Comparison of CAR T-cell vs. bispecific antibody as third- or later-line large B-cell lymphoma therapy: A Meta-analysis.

This meta-analysis evaluates the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We searched MEDLINE, Embase, and Cochrane databases until July 2023 for trials assessing CAR T-cell therapies and CD20×CD3 bispecific antibodies as third- or subsequent-line in R/R DLBCL. Random effects models estimated the complete response (CR) rate and secondary outcomes, with meta-regressions adjusting for relevant covariates. Sixteen studies comprising 1,347 patients were included in the pooled analysis. The pooled CR rate for bispecific antibodies was 0.36 (95% CI, 0.29 to 0.43), compared to 0.51 (0.46 to 0.56) for CAR T-cell therapy (p<0.01). This superiority persisted when comparing the CAR-T naïve patients within the bispecific antibody group, CR rate of 0.37 (0.32 to 0.43). Multivariable meta-regression also revealed better efficacy of CAR-T with adjustment for the proportion of double-hit lymphoma. The pooled one-year progression-free survival rate mirrored these findings (0.32 [0.26 to 0.38] vs 0.44 [0.41 to 0.48], p<0.01). For adverse events of ≥ grade 3, the bispecific antibody had incidences of 0.02 (0.01 to 0.04) for cytokine release syndrome, 0.01 (0.00 to 0.01) for neurotoxicity, and 0.10 (0.03 to 0.16) for infections. The CAR-T cell had rates of 0.08 (0.03 to 0.12), 0.11 (0.06 to 0.17), and 0.17 (0.11 to 0.22), respectively, with significant differences observed in the first two categories. In summary, CAR-T cell therapy outperformed bispecific antibody in achieving higher CR rates, though with an increase in severe adverse events.

The influence of microbial dysbiosis on immunochemotherapy-related efficacy and safety in diffuse large B-cell lymphoma.

The gut microbiome influences cancer development and the efficacy and safety of chemotherapy but little is known about its effects on lymphoma. We obtained stool samples from treatment-naive, newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) (n = 189). We first performed 16S ribosomal RNA gene sequencing (n = 158) and then conducted whole-genome shotgun sequencing on additional samples (n = 106). We compared the microbiome data from these patients with data from healthy controls and assessed whether microbiome characteristics were associated with treatment outcomes. The alpha diversity was significantly lower in patients with DLBCL than in healthy controls (P < .001), and the microbial composition differed significantly between the groups (P < .001). The abundance of the Enterobacteriaceae family belonging to the Proteobacteria phylum was markedly higher in patients than in healthy controls. Functional analysis of the microbiome revealed an association with opportunistic pathogenesis through type 1 pili, biofilm formation, and antibiotics resistance. Enterobacteriaceae members were significantly enriched in patients who experienced febrile neutropenia and in those who experienced relapse or progression (P < .001). Interestingly, greater abundance of Enterobacteriaceae correlated with shorter progression-free survival (P = .007). The cytokine profiles of patients whose microbiome was enriched with Enterobacteriaceae were significantly associated with interleukin 6 (P = .035) and interferon gamma (P = .045) levels. In summary, patients with DLBCL exhibited gut microbial dysbiosis. The abundance of Enterobacteriaceae correlated with treatment outcomes and febrile neutropenia. Further study is required to elucidate the origin and role of gut dysbiosis in DLBCL.

Optimization of immune checkpoint inhibitor treatment planning for relapsed or refractory extranodal NK/T cell lymphoma.

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3 months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1 months, and the median overall survival (OS) was 7.1 months. The failure group, which was characterized by Deaville score (DS) 3-4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected) and low-risk groups (DS 1-2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1-2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL.

Real-world outcome of patients with extensively pretreated multiple myeloma who were treated with selinexor and dexamethasone: a Korean multicenter retrospective analysis.

The outcomes of patients with myeloma after exposed to penta-classes are extremely poor. Selinexor is the first approved exportin inhibitor for those patients, but intractable toxicities may limit its use. This retrospective study evaluated the real-world efficacy and safety of selinexor plus dexamethasone (XD) and involved 48 patients with multiple myeloma, who were treated from November 2020 to October 2022. Their median age was 64 years, and the median number of prior lines of therapy was 6. The overall response rate was 25%, and the median progression-free survival (PFS) was 2.1 months (95% confidence interval (CI), 1.7-2.5). Patients on a reduced initial dose, delayed treatment, and dose reduction had better PFS. After XD treatment failure, 17 patients received subsequent therapy and had a median PFS of 2.4 months. The median overall survival was 4.6 months (95% CI, 2.3-6.9). Among the patients, 12 (25%) and 17 (35%) experienced dose reduction and delayed treatment, respectively. Our data show that the real-world efficacy of XD treatment in heavily pretreated patients was modest and that improving treatment adherence through reducing initial doses or delaying treatments may improve patient outcomes.

