scholarly journals Lymphoma Microenvironment Deconvolution Links M1 Macrophage Infiltration to Clinical Outcome in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Mark Yan ◽  
Yi Meng Chang ◽  
Vibha Raghavan ◽  
Estella Dong ◽  
Christian Klein ◽  
...  
Keyword(s):  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
Publicly Traded ◽  
Private Company ◽  
M1 Macrophages ◽  
Large B Cell Lymphoma ◽  
M1 Macrophage

Introduction: The lymphoma microenvironment is increasingly recognized as crucial to sustaining lymphoma cell growth and an important contributor to treatment outcome, especially in the context of immunotherapies. CD20-targeted monoclonal antibodies (e.g. obinutuzumab [G] and rituximab [R]) function by several mechanisms, including antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Immune effector cells, such as natural killer (NK) cells and phagocytes (i.e. macrophages and dendritic cells), and the Fc gamma receptor (FcγR) found on the surface of these cells, are critical to antibody treatment efficacy. Here we evaluated how the lymphoma microenvironment may affect clinical outcome in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) receiving immunochemotherapy. Methods: We leveraged two large Phase III clinical trials of pts with previously untreated DLBCL (GOYA [NCT01287741] and MAIN [NCT00486759]) to produce comprehensive lymphoma immune microenvironment profiles from 604 tissue biopsies from pts treated with R plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or G plus CHOP (G-CHOP) using the RNA-Seq deconvolution and marker gene methods: quanTIseq and xCell. The infiltration scores in each pt for various immune and stromal cell types were assessed, and their contribution to disease biology and treatment outcome was examined. Results: The extent of lymphoma microenvironment heterogeneity highlighted by the deconvolution analyses was consistent with previous studies (Figure A). Of the infiltrating cell types analyzed, the M1 macrophage signature quantified by either quanTIseq or xCell was most strongly associated with lower risk of progression (progression-free survival [PFS]; quanTIseq: HR, 0.596; 95% CI: 0.441-0.805; 24-month PFS: 82% [M1 high] vs 68% [M1 low] and xCell: HR, 0.627; 95% CI: 0.465-0.844; 24-month PFS: 80% [M1 high] vs 70% [M1 Low]; Figure B, C, D) and improved overall survival (OS; quanTIseq: HR, 0.465; 95% CI: 0.318-0.679; and xCell: HR, 0.527; 95% CI: 0.365-0.762). This finding was confirmed by both algorithms. This prognostic trend was stronger amongst G-treated pts than R-treated pts, consistent with the previous finding that G exhibits higher ADCC versus R (Mössner, et al. Blood 2010). Pts with PFS >24 months had significantly higher levels of M1 macrophage scores than pts with PFS <24 months. Despite the correlation with delayed disease progression, there was no differential enrichment of M1 macrophages in pts with complete response versus non-responders at end of treatment, or depending on International Prognostic Index. M1 scores did not significantly differ depending on cell of origin, although there was a trend for higher M1 macrophage scores in germinal center B-cell DLBCL. Aside from M1 macrophages, CD4+Th2 cells showed the strongest prognostic trend in DLBCL (PFS; HR, 0.745; 95% CI: 0.553-1.000; Figure C). In contrast to M1 macrophages, pts with M2 macrophage infiltration tended to have shorter PFS and OS although relatively low levels were observed for these signatures (Figure B, C). This suggests that lymphoma-infiltrating macrophages more commonly resemble the classically activated M1 polarization phenotype and are linked to prolonged PFS, while alternatively activated M2 macrophages, although their frequency is lower in DLBCL, are associated with shorter PFS. Consistent with previous work showing that programmed death-ligand 1 (PD-L1) levels correlate with a macrophage signature in DLBCL (McCord, et al. Blood Adv 2019), M1, but not M2, macrophage infiltration correlated with PD-L1 mRNA expression. M1 enrichment was highly correlated with CD8+ T cell signatures (including central and effector memory CD8+ T cells) in DLBCL. Conclusions: Data suggest macrophage polarization may be an important contributor to immunochemotherapy outcome in DLBCL. Previous studies aiming to link tumor-associated macrophages to R-CHOP outcome have yielded conflicting results, perhaps as most relied on CD68/CD163 staining alone as markers. Although R and G are thought to function via NK cell-mediated ADCC, FcγR-dependent stimulation of M1 macrophage-mediated ADCP may be key to sustaining their anti-lymphoma activity. Strategies facilitating the recruitment of M1 macrophages or macrophage repolarization may augment responses to immunochemotherapy in DLBCL. Disclosures Yan: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Chang:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Raghavan:F. Hoffmann-La Roche: Current Employment. Dong:In graduate school: University of Toronto, MSc Biostatistics: Ended employment in the past 24 months; F. Hoffmann-La Roche, Mississauga, Biometrics: Current Employment. Klein:Roche: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Paulson:Genentech, Inc: Current Employment; F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company. Hatzi:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment.

