Prognostic mutation signature would serve as a potential prognostic predictor in patients with diffuse large B-cell lymphoma.

The present study aimed to elucidate the prognostic mutation signature (PMS) associated with long-term survival in a diffuse large B-cell lymphoma (DLBCL) cohort. All data including derivation and validation cohorts were retrospectively retrieved from The Cancer Genome Atlas (TCGA) database and whole-exome sequencing (WES) data. The Lasso Cox regression analysis was used to construct the PMS based on WES data, and the PMS was determined using the area under the receiver operating curve (AUC). The predictive performance of eligible PMS was analyzed by time-dependent receiver operating curve (ROC) analyses. After the initial evaluation, a PMS composed of 94 PFS-related genes was constructed. Notably, this constructed PMS accurately predicted the 12-, 36-, and 60-month PFS, with AUC values of 0.982, 0.983, and 0.987, respectively. A higher level of PMS was closely linked to a significantly worse PFS, regardless of the molecular subtype. Further evaluation by forest plot revealed incorporation of international prognostic index or tumor mutational burden into PMS increased the prediction capability for PFS. The drug-gene interaction and pathway exploration revealed the PFS-related genes were associated with DNA damage, TP53, apoptosis, and immune cell functions. In conclusion, this study utilizing a high throughput genetic approach demonstrated that the PMS could serve as a prognostic predictor in DLBCL patients. Furthermore, the identification of the key signaling pathways for disease progression also provides information for further investigation to gain more insight into novel drug-resistant mechanisms.

The Prognosis Performance of a Neutrophil- and Lymphocyte-Associated Gene Mutation Score in a Head and Neck Cancer Cohort.

The treatment of head and neck squamous cell carcinomas (HNSCCs) is multimodal, and chemoradiotherapy (CRT) is a critical component. However, the availability of predictive or prognostic markers in patients with HNSCC is limited. Inflammation is a well-documented factor in cancer, and several parameters have been studied, with the neutrophil-to-lymphocyte ratio (NLR) being the most promising. The NLR is the most extensively researched clinical biomarker in various solid tumors, including HNSCC. In our study, we collected clinical and next-generation sequencing (NGS) data with targeted sequencing information from 107 patients with HNSCC who underwent CRT. The difference in the NLR between the good response group and the poor response group was significant, with more patients having a high NLR in the poor response group. We also examined the genetic alterations linked to the NLR and found a total of 41 associated genes across eight common pathways searched from the KEGG database. The overall mutation rate was low, and there was no significant mutation difference between the low- and high-NLR groups. Using a multivariate binomial generalized linear model, we identified three candidate genes (MAP2K2, MAP2K4, and ABL1) that showed significant results and were used to create a gene mutation score (GMS). Using the NLR-GMS category, we noticed that the high-NLR-GMS group had significantly shorter relapse-free survival compared to the intermediate- or low-NLR-GMS groups.

Serological Responses and Predictive Factors of Booster COVID-19 Vaccines in Patients with Hematologic Malignancies.

Patients with hematologic malignancies are reported to have a more severe course of coronavirus disease 2019 (COVID-19) and be less responsive to vaccination. In this prospective study, we aimed to evaluate the serological responses to booster COVID-19 vaccines of Taiwanese patients with hematologic malignancies and identify potential predictive markers for effective neutralizing immunity. This study enrolled 68 patients with hematologic malignancies and 68 age- and gender-matched healthy control subjects who received three doses of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 1 January 2022 to 31 October 2022. The SARS-CoV-2 immunoglobulin G (IgG) spike antibody level was measured with the Abbott assay. The effective neutralization capacity was defined as an anti-spike IgG level of ≥4160 AU/mL. Among the 68 patients with hematologic malignancies, 89.7% achieved seroconversion after booster doses. Seven patients with actively treated lymphoma remained seronegative and had the lowest humoral responses among patients with different types of hematologic malignancies. Despite comparable antibody titers between patients and healthy individuals, rates of effective neutralization (66.2% vs. 86.8%, respectively; p = 0.005) were significantly reduced in patients with hematologic malignancies. In a multivariate analysis, the independent predictors for effective neutralization were a lack of B-cell-targeted agents within six months of vaccination (odds ratio, 15.2; 95% confidence interval, 2.7-84.2; p = 0.002) and higher immunoglobulin levels (odds ratio, 4.4; 95% confidence interval, 1.3-14.7; p = 0.017). In conclusion, the majority of patients with hematologic malignancies achieved seroconversion after booster vaccination. Patients with ongoing B-cell depletion and hypogammaglobinemia were identified as having negative predictive markers for effective neutralization.

