Therapy For T-cell Lymphoma Research Articles

A Highly Sensitive Nonextraction-Assisted HPLC Method with Fluorescence Detection for Quantification of Duvelisib in Plasma Samples and its Application to Pharmacokinetic Study in Rats.

BackgroundDuvelisib (DUV) is a new oral phosphoinositide-3-kinase (PI3K)-δ and PI3K-γ inhibitor. It has been recently granted an accelerated approval for treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). It is also effective in therapy of T-cell lymphoma, solid tumors, and non-Hodgkin’s lymphoma. In literature, there is no method valid for quantitation of DUV in human plasma for its therapeutic monitoring and pharmacokinetic studies.PurposeThe purpose of this study is the establishment of a highly sensitive HPLC method with fluorescence detection for quantitation of DUV in plasma for its therapeutic monitoring and pharmacokinetic studies of DUV.MethodsThe resolution of DUV and the internal standard (IS) olaparib (OLA) was achieved on Nucleosil CN column, with a mobile phase composed of acetonitrile:water (25:75, v/v) at a flow rate of 1.7 mL min–1. The fluorescence of both DUV and OLA was detected at 410 nm after excitation at 280 nm. The method was validated according to the guidelines of bioanalytical method validation.ResultsThe method was linear in the range of 5–100 ng mL–1, and its limit of detection (LOD) and limit of quantitation (LOQ) were 2.12 ng mL–1 and 7 ng mL–1, respectively. The precisions of the method were ≤ 8.26%, and its accuracies were ≥ 95.32%. All the other validation parameters were satisfactory. The proposed method was successfully employed to the investigation of the pharmacokinetic profile of DUV in rats following a 25 mg/kg single dose of oral administration.ConclusionThe method is characterized with high sensitivity, accuracy, simple sample pretreatment, rapidity, eco-friendly as it consumes low volumes of organic solvent in the mobile phase and has high analysis throughput as its run time was short (~ 10 min).

Abstract IA17: CAR T cells for T-cell lymphoma

Abstract Development of CAR T-cell therapies for T-cell lymphoma has been hampered by a limited range of targetable antigens. Shared expression of most T-lineage antigens between malignant and normal T cells promotes fratricide of CAR T cells and increases the risk of T-cell aplasia. We developed a CAR targeting CD5, a pan-T cell antigen commonly expressed in T-cell lymphoma. CD5 CAR T cells evade fratricide by rapidly downregulating CD5 protein expression and retain high cytotoxicity against T-cell lymphoma. An ongoing phase I clinical trial demonstrates curative potential of autologous CD5 CAR T cells in patients with peripheral T-cell lymphoma. CD5 CAR T-cell infusions were well tolerated and did not produce prolonged ablation of endogenous T cells. Other CAR T cell-based approaches for T-cell lymphoma will also be discussed. Citation Format: Maksim Mamonkin. CAR T cells for T-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA17.

Artemisinin improves the efficiency of anti-PD-L1 therapy in T-cell lymphoma

Abstract Although immune checkpoint inhibitors targeting PD-1/PD-L1 pathway have obtained favorable results in T-cell lymphoma clinical trials, the majority of T-cell lymphoma patients appear to be minimally sensitive to PD-1/PD-L1 blockade. The malaria drug artemisinin has previously been identified as a potent anti-lymphoma drug and was tested as a combination treatment with anti-PD-L1 antibody in T-cell lymphoma. In this study, we found that artemisinin caused ferroptosis by up-regulating ROS levels and increasing misfolded protein in T-cell lymphoma via down-regulating ERK pathway. As expected, artemisinin or anti-PD-L1 monoclonal antibody therapy alone could inhibit EL4 T-cell lymphoma growth in Balb/c nude mice. Interestingly, combination therapy with artemisinin greatly improved the anti-lymphoma efficiency of anti-PD-L1 monoclonal antibody. These results provide further rationale for the combination therapy of artemisinin with anti-PD-L1 antibody in preclinical settings. This work was supported by the National Natural Science Foundation of China (Grant 81501356 and Grant 81373112), the Shenzhen Basic Science Research Project (Grants JCYJ20170413153158716 and JCYJ20170818164619194), Nanshan pilot team project (LHTD20160004), Start-up funding (CYZZ20180307154657923), Guangdong Provincial Research Award for Thousand Talents Program Scholars.

Histone Deacetylases (HDACs) Guided Novel Therapies for T-cell lymphomas.

T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas.

T-cell lymphomas associated gene expression signature: Bioinformatics analysis based on gene expression Omnibus.