scholarly journals GM-CSF enhanced the effect of CHOP and R-CHOP on inhibiting diffuse large B-cell lymphoma progression via influencing the macrophage polarization

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu Zhang ◽  
Jingjing Xiang ◽  
Xianfu Sheng ◽  
Ni Zhu ◽  
Shu Deng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Synergistic Effects ◽  
Macrophage Polarization ◽  
B Cell Lymphoma ◽  
M2 Macrophage ◽  
Gm Csf ◽  
Large B Cell Lymphoma ◽  
M1 Macrophage ◽  
Large B Cell

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is a common type of the Non-Hodgkin lymphomas (NHLs) formed by the neoplastic transformation of mature B cells. As the first-line therapeutics, CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy and R-CHOP (Rituximab + CHOP), either using alone or in combination with GM-CSF, have achieved great efficacy in DLBCL patients. However, the underlying mechanisms are still largely unknown. Methods In the present study, the combination use of CHOP and R-CHOP with GM-CSF was used to evaluate their effects on the tumor immune microenvironment of DLBCL. CHOP and R-CHOP administration was found to inhibit the growth and metastasis of DLBCL, with a higher efficacy in R-CHOP-challenged DLBCL mice. The anti-tumor effect of CHOP and R-CHOP was further amplified by GM-CSF. Results CHOP and R-CHOP therapeutics potentiated the anti-tumor properties of macrophages, as evidenced by the increased M1 macrophage and the decreased M2 macrophage accumulation in DLBCL-bearing mice. In a co-culture system, macrophages primed with CHOP and R-CHOP therapeutics inhibited multiple malignant behaviors of DLCBL cells. Mechanistically, CHOP/R-CHOP suppressed the activation of AKT signaling. These anti-tumor effects of CHOP/R-CHOP were all augmented by GM-CSF. Conclusions Our work provided new insights into the immune-regulatory roles of CHOP and R-CHOP in the treatment of DLBCL, as well as the synergistic effects of GM-CSF in CHOP and R-CHOP therapeutics. Although our results suggest the synergistic effect of GM-CSF on DLBCL already sensitive to CHOP and R-CHOP, however, future studies are warranted to explore the role of GM-CSF on R-CHOP-resistant DLBCL. Trial registration Not applicable.

scholarly journals Expression of IL ‐34 correlates with macrophage infiltration and prognosis of diffuse large B‐cell lymphoma

2019 ◽  
Vol 8 (8) ◽  
Author(s):  
Osamu Noyori ◽  
Yoshihiro Komohara ◽  
Hesham Nasser ◽  
Masateru Hiyoshi ◽  
Chaoya Ma ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Macrophage Infiltration ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

2020 ◽  
Author(s):  
Xiaoli Lou ◽  
Jianhong Fu ◽  
Xin Zhao ◽  
Xuemei Zhuansun ◽  
Chao Rong ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Target Gene ◽  
Fas Ligand ◽  
B Cell Lymphoma ◽  
Differentially Expressed ◽  
Aggressive Lymphoma ◽  
Low Grade ◽  
M1 Macrophages ◽  
M1 Macrophage