Primary nodal Epstein-Barr virus-positive T-cell/NK-cell lymphoma: Real-world experience.

PTCL-EBV is a disease entity newly recognized in the WHO-HAEMS5 and the ICC of Mature Lymphoid neoplasms classification. Previously, it was classified as a subtype within PTCL-NOS and was known to have a poor prognosis. However, the clinical feature and treatment outcomes are not well known. This retrospective observational study was conducted on patients diagnosed with PTCL-EBV at Samsung Medical Center through a pathology review from 2000 to 2020. We analyzed clinical data from 14 patients. We conducted an investigation of patients with PTCL-EBV into immunohistochemistry and analysis of survival outcomes for each treatment regimen. We analyzed both overall survival and progression-free survival for each treatment regimen. 25% were beta-F1 positive, and 67% were TCRγ positive. TIA-1 and granzyme B exhibited positive results in all cases, whereas the NK cell marker CD56 was negative in only 11% of patients. The CD3 was observed in all of patients. And, the CD4 was 43% positive. The CD8 were investigated in 8 patients, with 37.5% positive. Hepatosplenomegaly was observed in 55% of patients, and 70% of patients displayed B symptoms at the time of diagnosis. Patients who received CHOP or CVP treatment had a median PFS of 2.2 months (95% CI 1.9-2.5 months), and patients who received other treatments had a median PFS of 5.1 months (NA). The objective response rate (ORR) for ICE/dexa as the first or second line treatment was 100% (3 out of 3). But, ORR of CHOP or CVP as the first line treatment was 33.3% (3 out of 9). The median overall survival (OS) for the group that received HSCT after achieving a response was 34.6 months (95% CI 0-74.6 months), and the median OS for the group that did not receive HSCT was 5.0 months (95% CI 2.1-7.9 months) (p=0.04). In conclusion, in the context of PTCL-EBV, despite a limited sample size, the ICE/Dexa regimen shows potential benefits in terms of ORR and PFS. Furthermore, the application of HSCT following the attainment of a complete response may prove advantageous.

TET2 and LILRB1 mutations are frequent in Epstein-Barr virus-positive diffuse large B-cell lymphoma especially in elderly patients.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) harboring Epstein-Barr virus (EBV) primarily occurs in patients who have underlying immunodeficiency or in elderly patients but is also reported in young, immunocompetent patients. The authors investigated the pathologic differences in EBV-positive DLBCL in these three groups of patients. METHODS: In total, 57 patients with EBV-positive DLBCL were included in the study; of these, 16 patients had associated immunodeficiency, 10 were young (younger than 50 years), and 31 were elderly (aged 50 years or older). Immunostaining for CD8, CD68, PD-L1, and EBV nuclear antigen 2, and panel-based next-generation sequencing was performed on formalin-fixed, paraffin-embedded blocks. RESULTS: Immunohistochemistry revealed EBV nuclear antigen 2 positivity in 21 of the 49 patients. The degree of CD8-positive and CD68-positive immune cell infiltration and PD-L1 expression did not differ significantly in each group. Extranodal site involvement was more common in young patients (p = .021). In mutational analysis, the genes with the highest mutation frequency were PCLO (n = 14), TET2 (n = 10), and LILRB1 (n = 10). For the TET2 gene, all 10 mutations were found in elderly patients (p = .007). Compared with a validation cohort, both TET2 and LILRB1 showed a higher mutation frequency in EBV-positive patients than in EBV-negative patients. CONCLUSIONS: EBV-positive DLBCL occurring in three different age and immune status groups showed similar pathologic characteristics. Notably, a high frequency of TET2 and LILRB1 mutations was characteristic of this disease in elderly patients. Further studies are needed to determine the role of TET2 and LILRB1 mutations in the development of EBV-positive DLBCL along with immune senescence. PLAIN LANGUAGE SUMMARY: Epstein-Barr virus-positive diffuse large B-cell lymphoma occurring in three different groups (immunodeficiency-associated, young, and elderly) showed similar pathologic characteristics. The frequency of TET2 and LILRB1 mutations was high in elderly patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Dithieno[3,2-f:2',3'-h]quinoxaline-Based Photovoltaic-Thermoelectric Dual-Functional Energy-Harvesting Wide-Bandgap Polymer and its Backbone Isomer.

