by 2 cycles of COEPL regimen as consolidation. For patients with stage III/IV or primary extra-nasal ENKTL, treatment included 6-8 cycles of COEPL regimen with or without radiotherapy to local sites, and autologous stem cell transplantation was given in selected patients. Results: A total of 80 patients were enrolled. The median age was 41 years (range, 15-76 years). Sixteen patients (20%) had stage III/IV disease, and 10 (12.5%) had a PINK score≥2. Complete response and overall response rates were 75.9% and 87.3%, respectively. With a median follow-up of 41.4 months (range 2.7-76.2 months), the 3-year progression-free survival (PFS) and overall survival (OS) rates were 71.3% (95%CI 61.1-81.5%) and 73.3% (95%CI 63.1-83.5%), respectively. For patients with stage I/II nasal ENKTL (n=62), the 3-year PFS and OS were 78.1% and 81.2%, respectively. For patients with stage III/IV or primary extra-nasal ENKTL (n=18), 3-year PFS and OS were 48.1% and 45.7%, respectively. Major grade 3-4 adverse events were anemia (21.3%), leucopenia (22.5%), neutropenia (18.8%), and thrombocytopenia (7.6%). No treatment-related death was observed. Conclusions: Pegaspargase-COEP chemotherapy in combination with radiotherapy is highly effective and safe for patients with newly diagnosed ENKTL.

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BACKGROUND: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL). METHODS: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483). RESULTS: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. CONCLUSIONS: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Enfermedad de Hodgkin , Recurrencia Local de Neoplasia , Anticuerpos Monoclonales Humanizados/efectos adversos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Supervivencia sin Progresión , Resultado del Tratamiento

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BACKGROUND: Academic studies have proved that anti-programmed death-1 (PD-1) monoclonal antibodies demonstrated remarkable activity in relapsed/refractory classical Hodgkin lymphoma (cHL). However, most patients ultimately experienced failure or resistance. It is urgent and necessary to develop a novel strategy for relapsed/refractory cHL. The aim of this case report is to evaluate the combination approach of low-dose decitabine plus a PD-1 inhibitor in relapsed/ refractory cHL patients with prior PD-1 inhibitor exposure. CASE SUMMARY: The patient was a 27-year-old man who complained of enlarged right-sided cervical lymph nodes and progressive pain aggravation of the right shoulder over the past 3 mo before admission. Histological analysis of lymph node biopsy was suggestive of cHL. The patient experienced failure of eight lines of therapy, including multiple cycles of chemotherapy, PD-1 blockade, and anti-CD47 antibody therapy. Contrast-enhanced CT showed that the tumors of the chest and abdomen significantly shrunk or disappeared after three cycles of treatment with decitabine plus tislelizumab. The patient had been followed for 11.5 mo until March 2, 2021, and no progressive enlargement of the tumor was observed. CONCLUSION: The strategy of combining low-dose decitabine with tislelizumab could reverse the resistance to PD-1 inhibitors in patients with heavily pretreated relapsed/ refractory cHL. The therapeutic effect of this strategy needs to be further assessed.

RESUMEN

BACKGROUND: The unprecedented efficacy of chimeric antigen receptor T (CAR-T) cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumors. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo. METHODS: NALM-6, a human B-cell acute lymphoblastic leukemia (B-ALL) cell line, was used as target cells. CAR-T cells were injected into a mice model with or without target cells. Then we measured the distribution of CAR-T cells in mice. In addition, an exploratory clinical trial was conducted in 13 r/r B-cell non-Hodgkin lymphoma (B-NHL) patients, who received CAR-T cell infusion. The dynamic changes in patient blood parameters over time after infusion were detected by qPCR and flow cytometry. RESULTS: CAR-T cells still proliferated over time after being infused into the mice without target cells within 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at week 6. In the clinical trial, we found that CAR-T cells peaked at 7-21 days after infusion and lasted for 420 days in peripheral blood of patients. Simultaneously, mild side effects were observed, which could be effectively controlled within 2 months in these patients. CONCLUSIONS: CAR-T cells can expand themselves with or without target cells in mice, and persist for a long time in NHL patients without serious side effects. TRIAL REGISTRATION: The registration date of the clinical trial is May 17, 2018 and the trial registration numbers is NCT03528421 .

Asunto(s)

Antígenos CD19/inmunología , Leucemia de Células B/terapia , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos/metabolismo , Adulto , Animales , Línea Celular Tumoral , Femenino , Humanos , Inmunoterapia Adoptiva/métodos , Masculino , Ratones , Distribución Tisular

RESUMEN

Targeting T cell receptor ß-chain constant region 1 (TRBC1) CAR-T could specifically kill TRBC1+ T-cell malignancies. However, over-expressed CARs on anti-TRBC1 CAR transduced TRBC1+ T cells (CAR-C1) bound to autologous TRBC1, masking TRBC1 from identification by other anti-TRBC1 CAR-T, and moreover only the remaining unoccupied CARs recognized TRBC1+ cells, considerably reducing therapeutic potency of CAR-C1. In addition, co-culture of anti-TRBC1 CAR-T and TRBC1+ cells could promote exhaustion and terminal differentiation of CAR-T. These findings provide a rationale for pre-depleting TRBC1+ T cells before anti-TRBC1 CAR-T manufacturing.