Abstract Background: In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of microRNA (miRNA) was downregulated in transformed FL. Methods: Differentially expressed miRNAs were systematically analyzed compared in eleven lymph nodes tissue samples from patients at different stages of disease. Expression of miR-7e-5p was analyzed in 46 B-cell lymphomas, including 30 FLs and 16 DLBCLs. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitor treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis. Results: We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes. Conclusion: Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

Comparative Effectiveness of Bendamustine Plus Rituximab (BR) and Rituximab Plus Gemcitabine and Oxaliplatin (R-GemOx) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Felipe Castro ◽  
Andy Surinach ◽  
Aino Launonen ◽  
Per-Olof Thuresson ◽  
Federico Felizzi
Keyword(s):  
B Cell ◽  
Real World ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Similar Proportion ◽  
Publicly Traded ◽  
Health Maintenance ◽  
Large B Cell Lymphoma ◽  
Medicare Database ◽  
Large B Cell

Introduction: The treatment regimens bendamustine and rituximab (BR), and rituximab, gemcitabine, and oxaliplatin (R-GemOx) have proven to be efficacious and have manageable safety profiles for transplant-ineligible patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL; NCCN guidelines 2020). However, there is a paucity of published data from randomized clinical trials (RCTs) to determine the comparative efficacy of R/R DLBCL treatments (Vander Velde et al. Hematol Oncol 2019) and limited evidence from real world studies (Ionescu-Ittu et al. J Comp Eff Res 2019). One of the most recent RCTs to evaluate BR as a treatment backbone in this setting is the Phase Ib/II GO29365 study (NCT02257567). In this study, polatuzumab vedotin combined with BR (Pola+BR) significantly improved progression-free survival (PFS) and overall survival (OS), compared with BR alone in pts with R/R DLBCL (Sehn et al. J Clin Oncol 2020). In order to compare survival of pts treated with BR or R-GemOx in the second line (2L) setting, we performed a retrospective analysis using real-world data (RWD) from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) cancer registry linked to Medicare enrollment data and insurance claims. Methods: Pts with cancer diagnoses from 2004 to 2016 were identified using the SEER Medicare database. Pts diagnosed with DLBCL not otherwise specified (ICD-O-3 histology code: 9680) who received 2L BR or R-GemOx alone, were included. Additional inclusion criteria were: pts aged >65 years at diagnosis, with DLBCL as their first or only primary cancer diagnosis, and other standard SEER Medicare analysis criteria such as minimum Medicare enrollment of 12 months, to ensure sufficient data for analysis. Pts with evidence of prior hospice care were excluded. Accurate identification of transplant-ineligible pts is a limitation of using the database; transplant ineligibility was assumed for this population based on their age and associated risk factors. Survival was assessed by Kaplan-Meier and Cox regression analysis. The inverse probability-of-treatment weighting (IPTW) method was applied to balance baseline characteristics such as age at the start of 2L treatment, gender, stage of disease, race, Charlson Comorbidity Index (CCI), relapsed or refractory status, time from initial treatment to 2L treatment initiation, calendar year of 2L start, and health maintenance organization. Analyses of pts treated in the third line (3L) setting were also performed. Results: Of the 3,606 pts with DLBCL within the database, 439 pts (BR: n=308; R-GemOx: n=131) met all study criteria and were included in the analysis. Median follow-up was 12.42 months (interquartile range [IQR]: 4.78-28.41) for pts treated with BR, and 7.72 months (IQR: 3.02-21.14) for pts treated with R-GemOx. Pts treated with R-GemOx were more likely than pts treated with BR to be younger or male (Table). There was a similar proportion of pts who were primary refractory in each treatment group (BR: 20.8%; R-GemOx: 21.4%; p=0.99). The unadjusted median duration of 2L treatment was 11.4 weeks (IQR: 4.29-20.04) with BR and 8.14 weeks (IQR: 4.07-14.71) with R-GemOx. Median OS was 16.39 months (95% confidence interval [CI]: 13.01-19.48) with BR and 8.74 months (95% CI: 7.00-12.98) with R-GemOx (Figure A). After adjustment for covariates, median OS was 16.39 months (95% CI: 12.88-19.48) with BR and 9.26 months (95% CI: 7.10-14.36) with R-GemOx (Figure B); the hazard ratio (HR) for adjusted OS in 2L was 1.24 (95% CI: 0.97-1.58) for R-GemOx compared with BR. After propensity score adjustment, the HR for OS in 3L was 0.996 (95% CI: 0.70-1.42) for R-GemOx compared with BR. Conclusions: OS was not significantly different between pts with R/R DLBCL treated with BR or R-GemOx in this RWD analysis from the SEER Medicare database. This type of analysis is limited by the assumption that all important variables have been accounted for in the propensity scoring, and by the inclusion of only pts who were recorded in the database, which may impact how these results can be generalized. Nonetheless, in the absence of comparative data from RCTs, this RWD analysis demonstrates similar real-world effectiveness of the two regimens in R/R DLBCL. Disclosures Castro: F. Hoffmann-La Roche Ltd: Current Employment. Surinach:Seattle Genetics: Research Funding. Launonen:F Hoffman-La Roche Ltd: Current Employment; Novartis: Divested equity in a private or publicly-traded company in the past 24 months. Thuresson:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Felizzi:F. Hoffmann-La Roche Ltd: Current Employment.

