-
Cancer Immunology, Immunotherapy : CII Mar 2018We report a novel phase 2 clinical trial in patients with poor prognosis refractory non-Hodgkin lymphoma (NHL) testing the efficacy of haploidentical donor natural... (Randomized Controlled Trial)
Randomized Controlled Trial
We report a novel phase 2 clinical trial in patients with poor prognosis refractory non-Hodgkin lymphoma (NHL) testing the efficacy of haploidentical donor natural killer (NK) cell therapy (NK dose 0.5-3.27 × 10 NK cells/kg) with rituximab and IL-2 (clinicaltrials.gov NCT01181258). Therapy was tolerated without graft-versus-host disease, cytokine release syndrome, or neurotoxicity. Of 14 evaluable patients, 4 had objective responses (29%; 95% CI 12-55%) at 2 months: 2 had complete response lasting 3 and 9 months. Circulating donor NK cells persisted for at least 7 days after infusion at the level 0.6-16 donor NK cells/µl or 0.35-90% of total CD56 cells. Responding patients had lower levels of circulating host-derived Tregs (17 ± 4 vs. 307 ± 152 cells/µL; p = 0.008) and myeloid-derived suppressor cells at baseline (6.6 ± 1.4% vs. 13.0 ± 2.7%; p = 0.06) than non-responding patients. Lower circulating Tregs correlated with low serum levels of IL-10 (R = 0.64; p < 0.003; n = 11), suggestive of less immunosuppressive milieu. Low expression of PD-1 on recipient T cells before therapy was associated with response. Endogenous IL-15 levels were higher in responders than non-responding patients at the day of NK cell infusion (mean ± SEM: 30 ± 4; n = 4 vs. 19.0 ± 4.0 pg/ml; n = 8; p = 0.02) and correlated with day 14 NK cytotoxicity as measured by expression of CD107a (R = 0.74; p = 0.0009; n = 12). In summary, our observations support development of donor NK cellular therapies for advanced NHL as a strategy to overcome chemoresistance. Therapeutic efficacy may be further improved through disruption of the immunosuppressive environment and infusion of exogenous IL-15.
Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Child; Donor Selection; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Immunotherapy, Adoptive; Killer Cells, Natural; Lymphoma, Non-Hodgkin; Male; Middle Aged; Myeloid-Derived Suppressor Cells; Prognosis; Programmed Cell Death 1 Receptor; Prospective Studies; Receptors, Immunologic; Remission Induction; Transplantation, Homologous; Young Adult
PubMed: 29218366
DOI: 10.1007/s00262-017-2100-1 -
Cancer Immunology, Immunotherapy : CII Mar 2018Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC)....
Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4CD25 responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Cells, Cultured; Diphtheria Toxin; Drug Combinations; Female; Humans; Immune Tolerance; Immunosuppression Therapy; Interferon alpha-2; Interferon-alpha; Interleukin-2; Male; Middle Aged; Mycosis Fungoides; Recombinant Fusion Proteins; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes; T-Lymphocytes, Regulatory
PubMed: 29204699
DOI: 10.1007/s00262-017-2090-z -
The Journal of Dermatological Treatment Aug 2018To conduct an exploratory cost-effectiveness analysis of systemic treatment options for more advanced cutaneous T-cell lymphoma (CTCL).
PURPOSE
To conduct an exploratory cost-effectiveness analysis of systemic treatment options for more advanced cutaneous T-cell lymphoma (CTCL).
METHODS
A cost-effectiveness model compared systemic bexarotene, denileukin diftitox, interferon-α, methotrexate, pralatrexate, romidepsin, vorinostat, and extracorporeal photopheresis (ECP) treatment of CTCL. Treatment effectiveness data were extracted from published studies and/or US product labeling. Overall response, the primary effectiveness measure, was defined as the proportion of patients achieving complete or partial response. Costs were based on wholesale acquisition cost (medications) and Medicare reimbursement rates (ECP, medication administration, adverse drug effect treatment). The perspective of the study was from that of a payer.
RESULTS
Methotrexate was the lowest cost option [mean $436; standard deviation (SD) $284], followed by interferon-α (mean $32,174; SD $27,582), denileukin difitox (mean $40,107; SD $18,598), and ECP (mean $40,985; SD $45,633). Other treatments had costs greater than $50,000, ranging from vorinostat ($65,958; SD $40,637) to bexarotene ($239,424; SD $178,881). The incremental cost-effectiveness ratio per successfully treated patient was $396,725 (interferon) and $213,416 (ECP). Denileukin diftitox, romidepsin, and vorinostat were less effective and cost more than methotrexate.
CONCLUSION
Methotrexate is the most cost-effective option for CTCL; however, its low cost is offset by its limited effectiveness in advanced stages of CTCL. ECP and interferon appear the next most cost-effective therapies.