Both organic solar cells (OSCs) and organic thermoelectrics (OTEs) are promising energy-harvesting technologies for future renewable and sustainable energy sources. Among various material systems, organic conjugated polymers are an emerging material class for the active layers of both OSCs and OTEs. However, organic conjugated polymers showing both OSC and OTE properties are rarely reported because of the different requirements toward the OSCs and OTEs. In this study, the first simultaneous investigation of the OSC and OTE properties of a wide-bandgap polymer PBQx-TF and its backbone isomer iso-PBQx-TF are reported. All wide-bandgap polymers form face-on orientations in a thin-film state, but PBQx-TF has more of a crystalline character than iso-PBQx-TF, originating from the backbone isomeric structures of α,α '/ß,ß '-connection between two thiophene rings. Additionally, iso-PBQx-TF shows inactive OSC and poor OTE properties, probably because of the absorption mismatch and unfavorable molecular orientations. At the same time, PBQx-TF exhibits both decent OSC and OTE performances, indicating that it satisfies the requirements for both OSCs and OTEs. This study presents the OSC and OTE dual-functional energy-harvesting wide-bandgap polymer and the future research directions for hybrid energy-harvesting materials.

Remarkable Electrical Conductivity Increase and Pure Metallic Properties from Semiconducting Colloidal Nanocrystals by Cation Exchange for Solution-Processable Optoelectronic Applications.

The authors report a strategic approach to achieve metallic properties from semiconducting CuFeS colloidal nanocrystal (NC) solids through cation exchange method. An unprecedentedly high electrical conductivity is realized by the efficient generation of charge carriers onto a semiconducting CuS NC template via minimal Fe exchange. An electrical conductivity exceeding 10 500 S cm-1 (13 400 S cm-1 at 2 K) and a sheet resistance of 17 Ω/sq at room temperature, which are among the highest values for solution-processable semiconducting NCs, are achieved successfully from bornite-phase CuFeS NC films possessing 10% Fe atom. The temperature dependence of the corresponding films exhibits pure metallic characteristics. Highly conducting NCs are demonstrated for a thermoelectric layer exhibiting a high power factor over 1.2 mW m-1 K-2 at room temperature, electrical wires for switching on light emitting diods (LEDs), and source-drain electrodes for p- and n-type organic field-effect transistors. Ambient stability, eco-friendly composition, and solution-processability further validate their sustainable and practical applicability. The present study provides a simple but very effective method for significantly increasing charge carrier concentrations in semiconducting colloidal NCs to achieve metallic properties, which is applicable to various optoelectronic devices.

Retrospective analysis of diagnosis and therapeutic strategies for patients with hepatosplenic T cell lymphoma.

Hepatosplenic T cell lymphoma (HSTCL) is a rare and aggressive lymphoma with no standard treatment and poor treatment response. From 2001-2021, 20 from a lymphoma cohort of 7247 patients (0.27%) were diagnosed with HSTCL at Samsung Medical Center. The median age at the time of diagnosis was 37.5 (range, 17-72) years, and 75.0% of patients were male. Most patients had B symptoms, hepatomegaly, and splenomegaly. Lymphadenopathy was found in only 31.6% of patients, and increased PET-CT uptake was found in 21.1% of patients. Thirteen patients (68.4%) expressed T cell receptor (TCR) γδ, and 6 patients (31.6%) expressed TCRαß. The median progression-free survival (PFS) for the entire cohort was 7.2 months (95% CI, 2.9-12.8), and the median overall survival (OS) was 25.7 months (95% CI, not calculated). In subgroup analysis, the overall response rate (ORR) was 100.0% in the ICE/Dexa group and 53.8% in the anthracycline-based group, and the complete response rate was 83.3% in the ICE/Dexa group and 38.5% in the anthracycline-based group. The ORR was 50.0% in the TCRαß group and 83.3% in the TCRγδ group. The OS was not reached in the autologous hematopoietic stem cell transplantation (HSCT) group and was 16.0 months (95% CI, 15.1-16.9) in the non-transplant group at the data cutoff time (P value 0.015). In conclusion, HSTCL is rare but has a very poor prognosis. The optimal treatment strategy is not defined. More genetic and biological information is needed.