Due to the low incidence and the heterogeneity of subtypes, the biological process of T-cell lymphomas is largely unknown. Although many genes have been detected in T-cell lymphomas, the role of these genes in biological process of T-cell lymphomas was not further analyzed. Two qualified datasets were downloaded from Gene Expression Omnibus database. The biological functions of differentially expressed genes were evaluated by gene ontology enrichment and KEGG pathway analysis. The network for intersection genes was constructed by the cytoscape v3.0 software. Kaplan-Meier survival curves and log-rank test were employed to assess the association between differentially expressed genes and clinical characters. The intersection mRNAs were proved to be associated with fundamental processes of T-cell lymphoma cells. These intersection mRNAs were involved in the activation of some cancer-related pathways, including PI3K/AKT, Ras, JAK-STAT, and NF-kappa B signaling pathway. PDGFRA, CXCL12, and CCL19 were the most significant central genes in the signal-net analysis. The results of survival analysis are not entirely credible. Our findings uncovered aberrantly expressed genes and a complex RNA signal network in T-cell lymphomas and indicated cancer-related pathways involved in disease initiation and progression, providing a new insight for biotargeted therapy in T-cell lymphomas.

Proteasome and HDAC Inhibitor Therapy in T-Cell Lymphoma (TCL) and Hodgkin Lymphoma (HL): Nuclear Factor Erythroid 2 like 2 (NRF2)-Dependent Cell Death and Function

Background: Activation of NF-kB pathways are a hallmark feature of TCL and HL, making proteasome inhibition an attractive therapeutic target. Previous studies have demonstrated prominent in vivo efficacy of ixazomib, an oral proteasome inhibitor for both TCL and HL. Among the common significantly regulated genes identified via systems biology approach include upregulation of genes encoding for ubiquitin proteasome subunits (Ravi et al. Cancer Res. 2016). Further combination studies with HDACi belinostat were synergistic in Jurkat, HH and L428 cell lines, and NRF2 was discovered as mediator of proteasome gene expression. We hypothesized that HDACi abrogates NRF2 mediated proteasome recovery leading to synergistic effects on cell viability in combination with ixazomib.Methods: Global transcriptome analysis was performed on RNA isolated from multiple cell lines include TCL (Jurkat) and HL (L540, L428) treated with ixazomib and control, as well as Jurkat cell lines treated with single agent ixazomib, belinostat and combination. Significant genes were determined by applying a one-way ANOVA with an adjusted Bonferroni correction for a false discovery rate (FDR) < 0.05. Further pathway analysis from significant genes was performed by using a fold change greater than ±1.2 comparing all samples to each other and observing pathway relationships using Ingenuity Pathway Analysis. Gene Set Enrichment Analysis was performed with FDR <0.05 for functional analysis. Proteasome-Glo cell based assay was used to evaluate caspase-, chymotrypsin, and trypsin-like activity. Proteasome activity was measured at 24 and 72 hours after Jurkat cell lines were treated with control, ixazomib or belinostat as single agents, and in combination. SiRNA knockdown experiments were performed in Jurkat cell line with NRF2 and non-targeting (NT) SiRNA transfection. Real-time quantitative PCR (qPCR) for proteasome subunit and NRF2 genes was performed on RNA isolated from treated cells.Results: Transcriptome analysis revealed upregulation of proteasome genes in ixazomib treated cell lines Jurkat, L540 and L428 at 24 hours. In Jurkat TCL, ixazomib caused decreased caspase-like and chymotrypsin-like proteasome activity at 24 hours that was followed by recovery of these activities at 72 hours. The combination of ixazomib and belinostat significantly decreased proteasome activity for chymotrypsin-like, caspase-like and trypsin-like activity at 72 hours compared to single agent ixazomib or belinostat. In Jurkat cells, NRF2 was identified as a transcriptional regulator involved in proteasome gene regulation, showing upregulation of proteasomal genes and NRF2 with ixazomib single agent, downregulation with belinostat single agent and in combination with ixazomib. These results were confirmed with qPCR for NRF2 and proteasome genes in Jurkat and L428. SiRNA knockdown for NRF2 in Jurkat cells resulted in decreased cell viability, NRF2 and proteasome gene expression compared with NT SiRNA following ixazomib treatment.Conclusions: Treatment with single agent ixazomib induced prominent proteasome gene expression in all TCL and HL cell lines. In Jurkat, recovery of chymotrypsin and caspase-like proteasome activity occurred by 72 hours suggesting that transcriptional changes induced by proteasome inhibition contributed to proteasome function recovery. Combination therapy with belinostat resulted in downregulation of proteasome genes in Jurkat and L428 and prevented functional recovery of the proteasome observed in Jurkat. Our results suggest that targeting the proteasome itself with ixazomib and preventing the induced recovery of proteasome genes with belinostat contributes to synergistic effects observed on proteasome function and cell viability in TCL and HL. Further studies with CRISPR/Cas to confirm the effect of NRF2 on proteasome gene and functional recovery in the context of proteasome inhibition are ongoing and will be reported. DisclosuresEvens:Takeda: Other: Advisory board.

