PharmStatus.com
Oncology Intelligence

Non-Hodgkin's Lymphoma
News
OSLO, Norway--(BUSINESS WIRE)--Nordic Nanovector ASA (OSE:NANO)(OSE:NANOO) announces that the independent Safety Review Committee (SRC) for the ongoing Lymrit 37-01 clinical trial of Betalutin® in follicular lymphoma (FL) has given its support to the continuation of the trial potentially at a higher dose of Betalutin® and increased pre-dosing with lilotomab, as soon as safety data from Arm 4 of the same study become available. FL is one of the most prevalent forms of non-Hodgkin lymphoma (NHL).

Thursday, September 22, 2016 10:00 AM|Huang, Y.-C., Lin, S.-J., Lin, K.-M., Chou, Y.-C., Lin, C.-W., Yu, S.-C., Chen, C.-L., Shen, T.-L., Chen, C.-K., Lu, J., Chen, M.-R., Tsai, C.-H.|Blood LYMPHOID NEOPLASIA|Labels: NHL, HL

Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear. Here, we found that erythropoietin-producing hepatocellular receptor A4 (EphA4), which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the extracellular signal-regulated kinase (ERK) pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV tonsils but not in EBV+ PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV+ and EBV DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV+ PTLD and DLBCL.

Tuesday, September 20, 2016 12:14 PM|keane, C., Gould, C., Jones, K., Hamm, D., Talaulikar, D., Ellis, J., Vari, F., Birch, S., Han, E., Wood, P., Le Cao, K.-A., Green, M. R., Crooks, P., Jain, S., Tobin, J., Steptoe, R. J., Gandhi, M. K.|Clinical Cancer Research Online First Articles|Labels: PD-1/PD-L1, lymphoma

Purpose: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo Diffuse Large B-cell Lymphoma (DLBCL), and the TCR's impact on survival. Experimental Design: We performed high-throughput unbiased TCRBeta sequencing on a population based cohort of 92 DLBCL patients treated with conventional (i.e. non-checkpoint blockade) frontline 'R-CHOP' therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString{trade mark, serif}. The primary endpoints were 4-year overall and progression free survival (OS and PFS). Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (p<0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS of 60.0% (95% C.I. 31.7-79.6%), compared to 79.8% in patients with a low dominant clone (95% C.I. 66.7-88.5%, p=0.005). A highly dominant clone also predicted inferior 4-year PFS of 46.6% (95% C.I. 22.5-76.6%) versus 72.6% (95% C.I. 58.8-82.4%, p=0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV+ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1 and PD-L2 immune checkpoint molecules. Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy.

Monday, September 19, 2016 6:00 AM|PR Newswire Association LLC.|PR Newswire: Medical Pharmaceuticals|Attachments|Labels: MM, clinical trial, NHL

SAN FRANCISCO, Sept. 19, 2016 /PRNewswire/ -- Sutro Biopharma Inc. today announced that it has presented findings from two studies of investigational antibody drug conjugates, or ADCs, that it developed to target CD74, a protein highly expressed in hematologic malignancies.  The...


Friday, September 16, 2016 4:27 PM|John Wiley & Sons|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: Bcl-2, CLL, clinical trial, NHL

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin's Lymphoma

Journal of Clinical Pharmacology, Vol. , No. () pp. -
Venetoclax is a selective BCL‐2 inhibitor that is now approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors as well as low and high fat meals on venetoclax pharmacokinetics. Patients received a once daily venetoclax dose of 20 mg to 1200 mg. Pharmacokinetic parameters were estimated using non‐compartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low fat conditions and the mean terminal phase elimination half‐life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady‐state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low‐fat and high‐fat meals increased venetoclax exposures by approximately 4‐fold, relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60% while weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp‐up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax. This article is protected by copyright. All rights reserved