High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers. METHODS: TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples. RESULTS: The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells. CONCLUSION: G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.

Deciphering the Functions of Telomerase Reverse Transcriptase in Head and Neck Cancer.

Head and neck cancers (HNCs) are among the ten leading malignancies worldwide. Despite significant progress in all therapeutic modalities, predictive biomarkers, and targeted therapies for HNCs are limited and the survival rate is unsatisfactory. The importance of telomere maintenance via telomerase reactivation in carcinogenesis has been demonstrated in recent decades. Several mechanisms could activate telomerase reverse transcriptase (TERT), the most common of which is promoter alternation. Two major hotspot TERT promoter mutations (C228T and C250T) have been reported in different malignancies such as melanoma, genitourinary cancers, CNS tumors, hepatocellular carcinoma, thyroid cancers, sarcomas, and HNCs. The frequencies of TERT promoter mutations vary widely across tumors and is quite high in HNCs (11.9-64.7%). These mutations have been reported to be more enriched in oral cavity SCCs and HPV-negative tumors. The association between TERT promoter mutations and poor survival has also been demonstrated. Till now, several therapeutic strategies targeting telomerase have been developed although only a few drugs have been used in clinical trials. Here, we briefly review and summarize our current understanding and evidence of TERT promoter mutations in HNC patients.

Bispecific antibodies in multiple myeloma treatment: A journey in progress.

The incorporation of novel agents and monoclonal antibody-based therapies into the treatment of multiple myeloma (MM) has significantly improved long-term patient survival. However, the disease is still largely incurable, with high-risk patients suffering shorter survival times, partly due to weakened immune systems. Bispecific molecules, including bispecific antibodies (BisAbs) and bispecific T-cell engagers (BiTEs), encourage immune cells to lyse MM cells by simultaneously binding antigens on MM cells and immune effector cells, bringing those cells into close proximity. BisAbs that target B-cell maturation antigen (BCMA) and GPRC5D have shown impressive clinical activity, and the results of early-phase clinical trials targeting FcRH5 in patients with relapsed/refractory MM (RRMM) are also promising. Furthermore, the safety profile of these agents is favorable, including mainly low-grade cytokine release syndrome (CRS). These off-the-shelf bispecific molecules will likely become an essential part of the MM treatment paradigm. Here, we summarize and highlight various bispecific immunotherapies under development in MM treatment, as well as the utility of combining them with current standard-of-care treatments and new strategies. With the advancement of novel combination treatment approaches, these bispecific molecules may lead the way to a cure for MM.

γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation.

We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2 nM LY-411575 or 1 µM DAPT, robustly increased mBCMA densities on CD138+ but not CD3+ patient cells, concomitantly with minimum soluble/shed BCMA (sBCMA) in 1 day-culture supernatants. In ex vivo MM-T-cell co-cultures, GSIs overcame sBCMA-inhibited MM cell lysis and further enhanced autologous patient MM cell lysis induced by BCMAxCD3 BisAbs, accompanied by significantly enhanced cytolytic markers (CD107a, IFNγ, IL2, and TNFα) in patient T cells. In longer 7 day-co-cultures, LY-411575 minimally affected BCMAxCD3 BisAb (PL33)-induced transient expression of checkpoint (PD1, TIGIT, TIM3, LAG3) and co-stimulatory (41BB, CD28) proteins, as well as time-dependent increases in % effector memory/central memory subsets and CD8/CD4 ratios in patient T cells. Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome.

Emodin Ameliorates the Efficacy of Carfilzomib in Multiple Myeloma Cells via Apoptosis and Autophagy.