scholarly journals Cell type-specific Pathways Associated with Diffuse Large B-cell Lymphoma Metastasis Related to Neuro-Diseases

2021 ◽  
Author(s):  
Ashmita Dey ◽  
Ujjwal Maulik
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Single Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

Abstract Background: With the advancement of single-cell sequencing, it’s become rapid emergency to detect the cell-specific changes of Diffuse Large B-cell Lymphoma metastasis that leads to the central nervous system disorder. Results: In this study, single-cell RNA-seq of Peripheral blood mononuclear cell from a human sample is curated and cell types related to lymphocytes are identified. Subsequently, the potential markers of Diffuse Large B-cell Lymphoma are found. It is noticed that LEF1, TCF7 and CD79A/B markers of different cell types show an important role in this disease formation, progression and metastasis processes. To understand the impact of markers, associated pathways are studied in details by establishing a pathway semantic network. Moreover, this association validated the channel through which the pathways are triggered within the cell environment and resulted in metastasis. The connection between Diffuse Large B-cell Lymphoma metastasis and other central nervous system disorders is demonstrated by constructing a disease network. Conclusion: The study reveals how cell types are responsible for the pathway shifts. Furthermore, this information provides a cell-specific channel of triggering the progression of central nervous system diseases among Diffuse Large B-cell Lymphoma patients.

scholarly journals MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

2020 ◽  
Author(s):  
Xiaoli Lou ◽  
Jianhong Fu ◽  
Xin Zhao ◽  
Xuemei Zhuansun ◽  
Chao Rong ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Target Gene ◽  
Fas Ligand ◽  
B Cell Lymphoma ◽  
Differentially Expressed ◽  
Aggressive Lymphoma ◽  
Low Grade ◽  
M1 Macrophages ◽  
M1 Macrophage

Abstract Background: In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of microRNA (miRNA) was downregulated in transformed FL. Methods: Differentially expressed miRNAs were systematically analyzed compared in eleven lymph nodes tissue samples from patients at different stages of disease. Expression of miR-7e-5p was analyzed in 46 B-cell lymphomas, including 30 FLs and 16 DLBCLs. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitor treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis. Results: We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes. Conclusion: Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

scholarly journals MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Xiaoli Lou ◽  
Jianhong Fu ◽  
Xin Zhao ◽  
Xuemei Zhuansun ◽  
Chao Rong ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Target Gene ◽  
Fas Ligand ◽  
B Cell Lymphoma ◽  
Differentially Expressed ◽  
Aggressive Lymphoma ◽  
Low Grade ◽  
M1 Macrophages ◽  
M1 Macrophage

Abstract Background In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of microRNA (miRNA) was downregulated in transformed FL (tFL). Methods Differentially expressed miRNAs were systematically compared in 11 lymph nodes from patients at different stages of disease. Expression of miR-7e-5p was analyzed in 46 B-cell lymphomas, including 30 FL tissues and 16 DLBCL tissues. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitors treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis. Results We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes. Conclusion Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

scholarly journals Potent and Orally Bioavailable BCL6 PROTAC TM Degraders Demonstrate Efficacy in Pre-Clinical Models of Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2272-2272
Author(s):  
Sheryl M Gough ◽  
Dan Sherman ◽  
Lynn DeCarr ◽  
Sarah Eaton ◽  
Maja Milanovic ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Publicly Traded ◽  
The Past ◽  
Large B Cell Lymphoma ◽  
Orally Bioavailable ◽  
Large B Cell