Lower socioeconomic status associated with higher tuberculosis rate in South Korea.

BACKGROUND: Tuberculosis is an infectious disease influenced by social factors rather than a simple infectious disease. In this study, we investigated the relationship between tuberculosis rates and socioeconomic status. METHODS: This study was conducted using data of the 49,483 participants of the Korean National Health and Nutrition Examination Survey (KNHANES) VI-VIII (2013-2021). The relationships between tuberculosis rates and the quartiles of monthly household income and education level were examined using a multivariate logistic regression analysis. RESULTS: The KNHANES data revealed that the prevalence of tuberculosis as substantially related to monthly household income (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.1-32.0 for lowest vs. highest incomes) and education level (OR, 3.8; 95% CI, 1.2-12.0 for 10-12 years vs. ≥13 years; OR, 4.1; 95% CI, 1.2-14.8 for ≤ 6 years vs. ≥13 years). Furthermore, current tuberculosis treatment was significantly related to monthly household income and education level. CONCLUSION: There were substantial correlations between tuberculosis rates and socioeconomic status in South Korea.

Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study.

This study aimed to assess the efficacy and safety of treatment with avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (ENKTL). In this phase 2 trial, 21 patients with relapsed or refractory ENKTL were treated with 10 mg/kg of avelumab on days 1 and 15 of a 28-day cycle. The primary end point was the complete response (CR) rate based on the best response. Targeted sequencing and immunohistochemistry were performed using pretreatment tumor tissue, and blood samples were drawn before and after treatment for measurement of cytokines and soluble programmed cell death protein 1 (PD1), PD-L1, and PD-L2. The CR rate was 24% (5 of 21), and the overall response rate was 38% (8 of 21). Although nonresponders showed early progression, 5 responders currently continue to receive treatment and have maintained their response. Most treatment-related adverse events were grade 1 or 2; no grade 4 adverse events were observed. Treatment responses did not correlate with mutation profiles, tumor mutation burden, serum levels of cytokines, or soluble PD1/PD-L1 and PD-L2. However, the response to avelumab was significantly associated with the expression of PD-L1 by tumor tissue (P = .001). Therefore, all patients achieving CR showed high PD-L1 expression, and their tumor subtyping based on PD-L1 expression correlated with treatment response. In summary, avelumab showed single-agent activity in a subset of patients with relapsed or refractory ENKTL. The assessment of PD-L1 expression on tumor cells might be helpful for identifying responders to avelumab. This trial was registered at www.clinicaltrials.gov as #NCT03439501.

Prediction and prevention of central nervous system relapse in patients with extranodal natural killer/T-cell lymphoma.

Because non-anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline-based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.

Comprehensive comparison of international prognostic indexes for follicular helper T-cell lymphoma.

In 2016, World Health Organization classification of lymphoid neoplasms separated firmly-follicular helper (Tfh) cell origin lymphomas from peripheral T-cell lymphoma-not specified (PTCL-NOS) based on their unique immunogenic characteristics. Generally, Tfh cell origin lymphoma, which has an approximately 25% incidence, is classified into three categories: angioimmunoblastic T-cell lymphoma (AITL), follicular peripheral T-cell lymphoma (F-PTCL), and nodal peripheral T-cell lymphoma with a T-follicular helper phenotype (nodal PTCL with Tfh cell phenotype). Their prognosis has been estimated using four traditional prognostic tools for T-cell lymphoid malignancies: the international prognostic index (IPI), the prognostic index for peripheral T-cell lymphoma unspecified (PIT), the modified PIT (mPIT) and the international T-cell lymphoma project index. In addition, the AITL score that reflects AITL characteristics well has been introduced recently. However, there are no clear guidelines for evaluating the prognosis of Tfh cell lymphoma. Thus, we performed a comparative analysis to determine which of these five indexes is most suitable for Tfh cell lymphoma. We evaluated the accuracy of classification according to risk score and predicted survival rate. Based on review by lymphoma pathology experts, we enrolled 198 patients diagnosed with Tfh cell lymphoma in this retrospective study. AITL was the most common subtype (n = 168), followed by F-PTCL (n = 21) and nodal PTCL with Tfh cell phenotype (n = 9). The median progression-free survival and overall survival with front-line treatment was 0.8 years (95% confidence interval [CI], 0.6-1.1 years) and 2.9 years (95% CI, 1.6-4.2 years), respectively. The AITL score showed better differentiation than other scoring systems in terms of classification according to risk score. However, for predicting PFS (concordance-index [C-index], IPI vs. PIT vs. modified PIT vs. international T-cell lymphoma project index vs. AITL score; 0.617 vs. 0.605 vs. 0.576 vs. 0.591 vs. 0.592) and OS (C-index, IPI vs. PIT vs. modified PIT vs. international T-cell lymphoma project index vs. AITL score; 0.663 vs. 0.651 vs. 0.612 vs. 0.672 vs. 0.583), the IPI, and the international T-cell lymphoma project index showed better performance. In conclusion, there are unmet needs to develop a prognostic index for Tfh cell lymphoma because its characteristics differ from PTCL-NOS. Although the AITL score reflects Tfh cell-origin lymphoma characteristics well and clearly shows their power of classification according to risk score, there are concerns about accurate prediction of survival outcomes. Therefore, it seems too early to settle on a single scoring system in Tfh cell origin lymphoma. In the future, along with classification, a more effective tool for survival prediction needs to be developed that reflects the specific characteristics of T-cell lymphoma.