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, NHL
The purpose of this study is to test the benefit of a chemotherapy drug called romidepsin in patients with T Cell Non-Hodgkin Lymphoma (T NHL) who have undergone autologous transplantation.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: PD-1/PD-L1, lymphoma
This pilot clinical trial studies the side effects of pembrolizumab and combination chemotherapy in treating patients with previously untreated diffuse large B-cell lymphoma. Monoclonal antibodies, such as pembrolizumab and rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab together with combination chemotherapy may be with a better treatment for diffuse large B-cell lymphoma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: CLL, MM, clinical trial, NHL, HL
This phase II trial studies autologous peripheral blood stem cell transplant followed by donor bone marrow transplant in treating patients with high-risk hodgkin lymphoma, non-hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft-versus-host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses steam cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk hodgkin lymphoma, non-hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: PI3K, CLL, clinical trial, NHL
This phase II trial studies how well ibrutinib or idelalisib works in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma that is persistent or has returned (relapsed) after donor stem cell transplant. Ibrutinib and idelalisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, CLL, clinical trial, NHL
This phase I/II trial studies the side effects and best dose of laboratory treated T cells to see how well they work in treating patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia that have come back or have not responded to treatment. T cells that are treated in the laboratory before being given back to the patient may make the body build an immune response to kill cancer cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: NHL
This pilot clinical trial studies ibrutinib in treating patients with transformed indolent (a type of cancer that grows slowly) B-cell non-Hodgkin lymphoma that have returned after a period of improvement or do not respond to treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes (proteins) needed for cell growth.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, NHL
This phase II trial studies how well ixazomib citrate and rituximab work in treating patients with B-cell non-Hodgkin lymphoma that grows slowly (indolent). Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving ixazomib citrate together with rituximab may work better in treating indolent B-cell non-Hodgkin lymphoma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, NHL
A study of PF-05082566, a 4-1BB agonist monoclonal antibody (mAb), in patients with solid tumors or b-cell lymphomas, and in combination with rituximab in patients with CD20 positive Non-Hodgkin's Lymphoma (NHL).
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, NHL
The purpose of this study is to assess overall response rate (ORR, including complete response [CR] and partial response [PR]), of daratumumab in participants with cluster of differentiation 38 plus (CD38+) disease in each non-Hodgkin's lymphoma (a cancer of the lymph nodes [or tissues]-NHL) subtype and to evaluate association between ORR and CD38 expression level in order to determine a threshold for CD38 expression level in each NHL subtype, above which daratumumab activity is enhanced in participants with relapsed or refractory mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma.
This is a signaling study to assess whether nivolumab in combination with brentuximab vedotin is safe and effective in certain subtypes of non-hodgkin lymphomas.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, NHL
The study will examine the safety profile of SGN-CD19B administered as a single agent. The main purpose of the study is to estimate the highest dose that does not cause unacceptable side effects of SGN-CD19B in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) subtypes of diffuse large B-cell lymphoma (DLBCL) and Grade 3 follicular lymphoma (FL3). Additionally, the pharmacokinetic profile and antitumor activity of SGN-CD19B will be assessed.
This randomized, multicenter, open-label study will evaluate the safety and the efficacy of DCDT2980S in combination with MabThera/Rituxan (rituximab) or DCDS4501A in combination with MabThera/Rituxan in patients with relapsed or refractory follicular non-Hodgkin's lymphoma and relapsed/refractory diffuse large B-cell lymphoma.
Wednesday, September 14, 2016 1:49 PM|Medscape Medical News Headlines|Labels: NHL
Standardized CD19-specific chimeric antigen receptor (CAR)-modified T cells along with chemotherapy can more effectively guide treatment and improve response in patients with relapsed and refractory B cell non-Hodgkin's lymphoma, according to a new study.
Reuters Health Information
Tuesday, September 13, 2016 8:19 PM|Ting Zhang, Shang Xie, Jin-Hong Zhu, Qi-Wen Li, Jing He, Ai-Ping Zeng|Journal of Cancer (RSS 2.0)|Labels: NHL, IL

Numerous studies have investigated the association of IL10 -819C>T and -592C>A polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility, and yet reported conflicting results. With this in mind, we performed the current meta-analysis with an aim to verify actual causative variants underlying lymphomagenesis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Moreover, to explore the biological function of these polymorphisms, we also performed genotype-based mRNA expression analysis using online database derived from 270 subjects within three ethnicities. The final analysis included 11 studies with a total of 5859 NHL cases and 6893 controls for the IL10 -819C>T polymorphism, and 11 studies with 6277 cases and 7350 controls for the IL10 -592C>A polymorphism. No significant association was observed for these two polymorphisms in either the overall analysis or the stratification analyses by ethnicity and source of controls. Nevertheless, stratification analyses demonstrated a significant decreased risk associated with the IL10 -819C>T polymorphism (homozygous: OR=0.81, 95% CI=0.66-0.99, and recessive model: OR=0.80, 95%CI=0.65-0.98) and IL10 -592C>A polymorphism (homozygous: OR=0.80, 95% CI=0.66-0.99, and recessive model: OR=0.80, 95%CI=0.66-0.97) among patients with diffuse large B-cell lymphoma (DLBCL). Despite some limitations, this meta-analysis indicates that polymorphisms in IL10 gene may contribute to DLBCL susceptibility.