BACKGROUND: Carfilzomib, the proteasome inhibitor, can increase the overall survival rate of multiple myeloma (MM) patients undergoing targeted therapy. However, relapse and toxicity present great challenges for such treatment, so an urgent need for effective combination therapy is necessary. Emodin is a natural chemical compound that inhibits the proliferation of various cancers and can effectively combine with other treatments. In this study, we evaluated the sensitizing effect of emodin combined with carfilzomib on MM cells. METHODS: The cells were treated with emodin, carfilzomib, and a combination of drugs to determine their effects on cell proliferation and viability. The cell cycle distribution and reactive oxygen species (ROS) expression were measured by flow cytometry. The level of RNA and protein were analyzed through real-time qPCR and immunoblotting. RESULTS: Emodin acted synergistically with carfilzomib to reduce the proliferation and viability of MM cell lines in vitro. Furthermore, the combination of emodin and carfilzomib increased ROS production, inducing apoptosis and autophagy pathways via caspase-3, PARP, p62, and LC3B. CONCLUSIONS: These results provide a molecular target for combination therapy in MM patients.

Comparison of a novel lateral-flow device to galactomannan assay at different time periods for detections of invasive aspergillosis.

PURPOSE: To compare a lateral-flow device (LFD) method to the galactomannan assay (GM) for the diagnosis of invasive aspergillosis (IA). METHODS: First, 20 GM-positive serum samples stored for two years were retested with both the GM and LFD assays. Second, 153 serum samples from 91 immunocompromised patients suspected of having IA were tested prospectively, including 56 hematologic malignancies and 35 chronic illnesses with steroid therapy. RESULTS: For the twenty GM-positive stored samples, only ten were positive for the repeated GM assay and none were positive for IA according to the LFD test. The concordance of the LDF with the GM test was 79.81% (83/104) if both tests were performed on the sample collection day, with the rate reducing to 67.65% (23/34) (p < 0.05) if the LFD test was performed 2-7 days after the GM test. Furthermore, there was a significant difference in the discrepancy between the GM and LFD tests between previous and no anti-mold exposure subgroups (33.33% vs. 12.31%, p < 0.01). The sensitivity and specificity of the GM test were 89.65% and 98.66%, 68.96%, and 78.67% for the LFD assay. CONCLUSION: Serum samples that have been stored long term are not suitable for re-testing with the GM or LFD assay. There was a strong correlation between the LFD and GM assay results if the tests were performed on the same day, however, this decreased if the samples were stored for more than 2 days. Additionally, previous exposure to antibiotics and/or antifungal therapy could influence the LFD results, leading to discrepancies with the GM test results.

Revisit of the Association between Cytomegalovirus Infection and Invasive Fungal Infection after Allogeneic Hematopoietic Stem Cell Transplantation: A Real-World Analysis from a High CMV Seroprevalence Area.

Infection is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) especially cytomegalovirus (CMV) infection and invasive fungal infection (IFI). Taiwan is a high CMV seroprevalence area. Our study aimed to evaluate the incidence, risk factors, the impact on survival of CMV infection (including reactivation and disease) and the association of CMV infection and IFI in recipients after allo-HSCT during the first 100 days after transplantation. This was a retrospective study including 180 recipients of allo-HSCT. A total of 99 patients had CMV reactivation, and nine patients had CMV diseases. There were more mismatched donors, more ATG usage and more transplantation from CMV IgG-negative donor in patients with CMV reactivation. There was no survival difference in patients with or without CMV reactivation. A total of 34 patients had IFIs, and IFI after allo-HSCT was associated with significantly inferior survival. Patients with CMV reactivation did not increase the incidence of overall IFI, but they did result in more late-onset (>40 days) IFI (p = 0.056). In this study, we demonstrated real-world data of CMV infection and IFI from a high CMV seroprevalence area.

The Cost-Effectiveness Analysis of Transplant-Ineligible Myeloma Patients with Bortezomib plus Thalidomide plus Dexamethasone (VTD) or Bortezomib plus Melphalan plus Prednisolone (VMP) Treatment in Southern Taiwan.