Selective salvage radiotherapy could provide favorable outcomes in patients with refractory or relapsed primary central nervous system lymphoma.

INTRODUCTION: To date, there is no relevant data supporting the role of salvage radiotherapy (sRT) in patients with refractory or relapsed primary central nervous system lymphoma (PCNSL). Herein, we aimed to investigate the impact of sRT in patients with refractory or relapsed PCNSL following upfront HD-MTX. METHODS: We retrospectively reviewed 89 patients who had refractory (n = 16) or recurrent disease after an initial favorable response (n = 73); among them, 41 were treated with sRT and 48 were treated without sRT (nRT). Event-free survival (rEFS) and overall survival (rOS) after first recurrence were considered from the date of recurrence to date of each event. RESULTS: Overall, the first failure was diagnosed at a median of 11.0 months [interquartile range (IQR), 5.6-26.4] after first treatment. More than half of the patients had recurrent disease involving initial tumor bed (n = 47), deep structure (n = 67), and multiple lesions (n = 58). Among 19 patients who were initially treated with 23.4 Gy of whole brain RT, 10 patients received sRT as a re-irradiation; other 31 patients in sRT group were RT naïve patients. There was no significant difference in tumor characteristics between sRT and nRT group. Overall and complete response after salvage treatment were 80% and 48%, respectively; sRT provided higher overall response rate than nRT (93% vs. 69%, p = 0.011). With a median follow-up of 14.3 months (IQR, 7.9-31.4), 2-year rEFS and rOS rates were 27% and 57%, respectively. There were no differences in rEFS and rOS according to sRT (sRT vs. nRT, 26% vs. 28%, p = 0.730; 63% vs. 50%, p = 0.690). Poor performance, recurrence interval < 8 months, and unfavorable response following salvage treatment were associated with inferior rEFS and rOS. Additionally, sRT and stem cell transplantation improved response rate independently after multivariate analysis for complete/partial response. CONCLUSIONS: We found favorable response rate and comparable survival outcomes following sRT compared with non-local treatments for patients with refractory/relapsed PCNSL. Further studies of patient selection could stratify patients who can benefit from sRT.

Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Programmed cell death-1 (PD-1) inhibitor treatment can cause hyperprogressive disease (HPD), but the incidence, outcome, and predictive factors of HPD are unknown in patients with hepatocellular carcinoma (HCC). Herein, we assessed the existence and factors predictive of HPD in patients with advanced HCC treated with nivolumab. METHODS: We enrolled 189 patients with advanced HCC treated with nivolumab. Occurrence of HPD was investigated using tumour growth dynamics based on tumour growth kinetics (TGK) and tumour growth rate (TGR) before and after treatment, or time to treatment failure. We additionally analysed patients treated with regorafenib (n = 95) or best supportive care (BSC)/placebo (n = 103) after progression on sorafenib to compare tumour growth dynamics. RESULTS: Flare-up of tumour growth was observed in a fraction of patients upon PD-1 blockade, indicating the occurrence of HPD. Based on distinct patterns of disease progression exclusively observed in the nivolumab-treated cohort, but not in the regorafenib- or BSC/placebo-treated cohorts, 4-fold increases in TGK and TGR ratios as well as a 40% increase in TGR were the cut-off values used to define HPD; 12.7% of the patients (24/189) treated with nivolumab met all these criteria. Patients with HPD had worse progression-free survival (hazard ratio [HR] 2.194; 95% CI 1.214-3.964) and overall survival (HR 2.238; 95% CI 1.233-4.062) compared to patients with progressive disease without HPD. More than 90% of patients with HPD missed the opportunity for subsequent treatment because of rapid clinical deterioration. An elevated neutrophil-to-lymphocyte ratio (>4.125) was associated with HPD and an inferior survival rate. CONCLUSIONS: HPD occurs in a fraction of patients with HCC who receive PD-1 inhibitor treatment. Analyses of the baseline immune profile and on-treatment tumour growth dynamics could enable optimal patient selection and earlier identification of HPD. LAY SUMMARY: Hyperprogressive disease is an unexpected response pattern observed in patients treated with an immune checkpoint inhibitor. This study revealed that hyperprogressive disease occurs in a fraction of patients with advanced hepatocellular carcinoma treated with an anti-PD-1 antibody, providing evidence to encourage careful monitoring of patients to prevent clinical deterioration induced by PD-1 blockade.

Comparison of tumor mutation burden of 300 various non-Hodgkin lymphomas using panel based massively parallel sequencing.

BACKGROUND: Tumor mutation burden is an emerging biomarker for immunotherapy. Although several clinical trials for immunotherapy in lymphoma have been carried out, the mutation burden of various lymphomas is not well known yet. Thus, the objective of this study was to compare tumor mutation burden of various non-Hodgkin lymphomas using panel based massively parallel sequencing. METHODS: We conducted 405 gene panel based massively parallel sequencing of 300 non-Hodgkin lymphomas and investigate the number of SNV/Indel in each lymphoma. RESULTS: The number of SNV/Indel was higher in mature B-cell lymphoma than in mature T- and NK-cell lymphoma. (P < 0.001) The number of SNV/Indel in primary mediastinal large B-cell lymphoma and primary diffuse large B-cell lymphoma of the central nervous system was the highest, which was significantly higher than that in diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS).(P = 0.030 and P = 0.008, respectively) The SNV/Indel number in EBV-positive DLBCL NOS was significantly lower than that in DLBCL NOS. (P = 0.048) Peripheral T-cell lymphoma, NOS showed no significant difference in the number of SNV/Indel from extranodal NK/T-cell lymphoma, nasal type (P = 0.942) or angioimmunoblastic T-cell lymphoma (P = 0.739). The number of SNV/Indel in anaplastic large cell lymphoma, ALK-positive was significantly lower than that in anaplastic large cell lymphoma, ALK-negative (P = 0.049). It was the lowest among all the lymphomas considered. CONCLUSION: Various lymphomas have different mutation burdens. Thus, tumor mutation burden can be used as a promising biomarker for immunotherapy in lymphomas.

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.

Role of 23.4 Gy upfront whole-brain radiation therapy following high-dose methotrexate for primary central nervous system lymphoma: a comparative analysis of whole-brain radiation therapy versus no radiation therapy.

INTRODUCTION: We aimed to investigate the role of upfront whole-brain radiation therapy (RT), with a reduced dose of 23.4 Gy, following high-dose methotrexate (HD-MTX) in patients with primary central nervous system lymphoma (PCNSL). METHODS: We retrospectively reviewed 185 patients with PCNSL treated with HD-MTX between January 2013 and January 2020; 145 patients underwent no RT and 40 patients underwent upfront RT. Using propensity score matching (PSM) to adjust for clinical factors, 40 patients were selected from each treatment group. Event-free survival (EFS) and overall survival (OS) were compared between treatment groups. RESULTS: At baseline, patients in the upfront RT group were younger, had higher LDH levels, received less frequent rituximab and stem cell transplantation than those in the no-RT group. Patients in the upfront RT group also showed a lower response rate after initial HD-MTX than those in the no-RT group (73% vs. 88%, p = 0.038). The median follow-up was 25.1 (interquartile range 13.7-43.0) months. Comparable 2-year EFS and OS rates were observed between the upfront RT and no-RT groups (56.6% vs. 53.8%, p = 0.170; and 81.7% vs. 75.3%, p = 0.097, respectively). Upfront RT was related to improved EFS and OS in patients with stable disease or progressive disease after HD-MTX, but not in patients with complete or partial response after HD-MTX. Upfront RT was also an independent predictor of EFS and OS in the PSM cohort. The cumulative incidences of treatment-related neurotoxicity at 3 years were 20.2% and 21.2% in the upfront RT and no-RT groups, respectively (p = 0.630). CONCLUSIONS: Upfront RT with a reduced dose of 23.4 Gy, showed favorable outcomes in patients with stable disease or progressive disease after initial HD-MTX. In addition, upfront RT appears to be an effective treatment for PCNSL when rituximab or stem cell transplantation is not feasible.