Tuesday, September 13, 2016 11:46 AM|Onclive Articles|Labels: NHL
Chimeric antigen receptor T-cells offer highly effective therapy for patients with minimal residual disease or bulky disease in both aggressive and indolent B-cell non-Hodgkin lymphomas.
Thursday, September 8, 2016 10:00 AM|Lai, J., Tan, W. J., Too, C. T., Choo, J. A. L., Wong, L. H., Mustafa, F. B., Srinivasan, N., Lim, A. P. C., Zhong, Y., Gascoigne, N. R. J., Hanson, B. J., Chan, S. H., Chen, J., MacAry, P. A.|Blood current issue|Labels: lymphoma

Epstein-Barr virus (EBV) is an oncovirus associated with several human malignancies including posttransplant lymphoproliferative disease in immunosuppressed patients. We show here that anti-EBV T-cell receptor–like monoclonal antibodies (TCR-like mAbs) E1, L1, and L2 bound to their respective HLA-A*0201-restricted EBV peptides EBNA1562-570, LMP1125-133, and LMP2A426-434 with high affinities and specificities. These mAbs recognized endogenously presented targets on EBV B lymphoblastoid cell lines (BLCLs), but not peripheral blood mononuclear cells, from which they were derived. Furthermore, these mAbs displayed similar binding activities on several BLCLs, despite inherent heterogeneity between different donor samples. A single weekly administration of the naked mAbs reduced splenomegaly, liver tumor spots, and tumor burden in BLCL-engrafted immunodeficient NOD-SCID/Il2rg–/– mice. In particular, mice that were treated with the E1 mAb displayed a delayed weight loss and significantly prolonged survival. In vitro, these TCR-like mAbs induced early apoptosis of BLCLs, thereby enhancing their Fc-dependent phagocytic uptake by macrophages. These data provide evidence for TCR-like mAbs as potential therapeutic modalities to target EBV-associated diseases.

Thursday, September 8, 2016 10:00 AM|K.|JournalTOCs API - Blood (22 articles)|Labels: PD-1/PD-L1, leukemia, lymphoma

PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma
Miyoshi, H Kiyasu, J, Kato, T, Yoshida, N, Shimono, J, Yokoyama, S, Taniguchi, H, Sasaki, Y, Kurita, D, Kawamoto, K, Kato, K, Imaizumi, Y, Seto, M, Ohshima, K.
Blood, Vol. 128, No. 10 (2016) pp. 1374 - 1381
Programmed cell death ligand 1 (PD-L1) is expressed on both tumor and tumor-infiltrating nonmalignant cells in lymphoid malignancies. The programmed cell death 1 (PD-1)/PD-L1 pathway suppresses host antitumor responses, although little is known about the significance of PD-1/PD-L1 expression in the tumor microenvironment. To investigate the clinicopathological impact of PD-L1 expression in adult T-cell leukemia/lymphoma (ATLL), we performed PD-L1 immunostaining in 135 ATLL biopsy samples. We observed 2 main groups: 1 had clear PD-L1 expression in lymphoma cells (nPD-L1(+), 7.4% of patients), and the other showed minimal expression in lymphoma cells (nPD-L1(&ndash;), 92.6%). Within the nPD-L1(&ndash;) group, 2 subsets emerged: the first displayed abundant PD-L1 expression in nonmalignant stromal cells of the tumor microenvironment (miPD-L1(+), 58.5%) and the second group did not express PD-L1 in any cell (PD-L1(&ndash;), 34.1%). nPD-L1(+) ATLL (median survival time [MST] 7.5 months, 95% CI [0.4-22.3]) had inferior overall survival (OS) compared with nPD-L1(&ndash;) ATLL (MST 14.5 months, 95% CI [10.1-20.0]) (P = .0085). Among nPD-L1(&ndash;) ATLL, miPD-L1(+) ATLL (MST 18.6 months, 95% CI [11.0-38.5]) showed superior OS compared with PD-L1(&ndash;) ATLL (MST 10.2 months, 95% CI [8.0-14.7]) (P = .0029). The expression of nPD-L1 and miPD-L1 maintained prognostic value for OS in multivariate analysis (P = .0322 and P = .0014, respectively). This is the first report describing the clinicopathological features and outcomes of PD-L1 expression in ATLL. More detailed studies will disclose clinical and biological significance of PD-L1 expression in ATLL.

Wednesday, September 7, 2016 7:52 PM|Cancer News -- ScienceDaily|Labels: clinical trial, NHL
Data has been released from an early-phase study of patients with advanced non-Hodgkin lymphoma (NHL) who received JCAR014, a Chimeric Antigen Receptor (CAR) T cell treatment, and chemotherapy. CAR T cells are made from a patient's own immune cells that are then genetically engineered to better identify and kill cancer cells.
Friday, September 2, 2016 6:35 AM|Ying, Z. X., Jin, M., Peterson, L. F., Bernard, D., Saiya-Cork, K., Yildiz, M., Wang, S., Kaminski, M. S., Chang, A. E., Klionsky, D. J., Malek, S. N.|Clinical Cancer Research Online First Articles|Labels: mTOR, lymphoma

Purpose: This study was performed to further our understanding of the biological and genetic basis of follicular lymphoma and to identify potential novel therapy targets.

Experimental Design: We analyzed previously generated whole exome sequencing data of 23 follicular lymphoma cases and one transformed follicular lymphoma case and expanded findings to a combined total of 125 follicular lymphoma/3 transformed follicular lymphoma. We modeled the three-dimensional location of RRAGC-associated hotspot mutations. We performed functional studies on novel RRAGC mutants in stable retrovirally transduced HEK293T cells, stable lentivirally transduced lymphoma cell lines, and in Saccharomyces cerevisiae.