BACKGROUND: This study aimed to evaluate the cost-effectiveness of treating transplant-ineligible myeloma patients with either a bortezomib plus thalidomide plus dexamethasone (VTD) or a bortezomib plus melphalan plus prednisolone (VMP) treatment in Taiwan. METHODS: Newly diagnosed, transplant-ineligible myeloma patients with VTD or VMP therapy were enrolled from two medical centers in southern Taiwan. Quality-adjusted life years (QALYs) were used as the measurement unit of the effectiveness evaluation, and the incremental cost-effectiveness ratio (ICER) was used for comparison between the two groups. A net monetary benefit approach and cost-effectiveness acceptability curve were also used for the cost-effectiveness assessment. A one-way sensitivity analysis was used to check the impact of different parameters. In total, 77 patients were enrolled in the study with 43 patients in the VTD group and 34 patients in the VMP group. Clinical presentations were similar without significant difference, except the VTD group had a higher survival rate (p = 0.029). Comparisons of the two groups over an eight-month time horizon revealed a significant lower mean of direct medical costs in the VTD group than in the VMP group (p < 0.001), and a significantly higher average QALY was gained (p < 0.001). CONCLUSIONS: The study demonstrated the greater clinical benefit and cost-effectiveness of VTD compared to VMP therapy in transplant-ineligible, newly diagnosed myeloma patients.

Microenvironment Is a Key Determinant of Immune Checkpoint Inhibitor Response.

Utilizing advanced RNA-sequencing techniques and rigorous bioinformatics analysis, this study identified gene signatures predicting responsiveness to pembrolizumab monotherapy. T-cell-inflamed gene expression profile was predictive for better treatment response, while angiogenesis, monocytic myeloid-derived suppressor cell, and stroma/epithelial-mesenchymal transition/TGFß gene signatures were associated with lower treatment response. See related article by Cristescu et al., p. 1680.

Is it reasonable for the use of Rh-ee blood? A hospital-based survey from a southern medical center in Taiwan.

Identification of alloantibodies and achieving a reduction in the rate of red blood cell (RBC) alloimmunization are important issues to prevent transfusion complications. The aim of this study was to identify the antigen and alloantibodies in our patients and to study the association of alloimmunization with previous transfusion. Transfusion records from the blood bank of Kaohsiung Medical University Hospital between 2015 and 2017 were retrospectively enrolled in the study. Antigen and antibody identification was performed using routine blood bank methods. In total, 56,422 transfusion records from 2015 to 2017 were included in the study. Among them, 1858 alloantibody episodes were found in the pre-transfusion survey, and anti-Mia, anti-E, and cold antibodies were the most common alloantibodies, with a prevalence of 3.29% (1858/56,422). Among them, 130 episodes involved newly found alloantibodies with no alloantibodies found in the previous transfusion survey. Tracing back to these newly transfusion-induced alloantibodies, the antibody was found with a mean of 10.8 ± 7.8 units of packed RBC transfusion, a mean of 66.3 ± 52.8 days, and with a mean of 4.3 ± 2.7 times of transfusion from the first transfusion therapy. An antibody survey revealed that Rh-ee (62.1%) was the most common phenotype in these newly identified antibodies. In summary, this hospital-based study revealed that RBC alloantibody rates were present at rates of 3.29%, with anti-Mia, anti-E, and cold antibodies being the most common alloantibodies. Among them, anti-E was the most commonly developed alloantibody. Given that the Rh-ee group is the most common phenotype in our population, the strategy of using Rh-ee blood for Rh-ee recipients is reasonable for transfusion safety.

Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma.

The incorporation of novel agents in recent treatments in multiple myeloma (MM) has improved the clinical outcome of patients. Specifically, the approval of monoclonal antibody (MoAb) against CD38 (daratumumab) and SLAMF7 (elotuzumab) in relapsed and refractory MM (RRMM) represents an important milestone in the development of targeted immunotherapy in MM. These MoAb-based agents significantly induce cytotoxicity of MM cells via multiple effector-dependent mechanisms and can further induce immunomodulation to repair a dysfunctional tumor immune microenvironment. Recently, targeting B cell maturation antigen (BCMA), an even MM-specific antigen, has shown high therapeutic activities by chimeric antigen receptor T cells (CAR T), antibody-drug conjugate (ADC), bispecific T-cell engager (BiTE), as well as bispecific antibody (BiAb), with some already approved for heavily pretreated RRMM patients. New antigens, such as orphan G protein-coupled receptor class C group 5 member D (GPRC5D) and FcRH5, were identified and rapidly moved to ongoing clinical studies. We here summarized the pathobiological function of key MM antigens and the status of the corresponding immunotherapies. The potential challenges and emerging treatment strategies are also discussed.

Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma, and the disease course is often aggressive with poor prognosis outcomes. PCNSL undergoes germinal center reactions and impairs B-cell maturation. However, angiogenesis is also involved in the tumorigenesis and progression of PCNSL. This study investigated the effects of the tumor microenvironment and angiogenesis-associated genomic alterations on the outcomes of PCNSL. The analysis also evaluated the influence of treatment modality and timing on PCNSL survival using partial least squares variance-based path modeling (PLS-PM). PLS-PM can be used to evaluate the complex relationship between prognostic variables and disease outcomes with a small sample of measurements and structural models. A total of 19 immunocompetent PCNSL samples were analyzed by exome sequencing. Our results suggest that the timing of radiotherapy and mutations of ROBO1 and KAT2B are potential indicators of PCNSL outcomes and may be affected by baseline characteristics such as age and sex. Our results also showed that patients with no mutations of ROBO1 and KAT2B, SubRT subgroup showed favorable survival outcomes compared with no SubRT subgroup in short-term follow-up. All SubRT patients have received high-dose methotrexate induction chemotherapy in the initial treatment. Therefore, initial induction chemotherapy combined with subsequent radiotherapy might improve survival outcomes in PCNSL patients who have no ROBO1 and KAT2B somatic mutations in short-term follow-up. The overall findings suggest that the tumor microenvironment and angiogenesis-associated genomic alterations and treatment modalities are potential indicators of overall survival and may be affected by the baseline characteristics of PCNSL patients.

Poor Prognosis of Diffuse Large B-Cell Lymphoma with Hepatitis C Infection.

BACKGROUND: Hepatitis C virus (HCV) in diffuse large B-cell lymphoma (DLBCL) is associated with a higher prevalence and distinctive clinical characteristics and outcomes. METHODS: A retrospective analysis of adult DLBCL patients from 2011 to 2015 was studied. RESULTS: A total of 206 adult DLBCL were enrolled with 22 (10.7%) HCV-positive patients. Compared to HCV-negative patients, the HCV-positive group had a poor performance status (p = 0.011), lower platelet count (p = 0.029), and higher spleen and liver involvement incidences (liver involvement, p = 0.027, spleen involvement, p = 0.026), and they received fewer cycles of chemotherapy significantly due to morbidity and mortality (p = 0.048). Overall survival was shorter in HCV-positive DLBCL (25.3 months in HCV-positive vs. not reached (NR), p = 0.049). With multivariate analysis, poor performance status (p < 0.001), advanced stage (p < 0.001), less chemotherapy cycles (p < 0.001), and the presence of liver toxicity (p = 0.001) contributed to poor OS in DLBCL. Among HCV-positive DLBCL, the severity of liver fibrosis was the main risk factor related to death. CONCLUSION: Inferior survival of HCV-positive DLBCL was observed and associated with poor performance status, higher numbers of complications, and intolerance of treatment, leading to fewer therapy. Therefore, anti-HCV therapy, such as direct-acting antiviral agents, might benefit these patients in the future.

Progression Risk Score Estimation Based on Immunostaining Data in Oral Cancer Using Unsupervised Hierarchical Clustering Analysis: A Retrospective Study in Taiwan.

This study aimed to investigate whether the progression risk score (PRS) developed from cytoplasmic immunohistochemistry (IHC) biomarkers is available and applicable for assessing risk and prognosis in oral cancer patients. Participants in this retrospective case-control study were diagnosed between 2012 and 2014 and subsequently underwent surgical intervention. The specimens from surgery were stained by IHC for 16 cytoplasmic target markers. We evaluated the results of IHC staining, clinical and pathological features, progression-free survival (PFS), and overall survival (OS) of 102 oral cancer patients using a novel estimation approach with unsupervised hierarchical clustering analysis. Patients were stratified into high-risk (52) and low-risk (50) groups, according to their PRS; a metric consisting of cytoplasmic PLK1, PhosphoMet, SGK2, and SHC1 expression. Moreover, PRS could be extended for use in the Cox proportional hazard regression model to estimate survival outcomes with associated clinical parameters. Our study findings revealed that the high-risk patients had a significantly increased risk in cancer progression compared with low-risk patients (hazard ratio (HR) = 2.20, 95% confidence interval (CI) = 1.10-2.42, p = 0.026). After considering the influences of demographics, risk behaviors, and tumor characteristics, risk estimation with PRS provided distinct PFS groups for patients with oral cancer (p = 0.017, p = 0.019, and p = 0.020). Our findings support that PRS could serve as an ideal biomarker for clinical use in risk stratification and progression assessment in oral cancer.

