Incidence and in-vivo relevance of anti-interferon antibodies during treatment of low-grade cutaneous T-cell lymphomas with interferon alpha-2a combined with acitretin or PUVA

1996 ◽  
Vol 288 (9) ◽  
pp. 543-548 ◽  
Author(s):  
G. P. Rajan ◽  
B. Seifert ◽  
O. Prümmer ◽  
H. I. Joller-Jemelka ◽  
G. Burg ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
Low Grade ◽  
T Cell Lymphomas

Incidence and in-vivo relevance of anti-interferon antibodies during treatment of low-grade cutaneous T-cell lymphomas with interferon alpha-2a combined with acitretin or PUVA

1996 ◽  
Vol 288 (9) ◽  
pp. 543-548 ◽  
Author(s):  
G. P. Rajan ◽  
B. Seifer ◽  
O. Prümmer ◽  
H. I. Joller-Jemelka ◽  
G. Burg ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
Low Grade ◽  
T Cell Lymphomas

γδ T cells for immune therapy of patients with lymphoid malignancies

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Martin Wilhelm ◽  
Volker Kunzmann ◽  
Susanne Eckstein ◽  
Peter Reimer ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Low Dose ◽  
Γδ T Cells ◽  
Low Grade ◽  
Treatment Schedule ◽  
Γδ T Cell

Abstract There is increasing evidence that γδ T cells have potent innate antitumor activity. We described previously that synthetic aminobisphosphonates are potent γδ T cell stimulatory compounds that induce cytokine secretion (ie, interferon γ [IFN-γ]) and cell-mediated cytotoxicity against lymphoma and myeloma cell lines in vitro. To evaluate the antitumor activity of γδ T cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in combination with pamidronate in 19 patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial were to determine toxicity, the most effective dose for in vivo activation/proliferation of γδ T cells, and antilymphoma efficacy of the combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered the study received 90 mg pamidronate intravenously on day 1 followed by increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2 (0.25 to 3 × 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level in vivo, γδ T-cell activation/proliferation and response to treatment were disappointing with only 1 patient achieving stable disease. Therefore, the next 9 patients were selected by positive in vitro proliferation of γδ T cells in response to pamidronate/IL-2 and received a modified treatment schedule (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B), significant in vivo activation/proliferation of γδ T cells was observed in 5 patients (55%), and objective responses (PR) were achieved in 3 patients (33%). Only patients with significant in vivo proliferation of γδ T cells responded to treatment, indicating that γδ T cells might contribute to this antilymphoma effect. Overall, administration of pamidronate and low-dose IL-2 was well tolerated. In conclusion, this clinical trial demonstrates, for the first time, that γδ T-cell–mediated immunotherapy is feasible and can induce objective tumor responses. (Blood. 2003;102:200-206)

scholarly journals A Novel Approach for the Treatment of T Cell Malignancies: Targeting T Cell Receptor Vβ Families

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 631
Author(s):  
Jie Wang ◽  
Katarzyna Urbanska ◽  
Prannda Sharma ◽  
Reza Nejati ◽  
Lauren Shaw ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Lymphomas ◽  
Novel Approach ◽  
T Cell Malignancies

Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosis. The lack of targeted immunotherapeutic approaches for T cell malignancies results in part from potential risks associated with targeting broadly expressed T cell markers, namely T cell depletion and clinically significant immune compromise. The knowledge that the T cell receptor (TCR) β chain in human α/β TCRs are grouped into Vβ families that can each be targeted by a monoclonal antibody can therefore be exploited for therapeutic purposes. Here, we develop a flexible approach for targeting TCR Vβ families by engineering T cells to express a chimeric CD64 protein that acts as a high affinity immune receptor (IR). We found that CD64 IR-modified T cells can be redirected with precision to T cell targets expressing selected Vβ families by combining CD64 IR-modified T cells with a monoclonal antibody directed toward a specific TCR Vβ family in vitro and in vivo. These findings provide proof of concept that TCR Vβ-family-specific T cell lysis can be achieved using this novel combination cell–antibody platform and illuminates a path toward high precision targeting of T cell malignancies without substantial immune compromise.

scholarly journals 13-Methyltetradecanoic Acid Exhibits Anti-Tumor Activity on T-Cell Lymphomas In Vitro and In Vivo by Down-Regulating p-AKT and Activating Caspase-3

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65308 ◽  
Author(s):  
Qingqing Cai ◽  
Huiqiang Huang ◽  
Dong Qian ◽  
Kailin Chen ◽  
Junhua Luo ◽  
...  
Keyword(s):  
T Cell ◽  
Caspase 3 ◽  
T Cell Lymphomas ◽  
Anti Tumor Activity