Results: We report recurrent mutations, including multiple amino acid hotspots, in the small G-protein RRAGC, which is part of a protein complex that signals intracellular amino acid concentrations to MTOR, in 9.4% of follicular lymphoma cases. Mutations in RRAGC distinctly clustered on one protein surface area surrounding the GTP/GDP–binding sites. Mutated RRAGC proteins demonstrated increased binding to RPTOR (raptor) and substantially decreased interactions with the product of the tumor suppressor gene FLCN (folliculin). In stable retrovirally transfected 293T cells, cultured in the presence or absence of leucine, multiple RRAGC mutations demonstrated elevated MTOR activation as evidenced by increased RPS6KB/S6-kinase phosphorylation. Similar activation phenotypes were uncovered in yeast engineered to express mutations in the RRAGC homolog Gtr2 and in multiple lymphoma cell lines expressing HA-tagged RRAGC-mutant proteins.

Conclusions: Our discovery of activating mutations in RRAGC in approximately 10% of follicular lymphoma provides the mechanistic rationale to study mutational MTOR activation and MTOR inhibition as a potential novel actionable therapeutic target in follicular lymphoma. Clin Cancer Res; 1–11. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|Hogg, S. J., Newbold, A., Vervoort, S. J., Cluse, L. A., Martin, B. P., Gregory, G. P., Lefebure, M., Vidacs, E., Tothill, R. W., Bradner, J. E., Shortt, J., Johnstone, R. W.|Molecular Cancer Therapeutics current issue|Labels: Bcl-2, lymphoma

Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Mol Cancer Ther; 15(9); 2030–41. ©2016 AACR.

Thursday, September 1, 2016 10:01 AM|Chong, L. C., Twa, D. D. W., Mottok, A., Ben-Neriah, S., Woolcock, B. W., Zhao, Y., Savage, K. J., Marra, M. A., Scott, D. W., Gascoyne, R. D., Morin, R. D., Mungall, A. J., Steidl, C.|Blood LYMPHOID NEOPLASIA|Labels: PD-1/PD-L1, NHL

Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24.1; harboring PDL1/CD274 and PDL2/PDCD1LG2). We describe 36 novel PDL SRs, including 17 intrachromosomal events (inversions, duplications, deletions) and 19 translocations involving BZRAP-AS1, CD44, GET4, IL4R, KIAA0226L, MID1, RCC1, PTPN1 and segments of the immunoglobulin loci. Moreover, analysis of the precise chromosomal breakpoints reveals 2 distinct cluster breakpoint regions (CBRs) within either CD274 (CBR1) or PDCD1LG2 (CBR2). To determine the phenotypic consequences of these SRs, we performed immunohistochemistry for CD274 and PDCD1LG2 on primary pretreatment biopsies and found that PDL SRs are significantly associated with PDL protein expression. Finally, stable ectopic expression of wild-type PDCD1LG2 and the PDCD1LG2-IGHV7-81 fusion showed, in coculture, significantly reduced T-cell activation. Taken together, our data demonstrate the complementary utility of fluorescence in situ hybridization and capture sequencing approaches and provide a classification scheme for PDL SRs with implications for future studies using PDL immune-checkpoint inhibitors in B-cell lymphomas.

Thursday, September 1, 2016 7:48 AM|Blakkisrud, J., Londalen, A., Dahle, J., Turner, S., Holte, H., Kolstad, A., Stokke, C.|JNM Ahead of Print|Labels: clinical trial, NHL

Red bone marrow (RM) is often the primary organ at risk in radioimmunotherapy; irradiation of marrow may induce short and long term hematological toxicity. 177Lu-lilotomab satetraxetan is a novel anti-CD37 antibody-radionuclide-conjugate (ARC) currently in phase 1/2a. Two pre-dosing regimens have been investigated, one with 40 mg unlabeled lilotomab antibody (arm 1) and one without (arm 2). The aim of this work was to compare RM absorbed doses for the two arms and to correlate absorbed doses with hematological toxicity. Methods: Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin’s lymphoma were included for RM dosimetry. Hybrid Single Photon Emission Computed Tomography (SPECT) and Computed Tomography (CT) images were used to estimate activity concentration in the RM of lumbar L2-L4. Pharmacokinetic parameters were calculated after measurement of 177Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results: The mean absorbed doses to RM were 0.94 mGy/MBq for arm 1 (lilotomab+) and 1.53 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arm 1 and 2 (student t-test, P = 0.02). Total RM absorbed doses ranged from 67 to 124 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve (AUCblood) was higher with lilotomab pre-dosing compared to without pre-dosing (P = 0.001), while the volume of distribution and the clearance of 177Lu- lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with Grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with Grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging based, method underestimated the RM dose and did not show any correlation with toxicity. Conclusion: Pre-dosing with lilotomab reduces the RM absorbed dose for 177Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematological toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images.