Low Geriatric Nutritional Risk Index Is Associated with Poorer Prognosis in Elderly Diffuse Large B-Cell Lymphoma Patients Unfit for Intensive Anthracycline-Containing Therapy: A Real-World Study.

Nutritional assessments, including the Geriatric Nutritional Risk Index (GNRI), have emerged as prediction tools for long-term survival in various cancers. This study aimed to investigate the therapeutic strategy and explore the prognostic factors in the elderly patients (≥65 years) with diffuse large B cell lymphoma (DLBCL). The cutoff value of the GNRI score (92.5) was obtained using the receiver operating characteristic curve. Among these patients (n = 205), 129 (62.9%) did not receive standard R-CHOP chemotherapy. Old age (≥80 years), poor performance status, low serum albumin level, and comorbidities were the major factors associated with less intensive anti-lymphoma treatment. Further analysis demonstrated that a lower GNRI score (<92.5) was linked to more unfavorable clinical features. In the patients who received non-anthracycline-containing regimens (non-R-CHOP), multivariate analysis showed that a low GNRI can serve as an independent predictive factor for worse progression-free (HR, 2.85; 95% CI, 1.05-7.72; p = 0.039) and overall survival (HR, 2.98; 95% CI, 1.02-8.90; p = 0.045). In summary, nutritional evaluation plays a role in DLBCL treatment and the GNRI score can serve as a feasible predictive tool for clinical outcomes in frail elderly DLBCL patients treated with non-anthracycline-containing regimens.

BCMA-Specific ADC MEDI2228 and Daratumumab Induce Synergistic Myeloma Cytotoxicity via IFN-Driven Immune Responses and Enhanced CD38 Expression.

PURPOSE: Efforts are required to improve the potency and durability of CD38- and BCMA-based immunotherapies in human multiple myeloma. We here delineated the molecular and cellular mechanisms underlying novel immunomodulatory effects triggered by BCMA pyrrolobenzodiazepine (PBD) antibody drug conjugate (ADC) MEDI2228 which can augment efficacy of these immunotherapies. EXPERIMENTAL DESIGN: MEDI2228-induced transcriptional and protein changes were investigated to define significantly impacted genes and signaling cascades in multiple myeloma cells. Mechanisms whereby MEDI2228 combination therapies can enhance cytotoxicity or overcome drug resistance in multiple myeloma cell lines and patient multiple myeloma cells were defined using in vitro models of tumor in the bone marrow (BM) microenvironment, as well as in human natural killer (NK)-reconstituted NOD/SCID gamma (NSG) mice bearing MM1S tumors. RESULTS: MEDI2228 enriched IFN I signaling and enhanced expression of IFN-stimulated genes in multiple myeloma cell lines following the induction of DNA damage-ATM/ATR-CHK1/2 pathways. It activated cGAS-STING-TBK1-IRF3 and STAT1-IRF1-signaling cascades and increased CD38 expression in multiple myeloma cells but did not increase CD38 expression in BCMA-negative NK effector cells. It overcame CD38 downregulation on multiple myeloma cells triggered by IL6 and patient BM stromal cell-culture supernatant via activation of STAT1-IRF1, even in immunomodulatory drug (IMiD)- and bortezomib-resistant multiple myeloma cells. In vitro and in vivo upregulation of NKG2D ligands and CD38 in MEDI2228-treated multiple myeloma cells was further associated with synergistic daratumumab (Dara) CD38 MoAb-triggered NK-mediated cytotoxicity of both cell lines and autologous drug-resistant patient multiple myeloma cells. CONCLUSIONS: These results provide the basis for clinical evaluation of combination MEDI2228 with Dara to further improve patient outcome in multiple myeloma.