Zidovudine Blocks NF-κB activity in Vivo in Adult T-Cell Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2524-2524 ◽  
Author(s):  
Juan Carlos Ramos ◽  
Luis M. Diaz ◽  
Michele Manrique ◽  
Rosangela Lima ◽  
Ngoc L Toomey ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
Phase Ii ◽  
Target Genes ◽  
Recent Analysis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Resistant Disease

Abstract Adult T-cell leukemia (ATL) is a lymphoid malignancy caused by the human T-cell leukemia virus type I (HTLV-I), which carries a poor prognosis. A hallmark of ATL is the high constitutive expression of NF-κB, which predominantly exerts an anti-apoptotic effect contributing to chemotherapy resistance. Many of the elegant studies about the pathogenesis of ATL have focused on Tax, a viral transactivator of NF-κB, using HTLV-I expressing cell lines and mouse models, however in primary tumors the virus remains latent and Tax is not detected. We and other investigators have demonstrated the clinical efficacy of Zidovudine (AZT) and interferon-alpha (IFNα) combination therapy in both chronic and acute ATL subtypes with some patients achieving clinical remission or stable disease for many years while on maintenance therapy. The exact mechanisms of these antiviral drugs in ATL remain unclear. In a recent analysis of primary ATL tumors, we implicated the expression of both c-Rel and the NF-κB target gene product IRF-4/MUM-1 in AZT/IFN resistant disease. We have recently opened to accrual a Phase II clinical trial titled Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients with HTLV-I Associated Adult T Cell Leukemia Treated with Zidovudine Plus Interferon alpha-2b, which includes the novel use of pegylated interferon-alpha and valproic acid (as HDAC inhibitor) in the maintenance phase as an attempt to eradicate residual ATL clones, which usually occurs after AZT and IFNα therapy even after longterm remission. Our goals are also to study the anti-tumor mechanisms of these drugs in ATL, and define molecular criteria for response. As part of the correlative studies in our Phase II trial, we have analyzed leukemic ATL cells collected from patients during the first 48 hours of treatment (AZT given alone prior to IFN) and found in vivo stabilization of IκB (the repressor protein of NF-κB) by Western Blot in patients responding to the treatment, suggesting a role for this antiviral drug in blocking NF-κB activity as previously hypothesized in our laboratory. We also examined the expression of NF-κB related genes using a custom designed gene expression array by a novel technology (NanoString Inc.) of selected NF-κB target genes and found downregulation of most these genes in vivo by AZT alone. So far, all ATL tumors analyzed exhibited high expression of many NF-κB target genes, and over forty of these are differentially overexpressed in ATL specimens as compared to normal CD4+ T-cells. Some the differentially expressed genes include those encoding NF-κB/Rel, interferon regulatory factor (IRF), and bcl-2 related proteins. A comprehensive analysis of over forty ATL tumors, including specimens collected in both Miami and Brazil, is ongoing and expected to be completed soon. Baseline tumor characteristics and prognostic variables of previously collected tumors, as well interim results of our clinical and molecular studies will be reported.

The Histone Deacetylase-8 (HDAC8) Selective Inhibitor PCI-34051 Decreases Interleukin-1 Beta Secretion in Vitro and Reduces Inflammation in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2581-2581
Author(s):  
Sriram Balasubramanian ◽  
Susanne Steggerda ◽  
Mint Sirisawad ◽  
Marshall Schreeder ◽  
Luke Doiron ◽  
...  
Keyword(s):  
T Cell ◽  
Secretory Pathway ◽  
Interleukin 1 ◽  
Contact Hypersensitivity ◽  
Secretory Process ◽  
Mrna Levels ◽  
Interleukin 1 Beta ◽  
Caspase 1 ◽  
T Cell Lymphomas