Immune subtyping of extranodal NK/T-cell lymphoma: a new biomarker and an immune shift during disease progression.

Extranodal NK/T-cell lymphoma is an aggressive lymphoma that is strongly associated with Epstein-Barr virus infection. Although some extranodal NK/T-cell lymphoma patients have shown responses to immune checkpoint blockade, biomarkers for predicting extranodal NK/T-cell lymphoma patient response to immunotherapy have not yet been defined. To understand the tumor immune microenvironment, we analyzed the expression of 579 immune-related genes and characterized the immune cells using immunohistochemistries and in situ hybridization for EBER. Based on comprehensive analyses, we developed an immune subtyping model that classifies extranodal NK/T-cell lymphoma patients into four tumor immune microenvironment subgroups using three immunohistochemical markers (FoxP3, PD-L1, and CD68). The four tumor immune microenvironment subgroups were named immune tolerance, immune evasion-A, immune evasion-B, and immune silenced. The immune tolerance group was characterized by high-Treg counts and was frequently observed in early stage, and nasal extranodal NK/T-cell lymphoma. The immune evasion group showed high cytotoxic T-cell counts and high PD-L1 expression but low Treg counts. In the immune-silenced group, almost all immune responses were exhausted, most patients were at an advanced stage, and had the poorest disease prognosis among the tumor immune microenvironment subgroups. In some patients (n = 3), a shift in the tumor immune microenvironment subgroup classification was observed in sequential biopsies. The response rate to pembrolizumab, an anti-PD-1 antibody, was 100% (1/1) in the immune tolerance group, 60% (3/5) in the immune evasion group, and 0% (0/5) in the immune-silenced group. We classified extranodal NK/T-cell lymphoma into four tumor immune microenvironment subgroups using a new classification system. In conclusion, we propose that the tumor immune microenvironment of extranodal NK/T-cell lymphoma may change during disease progression and may serve as a useful biomarker for immunotherapy.

Full Color Tunable Aggregation-Induced Emission Luminogen for Bioimaging Based on an Indolizine Molecular Framework.

By taking advantage of a unique mechanism of aggregation-induced emission (AIE) phenomena, AIE luminogens (AIEgens) have been provided as a solution to overcome the limitations of conventional fluorophores bearing the feature of aggregation-caused quenching (ACQ) phenomena. Especially, AIEgens paved the way to develop fluorogenic probes ideal for fluorescent imaging in live cell conditions. Despite the high demand for discovery of new AIEgens, it is still challenging to find a versatile molecular platform to generate diverse AIEgens. Herein, we report a new colorful molecular framework, Kaleidolizine (KIz), as a molecular platform for AIEgen generation. The KIz system allows systematic tuning of the emission wavelength from 455 to 564 nm via perturbation of the electron density of substituents on the indolizine core. Increasing the water fraction of the KIz solution in the THF/water mixture induces the fluorescence intensity increase up to 120-fold. Crystal structure analysis, computational calculations, and solvatochromism studies suggest that a synergistic effect between the intramolecular charge transfer and restriction of intramolecular rotation acts as the AIE mechanism in the KIz system. Conjugation of the triphenylphosphonium moiety to KIz allows successful development of triphenylphosphonium (TPP)-KIz for real-time bioimaging of innate mitochondria in live cells, thereby revealing the potential of KIz as a versatile molecular platform to generate fluorogenic probes based on AIE phenomena. We do believe the KIz system could serve as a new, reliable, and generally applicable molecular platform to develop various AIEgens having desired photophysical properties along with an excellent signal-to-noise ratio and with experimental convenience especially for fluorogenic live cell imaging.