Wednesday, August 31, 2016 11:00 PM|O’Malley, Dennis P.; Fedoriw, Yuri; Weiss, Lawrence M.|Applied Immunohistochemistry & Molecular Morphology - Current Issue|Labels: NHL, HL
imageBackground: The diagnosis of “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma” represents an indeterminate or equivocal decision in relation to management because there remain differences in the management of Hodgkin and non-Hodgkin lymphomas. We developed a scoring system for this group of lymphomas using markers that are traditionally associated with diagnosis of classical Hodgkin lymphoma (CHL) and immunophenotypic markers associated with the “B-cell program” expressed in normal B cells. Materials and Methods: This system emphasized known criteria used to diagnose CHL that are rare in B-cell lymphoma (BCL) [CD15+, CD45−, CD20− or weak/variable, PAX5+ (weak or moderate), CD79a−, OCT-2−/BOB.1− or OCT-2+/BOB.1− or OCT-2−/BOB.1+, EBV+] versus findings that are common in BCL in contrast to CHL (CD15−, CD45+, CD20+ strong, PAX5+ strong, CD79a+, OCT-2+/BOB.1+, EBV−). After a preliminary test trial, MUM1 staining was also added. Results associated with CHL were assigned a score of +1 and score associated with BCL were assigned a score of −1. In the final grading system, a maximum score of +6 is possible for CHL and −6 for BCL. Results: An initial series of 38 cases was evaluated using a proprietary system that allows analysis of multiple stains on individual cells in a single section. An additional 23 cases were evaluated with results blinded until after scoring was performed. In general there was high concordance among cases originally diagnosed as CHL with high scores (score +4 to +6). Cases originally diagnosed as gray zone lymphomas exhibited a broader range of scores (+3 to −4). Cases of BCLs had low scores (−3 to −6). Conclusions: The primary goal of this study was to create a scoring system that allows a cumulative quantitative measure of immunohistochemical markers, based on expected results to compare cases that might have overlapping features. In most cases, scores that trend to one extreme or another are likely representative of CHL or BCL and do not lie in the gray zone. This scoring system allows for practical resolution of many borderline cases and provide some guidance in difficult cases.
Sunday, August 14, 2016 10:05 PM|Le, K.–S., Thibult, M.–L., Just–Landi, S., Pastor, S., Gondois–Rey, F., Granȷeaud, S., Broussais, F., Bouabdallah, R., Colisson, R., Caux, C., Menetrier–Caux, C., Leroux, D., Xerri, L., Olive, D.|Cancer Research recent issues|Labels: NHL, HL
The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor-infiltrating regulatory T cells (Treg). The mechanism of Treg enrichment in FL and their impact on malignant FL B cells remains to be elucidated. We analyzed 46 fresh lymph node biopsy samples, including FL (n = 20), diffuse large B-cell lymphoma (n = 10), classical Hodgkin lymphoma (n = 9), and reactive lymphadenitis (n = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25highCD127low/neg Tregs in FL tissues. These Tregs comprised activated ICOS+ Tregs that were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL in vitro and to generate CD25highFoxP3high Tregs expressing ICOS. Treg generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interactions between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. Our results highlight a key role for Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy for FL treatment. Cancer Res; 76(16); 4648–60. ©2016 AACR.
Sunday, August 14, 2016 10:05 PM|Ai, W., Yang, Y.-C. Y., Afghani, S., Gao, H., Pincus, L. P., Wang, L. W., Rakhshandhroo, T., Balassanian, R., Rubenstein, J., Gill, R., McCormick, F.|Clinical Cancer Research recent issues|Labels: lymphoma

Introduction: Cutaneous T cell lymphomas (CTCL) represent a heterogeneous group of diseases. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes of CTCL. Discovery of new therapeutic targets in T cell lymphomas has been hampered by lack of appropriate discovery platforms. Few T cell lymphoma cell lines are available; and it is likely that they have departed significantly from the original disease through long-term in vitro cultivation.

Objectives: To develop patient-derived T cell lymphoma mouse xenograft models (PDX) that recapitulate the clinical presentation of human diseases and to establish a drug discovery platform using these PDX models.

Materials and Methods: To establish PDX models for MF and SS, we injected lymphocytes obtained from patients into an NSG mouse (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) either subcutaneously or intravenously. Next, we investigated whether tumor derived plasma cell-free DNA can serve as a surrogate for disease burden in PDX. We first established this method in xenografts bearing a subcutaneous tumor derived from a MF cell line. We measured tumor volume by manual caliper methods twice weekly and simultaneously, we collected plasma from these mice. We measured human-actin-specific cell-free DNA concentrations in the plasma by qPCR and examined whether they can correlate with the tumor volume measured by the caliber method. After validated this method in xenografts established with a MF cell line, we examined this method in PDX. To this end, we measured human-actin-specific cell-free DNA concentrations in PDX plasma at various time points post-inoculation and investigated whether they correlated with tumor progression in PDX.