Asunto(s)

Citotoxicidad Inmunológica/inmunología , Inmunoterapia Adoptiva/métodos , Leucemia de Células T/terapia , Depleción Linfocítica/métodos , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Apoptosis , Proliferación Celular , Humanos , Leucemia de Células T/inmunología , Leucemia de Células T/metabolismo , Leucemia de Células T/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores Quiméricos de Antígenos/inmunología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Classical Hodgkin lymphoma (cHL) has been identified with universal genetic alterations of chromosome 9p24.1, which contains PD-L1/PD-L2 genes. The amplification of 9p24.1 is associated with the increased expression of PD-L1 and PD-L2 on RS cells, which promotes their immune evasion, and subsequently makes cHL sensitive to PD-1 blockade. Several PD-1 inhibitors have shown significant efficacies with overall response rate (ORR) of 70%-90% in relapse/refractory (r/r) cHL and have acquired the approvals for this indication. Recently, more and more studies are conducted to investigate PD-1 blockade in earlier disease course and in combination with neo-agents or chemotherapy. Unlike cHL, non-Hodgkin lymphoma (NHL) consists of numerous subtypes harboring highly biological heterogeneity. Only a few subtypes have been shown to have genetic alteration of9p24.1 including primary mediastinal B cell lymphoma (PMBL), gray zone lymphoma (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and cHL, primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL). Epstein-Barr virus (EBV)-associated lymphomas have a virally mediated overexpression of PD-L1, also making them sensitive to PD-1 blockade. Therefore, PD-1 inhibitors are less effective in most r/r NHL than in r/r cHL. Further understanding of the biological features of NHL and immune checkpoint inhibitors (ICPi) combined therapy is the research focus in the future. In this review, we outlined the recent progress of ICPi in lymphoma originating from clinical studies.

RESUMEN

BACKGROUND: The treatment outcomes and prognosis of lymphoma are affected by various factors such as hospital types. This study was to describe the temporal trend in the survival of lymphoma in an academic center in China. METHODS: A total of 3840 consecutive patients with lymphoma diagnosed between 1996 and 2015 were reviewed. Eighty patients were excluded, and finally, 3760 patients were analyzed in this study. The cohort was divided into four groups according to calendar periods at diagnosis: 1996-2000, 2001-2005, 2006-2010, and 2010-2015. The overall survival (OS) rates among the four groups were compared. RESULTS: The 5- and 10-year OS for the whole cohort were 62% and 52%, respectively. The 5-year OS of patient with classic Hodgkin lymphoma (cHL), mature B-cell lymphoma (BCL), and peripheral T-cell lymphoma (PTCL) were 79%, 63%, and 50%, respectively. Among mature BCL, the 5-year OS was highest in follicular lymphoma (77.8%), followed by Burkitt lymphoma (76.5%), marginal zone lymphoma (74.1%), diffuse large B-cell lymphoma (61.5%), small lymphocytic lymphoma/chronic lymphocytic leukemia (55.1%), and mantle cell lymphoma (44.3%). Among PTCL, the 5-year OS was highest in ALK+anaplastic large cell lymphoma (79.0%), followed by ALK-anaplastic large cell lymphoma (63.1%), natural killer/T-cell lymphoma (57.7%), angioimmunoblastic T-cell lymphoma (34.9%, and peripheral T-cell lymphoma not otherwise specified (27.6%). Significant improvement in the survival of lymphoma was observed, with the 5-year OS increasing from 48% in 1996-2000 to 65% in 2011-2015 (P < .001). The 5-year OS of patients with cHL, mature BCL, and PTCL changed from 55%, 49%, and 41% in 1996-2000 to 79%, 65%, and 51% in 2011-2015, respectively (P values were .014, .002, and .592, respectively). CONCLUSION: The survival of most types of lymphoma such as cHL and mature BCL, rather than PTCL, was improved significantly during the past two decades.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/mortalidad , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma Anaplásico de Células Grandes/mortalidad , Linfoma de Células del Manto/mortalidad , Linfoma de Células T Periférico/mortalidad , Centros Médicos Académicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Estudios de Seguimiento , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/patología , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Adulto Joven

RESUMEN

Patients with advanced-stage natural killer/T-cell lymphoma (NKTCL) usually have a poor prognosis. However, there is limited data of comprehensive analysis on this particular patient population due to the rarity of the disease. The present study aimed to investigate the treatment models, survival outcomes, and prognosis of advanced-stage NKTCL. Data from 336 patients with advanced-stage NKTCL diagnosed between 2006 and 2015 in the China Lymphoma Collaborative Group database were retrospectively analyzed. The median age was 42 years and the male/female ratio was 2.4:1. About 97% of patients had stage IV disease and 77% had >1 extranodal involvement site. All patients received chemotherapy, with the most common option being asparaginase (Asp)-containing regimens (n=146; 43.5%). Among 286 patients with available response data, the overall response rate (ORR) was 57.3% with a complete remission (CR) rate of 35.7%. Asp-containing regimens led to better ORRs (86/132, 65.2% vs. 54/113, 47.8%, P = 0.006) and CR rates (60/132, 45.5% vs. 27/113, 23.9%, P < 0.001) than non-Asp-containing regimens. The expected 5-year progression-free survival (PFS) and overall survival (OS) rates were 22.6 and 32.0%, respectively, for the whole cohort. Compared to non-Asp-containing chemotherapy, Asp-containing chemotherapy improved 5-year PFS (34.2 vs. 17.1%, P < 0.001) and OS (45.3 vs. 27.8%, P < 0.001). A trend toward improvement in OS was observed when gemcitabine was added to Asp-containing chemotherapies. Moreover, those undergoing autologous hematopoietic stem cell transplantation had prolonged survival time. In conclusion, Asp-containing chemotherapy could improve the prognosis of advanced-stage NKTCL, and refinement of treatment models is warranted in the future.