Abstract The BCL6 transcription repressor (B-cell lymphoma 6, BCL6) protein has been shown to be a key molecular driver of diffuse large B-cell lymphoma (DLBCL). Somatic mutations of the BCL6 gene include gross- or cryptic-chromosome translocations and point mutations that have been shown to result in the deregulation of BCL6 expression. These BCL6 abnormalities also contribute to a subgroup of high-risk (HR) aggressive double- and triple-hit (DH/TH) lymphomas with very poor outcomes. We have developed highly specific, potent and orally bioavailable BCL6 PROteolysis TArgeting Chimera (PROTAC TM) degraders that demonstrate potent in-vitro and in-vivo efficacy in multiple pre-clinical DLBCL models. Ten of 12 germinal center B-cell (GCB) and two of four activated B-cell (ABC) DLBCL cell lines show significant growth inhibition in-vitro with BCL6 PROTAC TM treatment, demonstrating a critical dependence on BCL6. This array of sensitivity across genetically variable cell lines suggests that BCL6-dependence is not just associated with BCL6-mutated DLBCLs. A more advanced BCL6 PROTAC TM, ARVN-71228, achieves >95% BCL6 D max in-vitro at a DC 50 of <1 nM in the OCI-Ly1 model following 24 hr treatment, degrading BCL6 equally well in the nuclear, chromatin-bound and cytosolic cell fractions. BCL6 degradation is associated with dose-dependent G1 cell cycle arrest and elevated apoptosis that increases over time (24 vs 72 hours). In head-to-head BCL6 degradation and growth inhibition studies using OCI-Ly1, the ARVN-71228 BCL6 PROTAC TM demonstrates superior activity compared to recently published BCL6-targeted degraders/inhibitors and heterobifunctional molecules. Importantly, medicinal chemistry efforts have resulted in the successful development of orally bioavailable BCL6 PROTAC TM degraders for in-vivo dosing. Time-course studies show >95% BCL6 loss within four hours which is maintained at 8-, 16- and 24-hours. Genes repressed by BCL6 such as BLIMP1 and PTPN6 are derepressed and show increased protein levels 24 hours post-dose. ARVN-71228 achieves regressions in the GCB OCI-Ly1 CDX model. Future studies plan to look at rational drug combinations with BCL6 PROTAC TM degraders to find collaborative or synergistic pathways to target, especially in the HR-DLBCL subtypes where there is a high unmet medical need. Disclosures Gough: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Sherman: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. DeCarr: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Eaton: Arvinas: Current Employment, Current equity holder in publicly-traded company. Milanovic: Arvinas: Current Employment, Current equity holder in publicly-traded company. Bookbinder: Arvinas: Current Employment, Current equity holder in publicly-traded company. Pizzano: Arvinas: Current Employment, Current equity holder in publicly-traded company. Altieri: Arvinas: Current Employment, Current equity holder in publicly-traded company. Corradi: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Xiao: Arvinas: Current Employment, Current equity holder in publicly-traded company. Gallego: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Soto: Arvinas: Current Employment, Current equity holder in publicly-traded company. Lingamaneni: Arvinas: Current Employment, Current equity holder in publicly-traded company. Chen: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Zhang: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Wang: Arvinas: Current Employment, Current equity holder in publicly-traded company. Dong: Arvinas: Current Employment, Current equity holder in publicly-traded company. Chirnomas: Arvinas: Current Employment, Current equity holder in publicly-traded company. Berlin: Arvinas: Current Employment, Current equity holder in publicly-traded company. Hornberger: Arvinas: Current Employment, Current equity holder in publicly-traded company. Snyder: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Taylor: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months.

Sign in / Sign up

Export Citation Format

Share Document