Results: Three weeks after inoculation of patient-derived malignant lymphocytes, the MF PDX mouse developed clinical syndrome of MF with erythematous, scaly skin lesions and alopecia. Necropsy revealed lymphocyte infiltration in the skin, spleen, liver and lungs, resembling the disease distribution of MF in humans. The erythematous skin lesions showed atypical lymphocyte infiltration in the epidermis, a diagnostic hallmark for MF. Additionally, immunohistochemistry staining reveled malignant cells in the epidermis expressed CD3 and CD4 without co-expression of CD7, which is identical to those of the donor patient's. Furthermore, we analyzed T cell receptor (TCR) clonality by PCR and demonstrated a clonal T-cell population in both patient and mouse specimens with similar amplified peaks, consistent with successful xenograft.

Similarly, the PDX mouse for SS developed the clinical syndromes with skin rashes, alopecia and was found to have Sezary cells in the blood, a diagnostic hallmark for SS. Malignant cells isolated from the spleen of a SS PDX animal had the same immunophenotype and TCR clonality as that of the donor patients, indicating successful xenografts. Importantly, we were able to passage malignant cells from one generation of PDX to the next while maintaining the clinical presentation of the disease.

Finally, we were able to demonstrate that in cell-line derived xenograft mice bearing subcutaneous tumors, human-actin-specific cell-free DNA concentrations in the plasma correlated with tumor volume assessed by manual caliber measurements. Next, we extended these results to MF/SS PDX, and were able to correlate human-actin cell-free DNA concentrations with tumor progression in in these mice.

Conclusion: We established PDX models that recapitulate the clinic syndrome of MF and SS with characteristic skin, nodes and blood involvement by the malignant cells. Additionally, we demonstrated that tumor-specific cell-free DNA concentration can be used as a surrogate for tumor burden in PDX. Together, our results demonstrated that we can establish a drug discovery platform using clinically relevant PDX models for T cell lymphomas.

Citation Format: Wei Ai, Yen-Chen Yang Yang, Shervin Afghani, Huaxin Gao, Laura Pincus Pincus, Linlin Wang Wang, Taha Rakhshandhroo, Ronald Balassanian, James Rubenstein, Ryan Gill, Frank McCormick. Development of a drug discovery platform using clinically relevant patient-derived xenograft models for cutaneous T cell lymphomas. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A06.

Friday, August 12, 2016 12:58 PM|Ogura, M., Tobinai, K., Hatake, K., Davies, A., Crump, M., Ananthakrishnan, R., Ishibashi, T., Paccagnella, M. L., Boni, J., Vandendries, E., MacDonald, D.|Clinical Cancer Research Online First Articles|Labels: clinical trial, NHL

Purpose: To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL).

Experimental Design: In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of <33% in cycle 1 and <33% of patients discontinuing before cycle 3 due to treatment-related adverse events (AEs). Part 3 (n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP.

Results: The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2. The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21).

Conclusions: Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 1–10. ©2016 AACR.

Thursday, August 4, 2016 6:57 AM|Blakkisrud, J., Londalen, A., Martinsen, A. C. T., Dahle, J., Holtedahl, J. E., Bach-Gansmo, T., Holte, H., Kolstad, A., Stokke, C.|JNM Ahead of Print|Labels: clinical trial, NHL

177Lu-lilotomab satetraxetan is a novel antibody radionuclide conjugate (ARC) currently tested in a phase 1/2a first-in-human dosage escalation trial for patients with relapsed CD37+ indolent non-Hodgkin’s lymphoma. The aim of this work was to develop dosimetric methods and calculate tumor absorbed radiation doses for patients treated with 177Lu-lilotomab satetraxetan. Methods: Patients were treated at escalating injected activities (10, 15 and 20 MBq/kg) of 177Lu-lilotomab satetraxetan and with different pre-dosing; with or without 40 mg unlabeled lilotomab. Eight patients were included for the tumor dosimetry study. Tumor radioactivity concentrations were calculated from Single Photon Emission Computer Tomography (SPECT) acquisitions at multiple time points, and tumor masses were delineated from corresponding Computer Tomography (CT) scans. Tumor absorbed doses were then calculated using the OLINDA sphere model. To perform voxel dosimetry, the SPECT/CT data and an in-house developed MATLAB program were combined to investigate the dose rate homogeneity. Results: Twenty-six tumors in 8 patients were ascribed a mean tumor absorbed dose. Absorbed doses ranged from 75 cGy to 794 cGy with a median of 268 cGy across different dosage levels and different pre-dosing. A significant correlation between the dosage level and tumor absorbed dose was found. Twenty-one tumors were included for voxel dosimetry, and parameters describing dose-volume coverage calculated. The investigation of intra-tumor voxel doses indicates that mean tumor dose is correlated to these parameters. Conclusion: Tumor absorbed doses for patients treated with 177Lu-lilotomab satetraxetan are comparable to doses reported for other radioimmunotherapy compounds. Although the inter-tumor variability was considerable, a correlation between tumor dose and patient dosage level was found. Our results indicate that mean dose may be used as the sole dosimetric parameter on the lesion level.