Novel therapies for peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs) are a diverse family of lymphoid neoplasms with poor prognosis. They represent approximately 6-10% of non-Hodgkin lymphomas with significant geographic variation. The median age at diagnosis varies with histology, however the majority of patients with PTCL are in their fifth or sixth decade of life. Until recently clinical development of new agents for PTCL was slow due to difficulties in making the correct diagnosis, lack of uniform classification and combination of rarity and biologic diversity of the group. In the last 5 years, significant advances were made to overcome these obstacles, leading to the approval of three new agents for relapsed and refractory PTCL by the Food and Drug Administration, based on well conducted prospective studies. Pralatrexate, a unique antifol, was the first agent granted approval, followed by romidepsin, a histone deacetylase inhibitor, and brentuximab vedotin, an immunoconjugate. Owing to the unique nature of these agents, durable responses were seen in patients with highly refractory disease, and some of these responses are long lasting after discontinuation of therapy. Accumulating data indicate that these novel agents have little cumulative toxicity and can be administered continuously to patients who are not candidates for consolidative stem-cell transplantation (SCT), with little impact on quality of life. They might also provide a new salvage option for patients eligible for SCT with no impact on autologous stem-cell collection or subsequent engraftment. New studies are underway to evaluate efficacy and safety of new agents in combination regimens for both newly diagnosed and relapsed/refractory PTCL. Several other investigational drugs showed promise in recent trials. This review focuses on novel therapies for T-cell lymphomas, their place in current treatment paradigms and future directions.

THP‐COP regimen for the treatment of peripheral T‐cell lymphoma and adult T‐cell leukemia/lymphoma: a multicenter phase II study

The efficacy of pirarubicin (THP)-COP was previously compared with cyclophophamide + doxorubicin + vincristine + prednisolone (CHOP) in elderly patients with lymphoma. The subset analysis showed that T-cell lymphoma had a significantly better response with THP-COP, whereas no such difference was observed in B-cell lymphoma. The aim of this study is to confirm the efficacy of THP-COP in the treatment of T-cell lymphoma. We underwent a multicenter phase II study of THP-COP as a first-line treatment for T-cell lymphoma. The overall response rate, survival period, and toxicity were analyzed. Fifty-three patients were enrolled in this study. Seventeen patients had peripheral T-cell lymphoma (PTCL), including nine of PTCL not otherwise specified (PTCL-NOS) and eight of angioimmunoblastic T-cell lymphoma (AITL). Thirty-six patients had adult T-cell leukemia/lymphoma (ATLL), including 20 of acute type and 16 of lymphoma type. A treatment response was obtained in 35 (66%) patients, including 17 (32%) complete responses. Median overall survival (OS) and progression-free survival (PFS) times were 14.3 months and 5.2 months, respectively. Patients with ATLL showed a tendency to obtain low response rate (61% vs. 77%, P = 0.27) and had a significantly inferior OS (13.3 vs. 28.6 months, P = 0.04) and PFS (4.6 vs. 8.1 months, P = 0.01) in comparison with PTCL. Grade 3 to 4 neutropenia, anemia, and thrombocytopenia occurred in 72%, 34%, and 58% of the patients, respectively. Febrile neutropenia was observed in 51% and grade 3 non-hematological toxicities in 2-9% of the patients. The efficacy of THP-COP is equivalent to that of CHOP for the first-line therapy in T-cell lymphoma.

New Targets of Therapy in T-Cell Lymphomas

T-cell lymphomas (TCL) are characterized by poor response to chemotherapy and generally poor outcome. While molecular profiling has identified distinct biological subsets and therapeutic targets in B-cell lymphomas, the molecular characterization of TCL has been slower. Surface markers expressed on malignant T-cells, such as CD2, CD3, CD4, CD25, and CD52 were the first TCL-specific therapeutic targets to be discovered. However, the presence of these receptors on normal T-cells means that monoclonal antibody (mAb)- or immunotoxin (IT)-based therapy in TCL inevitably results in variable degrees of immunosuppression. Thus, although some mAbs/IT have significant activity in selected subsets of TCL, more specific agents that target signaling pathways preferentially activated in malignant T-cells are needed. One such novel class of agents is represented by the histone deacetylase (HDAC) inhibitors. These molecules selectively induce apoptosis in a variety of transformed cells, including malignant T-cells, both in vitro and in vivo. Several HDAC inhibitors have been studied in TCL with promising results, and have recently been approved for clinical use. Immunomodulatory drugs, such as interferons and Toll Receptor (TLR) agonists have significant clinical activity in TCL, and are particularly important in the treatment of primary cutaneous subtypes (CTCL). Although most classical cytotoxic drugs have limited efficacy against TCL, agents that inhibit purine and pyrimidine metabolism, known as nucleoside analogues, and novel antifolate drugs, such as pralatrexate, are highly active in TCL. With improved molecular profiling of TCL novel pharmacological agents with activity in TCL are now being discovered at an increasingly rapid pace. Clinical trials are in progress and these agents are being integrated in combination therapies for TCL, both in the relapsed/refractory setting as well as front line.

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.