Topics: Antineoplastic Agents; Bexarotene; Cost-Benefit Analysis; Diphtheria Toxin; Humans; Hydroxamic Acids; Interferon-alpha; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Methotrexate; Photopheresis; Recombinant Fusion Proteins; Skin Neoplasms; Tetrahydronaphthalenes; Treatment Outcome; Vorinostat
PubMed: 29191068
DOI: 10.1080/09546634.2017.1412064 -
The Journal of Infectious Diseases Dec 2017Regulatory T cells (Tregs) suppress T-cell immune activation and human immunodeficiency virus type 1 (HIV-1) replication, but the role of Tregs in HIV-1 reservoir...
BACKGROUND
Regulatory T cells (Tregs) suppress T-cell immune activation and human immunodeficiency virus type 1 (HIV-1) replication, but the role of Tregs in HIV-1 reservoir persistence is poorly defined.
METHODS
Tregs were depleted by denileukin diftitox in humanized mice with chronic HIV-1 infection. Viral replication in lineage cells was determined by p24 expression. Levels of HIV-1 RNA and DNA in human cells, as well as replication-competent-virus-producing cells, were measured to quantified viral replication and reservoirs.
RESULTS
Treg depletion resulted in a blip of HIV-1 replication in T cells but not in myeloid cells. The major activated reservoir cells were memory CD4+ T cells in vivo. Interestingly, the transient activation of viral replication led to HIV-1 reservoir reduction after viremia resuppression, as indicated by the quantity of HIV-1 DNA and replication-competent-virus-producing cells. Furthermore, we demonstrated that Tregs use cyclic adenosine monophosphate (cAMP)-dependent protein kinase A pathway to inhibit HIV-1 activation and replication in resting conventional T cells in vitro.
CONCLUSION
Tregs suppress HIV-1 replication in T cells and contribute to HIV-1 reservoir persistence. cAMP produced in Tregs is involved in their suppression of viral gene activation and expression. Treg depletion combined with combination antiretroviral therapy provides a novel strategy for HIV-1 cure.
Topics: Animals; Cyclic AMP; DNA, Viral; Disease Models, Animal; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Leukocyte Reduction Procedures; Mice; Mice, SCID; RNA, Viral; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Viral Load; Virus Replication
PubMed: 29045701
DOI: 10.1093/infdis/jix547 -
Immunopharmacology and Immunotoxicology Dec 2017We have reported previously that DAB389IL-2 recombinant fusion toxin targets IL-2R bearing CD4 cells, and suppresses demyelinating disease in acute (A) - and chronic (C)...
CONTEXT
We have reported previously that DAB389IL-2 recombinant fusion toxin targets IL-2R bearing CD4 cells, and suppresses demyelinating disease in acute (A) - and chronic (C) - experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis.
OBJECTIVES
The present study was undertaken to investigate the effect of DAB389IL-2 treatment on various cytokine-secreting cell populations in A-EAE and C-EAE mice.
MATERIALS AND METHODS
The effects of DAB389IL-2 at doses of 200-, 800-, or 1600 kU administered i.v. on days 11-13 and 15 on the clinical score and cytokine-secreting cell populations were examined using flow cytometry.
RESULTS
C-EAE mice treated with 1600kU DAB389IL-2, but not A-EAE mice treated with 800 kU had significantly reduced disease. The CD3+CD25+ sub-population in spleens and spinal cords of A-EAE mice treated with 800 kU DAB389IL-2 a was increased, whereas in C-EAE mice treated with 1600 kU this population was increased. DABIL-2 treatment reduced CD3CD4, CD3CD8, CD4CD8, CD3IL-2, CD3IFN-γ and CD3TNF-α T cell subpopulations in the spinal cord in A-EAE, and C-EAE mice on day 16. CD11b+ macrophages that were IL-2-, IFN-γ-, and TNF-α- positive were reduced in A-EAE mice. DAB389IL-2 treatment reduced CD19 B-cells positive for IL-2 or CD11b in the spinal cord in acute and chronic disease. DAB389IL-2 treatment also reduced lymph node CD3CD8, CD4CD8, CD3CD25 populations on day 16, and lymph node CD3IL-10 and peripheral blood CD3CD25 populations on day 24.
DISCUSSION AND CONCLUSIONS
Our study demonstrates that DABIL-2 fusion toxin suppresses EAE in a dose-dependent manner, and alters inflammatory cell sub-populations during disease development.
Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Diphtheria Toxin; Encephalomyelitis, Autoimmune, Experimental; Female; Interferon-gamma; Interleukin-10; Interleukin-2; Lymph Nodes; Lymphocyte Activation; Macrophages; Mice; Multiple Sclerosis; Recombinant Fusion Proteins; Spinal Cord; Spleen; Tumor Necrosis Factor-alpha
PubMed: 28929835
DOI: 10.1080/08923973.2017.1369099 -
The Journal of Infectious Diseases Jun 2017Host-directed therapies that augment host immune effector mechanisms may serve as important adjunctive therapies for tuberculosis treatment. We evaluated the activity of...