Sunday, July 31, 2016 10:05 PM|Morfoisse, F., Tatin, F., Hantelys, F., Adoue, A., Helfer, A.-C., Cassant-Sourdy, S., Pujol, F., Gomez-Brouchet, A., Ligat, L., Lopez, F., Pyronnet, S., Courty, J., Guillermet-Guibert, J., Marzi, S., Schneider, R. J., Prats, A.-C., Garmy-Susini, B. H.|Cancer Research recent issues|Labels: HSP, VEGF, lymphoma
The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5′ UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5′UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394–405. ©2016 AACR.
Friday, July 1, 2016 9:33 AM|Vallois, D., Dobay, M. P. D., Morin, R. D., Lemonnier, F., Missiaglia, E., Juilland, M., Iwaszkiewicz, J., Fataccioli, V., Bisig, B., Roberti, A., Grewal, J., Bruneau, J., Fabiani, B., Martin, A., Bonnet, C., Michielin, O., Jais, J.-P., Figeac, M., Bernard, O. A., Delorenzi, M., Haioun, C., Tournilhac, O., Thome, M., Gascoyne, R. D., Gaulard, P., de Leval, L.|BLOOD First Edition Papers|Labels: lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCL) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n=72) or other TFH-derived PTCL (n=13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51/85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1(6%) and GTF2I (6%). By in vitro assays in transfected cells, we demonstrated that 9/10 PLCG1 and 3/3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-kB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed , the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas.

Thursday, June 30, 2016 11:00 PM|Juilland, Mélanie; Thome, Margot|Current Opinion in Hematology - Most Popular Articles|Labels: leukemia, lymphoma
imagePurpose of review: The CARMA1/BCL10/MALT1 (CBM) complex is a multimeric signaling complex controlling several important aspects of lymphocyte activation. Gain-of-function mutations in the genes encoding CBM proteins or their upstream regulators are associated with lymphoid malignancies, whereas loss-of-function mutations lead to immunodeficiency. This review reports on recent findings advancing our understanding of how CBM proteins contribute to malignant and nonmalignant hematological diseases in humans. Recent findings: Somatic gain-of-function mutations of CARMA1 (also known as CARD11), originally described for patients with diffuse large B-cell lymphoma, have recently been identified in patients with acute T-cell leukemia/lymphoma or Sézary syndrome, and in patients with a B-cell lymphoproliferative disorder known as BENTA. Loss-of-function mutations of CARMA1 and MALT1, on the other hand, have been reported to underlie human immunodeficiency. Lately, it has become clear that CBM-dependent signaling promotes lymphomagenesis not only via NF-κB activation, but also via the AP-1 family of transcription factors. The identification of new substrates of the protease MALT1 and the characterization of mice expressing catalytically inactive MALT1 have deepened our understanding of how the CBM complex controls lymphocyte proliferation through promoting MALT1's protease activity. Summary: The discovery of CARMA1 gain-of-function mutations in T-cell malignancies and BENTA patients, as well as the association of CARMA1 and MALT1 mutations with human immunodeficiency highlight the importance of CBM proteins in the regulation of lymphocyte functions, and suggest that the protease activity of MALT1 might be targeted to treat specific lymphoid malignancies.
Monday, June 27, 2016 10:52 AM|SCHMEEL, L. C., SCHMEEL, F. C., SCHMIDT-WOLF, I. G. H.|Anticancer Research recent issues|Labels: lymphoma, MM

Background/Aim: Multiple myeloma (MM), a hematological malignancy of monoclonal B-lymphocytes, remains largely incurable and novel treatments are urgently required. Aberrant activation of wingless-related integration site (WNT)/β-catenin signaling has been demonstrated in both lymphoma and MM, rendering its signaling molecules attractive for the development of new targeted-therapies. Clofibrate has proven anticarcinogenic effects attributed to peroxisome proliferator-activated receptor alpha (PPARα) agonism, also affecting WNT-associated signaling molecules. Materials and Methods: The antitumor apoptotic effect of clofibrate at doses ranging from 0.1-600 μM was investigated on four human and one murine myeloma cell lines, as well as in two human lymphoma cell lines, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay. Results: Clofibrate significantly reduced cell viability in all tested myeloma and lymphoma cell lines in a dose-dependent manner, while healthy cells were hardly affected. Conclusion: Given the known safety profile and induction of apoptosis at low effective doses, our data warrant further investigation of clofibrate as a novel therapy agent in MM.