Abstract Inhibitors of histone deacetylases (HDACs) which are currently in clinical testing for treating various cancers typically inhibit multiple isoforms of the 11-member HDAC family. We have developed an isoform-selective HDAC inhibitor, PCI-34051, that inhibits HDAC8 with a Ki of 10 nM and greater than 200-fold selectivity over other HDAC isoforms (Balasubramanian et al. (2008) Leukemia,22:1026–34). We have shown that PCI-34051 selectively induced apoptosis in cell lines derived from T-cell lymphomas and leukemias, but not in other tumor or normal cell types. Here we show that it potently inhibits the secretion of the pro-inflammatory cytokine interleukin-1 beta (IL-1b) in lipopolysaccharide (LPS)-stimulated peripheral mononuclear blood cells (PBMC) and isolated monocytes. PCI-34051 inhibited IL-1b secretion (by 80% compared to control) from LPS-stimulated human PBMC with an IC50 of 0.6 uM, which is much lower than the growth inhibitory concentrations of 2.4–4 uM required in T-cell lymphomas. We found that PCI-34051 also inhibited the secretion of interleukin-18 (IL-18) to a similar extent as IL-1b, but secretion of other pro-inflammatory cytokines, including MIP-1b, MCP-1, TNFa, and IL-6, was inhibited to a smaller extent. Interestingly, IL-18, like IL-1b, is synthesized without a signal peptide, and also utilizes the same non-classical endosomal secretory pathway as IL-1b including cleavage of the pro-form by caspase-1. Thus, we theorized that the modulatory effect of PCI-34051 is likely to involve modulation of the post-translational secretory process. In accordance, we found that the IL-1b mRNA levels were reduced by only 20% compared to control, but the intracellular protein levels of the pro-form was increased by >50% in primary monocytes after treatment with PCI-34051, indicating that the mechanism was due to inhibition of the processing from the pro- to the mature form of the cytokine. We showed that this was not due to a direct inhibition of caspase-1 or TACE (TNF-alpha converting enzyme), but is likely due to an as-yet unidentified substrate of HDAC8. In vivo, PCI-34051 inhibited ear swelling induced by oxazolone in a model of contact hypersensitivity in mice, and we showed that this was accompanied by a reduction in IL-1b at both the protein and mRNA levels. Based on this result, we examined the effect of PCI-34051 on IL-1b secretion in human keratinocytes, as well as in PBMC from psoriasis patients, and found that it could reduce IL-1b secretion in both. We found that PCI-34051 decreased IL-1b by 60% in LPS-stimulated PBMC from rheumatoid arthritis (RA) patients, but the pan-HDAC inhibitors which were only weakly inhibitory to HDAC8 did not have this effect, indicating a specific role for HDAC8 in the secretory process. Finally, we found that in unstimulated PBMC from RA patients that had basal production of IL-1b that this could be decreased by 90% by treatment with PCI-34051. Taken together, these findings indicate that PCI-34051 is an active drug that could be useful for the treatment of T-cell lymphoma as well as for autoinflammatory diseases such as RA and psoriasis.

Enhanced In Vivo activation of Adoptively Transferred Genetically Targeted T Cells Following Cyclophosphamide Chemotherapy: Initial Results From a Phase I Clinical Trial Treating CLL Patients with Autologous CD19-Targeted T Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3436-3436
Author(s):  
Renier J. Brentjens ◽  
Daniel Hollyman ◽  
Jae Park ◽  
Elmer Santos ◽  
Raymond Yeh ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
High Efficiency ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Autologous Tumor

Abstract Abstract 3436 Poster Board III-324 Patient T cells may be genetically modified to express chimeric antigen receptors (CARs) targeted to antigens expressed on tumor cells. We have initiated a clinical trial treating chemotherapy-refractory chronic lymphocytic leukemia (CLL) patients with autologous T cells modified to express the 19-28z CAR targeted to the CD19 antigen expressed on most B cell malignancies. In the first cohort of this trial, patients were infused with the lowest planned dose of modified T cells alone. All patients treated in this cohort experienced low-grade fevers following modified T cell infusion, and 2 of 3 treated patients exhibited subjective and laboratory evidence of transient reductions in tumor burden. The first patient treated on the second cohort of this study received prior cyclophophamide chemotherapy followed by the same dose of modified T cells administered to the first cohort of patients. This patient experienced persistent fevers, dyspnea, hypotension, renal failure, and died 44 hours following modified T cell infusion, likely secondary to sepsis. Modified T cells were not detectable in the peripheral blood of treated patients at 1 hour following completion of T cell infusion. However, post mortem analyses revealed a rapid infiltration of targeted T cells into anatomical sites of tumor involvement. Serum levels of the inflammatory cytokines IL-5, IL-8, and GM-CSF, but not TNFα, markedly and rapidly increased following infusion of genetically targeted T cells in this patient, mirroring the in vitro cytokine secretion profile of this patient's T cells, and consistent with marked in vivo activation of the modified T cells. Similar cytokine signatures were not found in patients from the first cohort. Significantly, serum cytokine analyses from the second cohort patient revealed a marked increase in the pro-proliferative cytokines IL-2, IL-7, IL-12, and IL-15 following cyclophosphamide therapy, in contrast to the baseline levels found in the first cohort. This report demonstrates the high efficiency trafficking of CD19-targeted T cells and in vivo activation of T cells encoding a second generation CD28/zeta chain-based chimeric antigen receptor. Furthermore, these data highlight mechanisms whereby cyclophosphamide may generate an in vivo milieu that enhances the anti-tumor efficacy of autologous tumor targeted T cells. Disclosures No relevant conflicts of interest to declare.

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