Host-directed therapies that augment host immune effector mechanisms may serve as important adjunctive therapies for tuberculosis treatment. We evaluated the activity of denileukin diftitox in an acute mouse model of tuberculosis (TB) infection and analyzed the cellular composition and bacterial burden in lungs and spleens. These in vivo studies show that denileukin diftitox potentiates standard TB treatment in the mouse model, an effect which may be due to depletion of T-regulatory and myeloid-derived suppressor cells during TB infection. Our results indicate that denileukin diftitox and other suppressor cell-depleting therapies may be useful adjunctive, host-directed therapies for TB.
Topics: Animals; Diphtheria Toxin; Disease Models, Animal; Humans; Immunotherapy; Interleukin-2; Lung; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Myeloid-Derived Suppressor Cells; Recombinant Fusion Proteins; Recombinant Proteins; Spleen; T-Lymphocytes, Regulatory; Tuberculosis
PubMed: 28863467
DOI: 10.1093/infdis/jix208 -
Expert Opinion on Emerging Drugs Sep 2017Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release... (Review)
Review
Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects. Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Drug Delivery Systems; Humans; Immunoconjugates; Leukemia; Lymphoma; Multiple Myeloma
PubMed: 28792782
DOI: 10.1080/14728214.2017.1366447 -
Journal of Immunological Methods Sep 2017Ontak® is a FDA-approved diphtheria toxin-based recombinant fusion toxin for treatment of human CD25 cutaneous T cell lymphoma (CTCL). However, it has been discontinued... (Comparative Study)
Comparative Study
Ontak® is a FDA-approved diphtheria toxin-based recombinant fusion toxin for treatment of human CD25 cutaneous T cell lymphoma (CTCL). However, it has been discontinued clinically due to the production issue related to the bacterial expression system with difficult purification. Recently we have developed monovalent and bivalent human IL-2 fusion toxins targeting human CD25 cells using advanced unique diphtheria toxin resistant yeast Pichia Pastoris expression system. In vitro efficacy characterization using human CD25 HUT102/6TG cells demonstrated that both monovalent and bivalent isoforms are potent and the bivalent isoform is approximately two logs more potent than the monovalent isoform. In this study, we further assessed the in vivo efficacy of the human IL-2 fusion toxins using human CD25 HUT102/6TG tumor-bearing NSG mouse model. The data demonstrated that both monovalent and bivalent human IL-2 fusion toxins significantly prolonged the survival of the human CD25 tumor-bearing NSG mice in a dose-dependent manner. Then we further assessed the residual tumor cells from the HUT102/6TG tumor-bearing NSG mice using the residual tumor cell bearing NSG mouse model. The results demonstrated that the residual tumor cells were still sensitive to the continual treatment with the human IL-2 fusion toxin. This yeast-expressed human IL-2 fusion toxin will be a promising candidate to replace the clinically discontinued Ontak®.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Diphtheria Toxin; Dose-Response Relationship, Drug; Humans; Immunoconjugates; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphoma, T-Cell, Cutaneous; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Pichia; Recombinant Fusion Proteins; Safety-Based Drug Withdrawals; Skin Neoplasms; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 28551309
DOI: 10.1016/j.jim.2017.05.008 -
Journal of Immunology (Baltimore, Md. :... Dec 2016T regulatory cells (Tregs) are critical in shaping the latent HIV/SIV reservoir, as they are preferentially infected, reverse CD4 T cell activation status, and suppress...
T regulatory cells (Tregs) are critical in shaping the latent HIV/SIV reservoir, as they are preferentially infected, reverse CD4 T cell activation status, and suppress CTL responses. To reactivate latent virus and boost cell-mediated immune responses, we performed in vivo Treg depletion with Ontak (denileukin diftitox) in two SIVsab-infected controller macaques. Ontak induced significant (>75%) Treg depletion and major CD4 T cell activation, and only minimally depleted CD8 T cells. The overall ability of Tregs to control immune responses was significantly impaired despite their incomplete depletion, resulting in both reactivation of latent virus (virus rebound to 10 viral RNA copies/ml plasma in the absence of antiretroviral therapy) and a significant boost of SIV-specific CD8 T cell frequency, with rapid clearance of reactivated virus. As none of the latency-reversing agents in development have such dual activity, our strategy holds great promise for cure research.
Topics: Animals; Antibodies, Viral; Antigens, Viral; CD8-Positive T-Lymphocytes; Cells, Cultured; Diphtheria Toxin; Humans; Immunity, Cellular; Interleukin-2; Lymphocyte Activation; Lymphocyte Depletion; Macaca mulatta; RNA, Viral; Recombinant Fusion Proteins; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; T-Lymphocytes, Regulatory; Viral Load; Virus Activation; Virus Latency; Virus Replication
PubMed: 27837106
DOI: 10.4049/jimmunol.1601539