Tuesday, May 31, 2016 10:05 PM|Rufener, G. A., Press, O. W., Olsen, P., Lee, S. Y., Jensen, M. C., Gopal, A. K., Pender, B., Budde, L. E., Rossow, J. K., Green, D. J., Maloney, D. G., Riddell, S. R., Till, B. G.|Cancer Immunology Research recent issues|Labels: NHL

CD20 is an attractive immunotherapy target for B-cell non-Hodgkin lymphomas, and adoptive transfer of T cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD20 is a promising strategy. A theoretical limitation is that residual serum rituximab might block CAR binding to CD20 and thereby impede T cell–mediated anti-lymphoma responses. The activity of CD20 CAR-modified T cells in the presence of various concentrations of rituximab was tested in vitro and in vivo. CAR-binding sites on CD20+ tumor cells were blocked by rituximab in a dose-dependent fashion, although at 37°C blockade was incomplete at concentrations up to 200 μg/mL. T cells with CD20 CARs also exhibited modest dose-dependent reductions in cytokine secretion and cytotoxicity, but not proliferation, against lymphoma cell lines. At rituximab concentrations of 100 μg/mL, CAR T cells retained ≥50% of baseline activity against targets with high CD20 expression, but were more strongly inhibited when target cells expressed low CD20. In a murine xenograft model using a rituximab-refractory lymphoma cell line, rituximab did not impair CAR T-cell activity, and tumors were eradicated in >85% of mice. Clinical residual rituximab serum concentrations were measured in 103 lymphoma patients after rituximab therapy, with the median level found to be only 38 μg/mL (interquartile range, 19–72 μg/mL). Thus, despite modest functional impairment in vitro, the in vivo activity of CD20-targeted CAR T cells remains intact at clinically relevant levels of rituximab, making use of these T cells clinically feasible. Cancer Immunol Res; 4(6); 509–19. ©2016 AACR.

See related Spotlight by Sadelain, p. 473.

NORTH CHICAGO, Ill., May 9, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) updated the IMBRUVICA® (ibrutinib) Prescribing Information (PI) to include new data from two Phase 3 trials supporting its expanded use in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).[1] The label now includes overall survival (OS) results in previously untreated CLL/SLL patients from the Phase 3 RESONATETM-2 (PCYC-1115) trial.

Tuesday, April 19, 2016 3:19 AM|oslocancer|investoropportunities – Oslo Cancer Cluster|Labels: clinical trial, NHL

Nordic Nanovector, a biotechnology company focusing on the development of novel targeted therapeutics in haematology and oncology, announces updated results of its ongoing Phase 1/2 study with Betalutin® in relapsed non-Hodgkin lymphoma (NHL) patients.

 

Betalutin® was generally well tolerated and showed a 63.2% Overall Response Rate (ORR) including 31.6% Complete Response (CR) among 21 patients with previously treated CD37+ NHL patients. This data include two additional patients whose efficacy data has become available following submission of the abstract.

The data being presented in the poster at AACR are from the ongoing Phase 1/2 single dose, open label, dose-finding study investigating three dose levels of Betalutin® in 21 patients with relapsed CD37+ NHL, 19 with Follicular Lymphoma and two with Mantle Cell Lymphoma, previously treated with one to eight treatment regimens. One patient recruited into the study had transformed disease and was excluded from the response rate calculation.

The updated data in the poster confirm the favourable safety profile of Betalutin® and its promising efficacy as a single agent in patients who have failed many prior regimens, characterised by a sustained duration of response.

 

Key conclusions from the update include:

• Betalutin® is well tolerated, with a predictable and manageable safety profile: most adverse events are haematological in nature, and all have been transient and reversible

• Betalutin® delivers a highly favourable response rate (best response) in this heavily pre-treated patient population (Overall Response Rate 63.2% and Complete Response 31.6%)

• The median Duration of Response (DoR) has not yet been reached. Clinical responses observed are sustained, with DoR exceeding 12 months in most responders

Luigi Costa, Nordic Nanovector’s Chief Executive Officer, commented: “These new data continue to confirm Betalutin’s efficacy potential and favourable safety profile. In addition, Duration of Response (DOR) in patients who responded to treatment with Betalutin® has further improved confirming the product’s potential to become a significant treatment of NHL. These encouraging results support the continued clinical development of Betalutin®. We are pleased with the progress that we are making in executing our revised Phase 1/2 study and look forward to confirming the optimal dosing regimen for the pivotal Phase 2 study, PARADIGME, expected in Q1 2017.”

Wednesday, January 13, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: NHL
Cell fate decisions, such as whether to self-renew or to differentiate, are regulated in large part by epigenetic mechanisms. Dysregulation of epigenetic machinery, such as histone methyltransferases, in certain progenitor cell contexts can promote increased self-renewal, decreased differentiation and ultimately oncogenesis. For example, EZH2, the histone H3K27 methyltransferase, has been implicated in a diverse set of cancer indications. As the catalytic subunit of the polycomb repressive complex 2 (PRC2), EZH2 is responsible for the initiation of gene silencing during embryonic development and in maintenance of pluripotency in certain adult stem cell settings. On the other hand, EZH2 activity is downregulated in the majority of adult somatic cells to facilitate the expression of lineage-...