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Cancer Research Jan 2017mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the...
mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T-cell lymphoma. Typical pharmacologic rapamycin (1-8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of antitumor immunity. Denileukin diftitox (DD)-mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T-cell-dependent fashion. However, typical rapamycin inhibited T-cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low-dose (LD) rapamycin (75 μg/kg) increased potentially beneficial CD44hiCD62L CD8 central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of antitumor immunity. Instead, rapamycin upregulated EL4 IL2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B-cell lymphoma, but not against human Jurkat T-cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T-cell lymphomas. Cancer Res; 77(2); 520-31. ©2016 AACR.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Diphtheria Toxin; Disease Models, Animal; Flow Cytometry; Humans; Immunotherapy; Interleukin-2; Jurkat Cells; Lymphocyte Activation; Lymphoma, T-Cell; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Recombinant Fusion Proteins; Sirolimus; T-Lymphocytes
PubMed: 27737881
DOI: 10.1158/0008-5472.CAN-16-1140 -
Journal For Immunotherapy of Cancer 2016Depletion of CD25(+) Tregs improves anti-tumor immunity in preclinical models. Denileukin diftitox is a recombinant fusion protein of human IL-2 and diptheria toxin...
Single dose denileukin diftitox does not enhance vaccine-induced T cell responses or effectively deplete Tregs in advanced melanoma: immune monitoring and clinical results of a randomized phase II trial.
BACKGROUND
Depletion of CD25(+) Tregs improves anti-tumor immunity in preclinical models. Denileukin diftitox is a recombinant fusion protein of human IL-2 and diptheria toxin fragment that also can kill CD25(+) T cells. Prior clinical trials of denileukin diftitox suggested reduction of FoxP3(+) Tregs and some clinical responses.
METHOD
To investigate the immunologic effects of denileukin difitox on vaccine-specific immune responses in melanoma, a randomized clinical trial of single dose denileukin diftitox prior to vaccination versus vaccination alone in subjects with HLA-A2(+) metastatic melanoma was performed. Treatment included randomization to a 4-peptide vaccine (Melan-A, gp100, MAGE3 and NA17 with GM-CSF emulsified in Montanide) alone or after single dose of denileukin diftitox (18 mcg/kg). Vaccine was given every 2 weeks for 3 doses and, absent clinical progression, continued every 2 weeks. Blood and tumor biopsies were obtained pretreatment and after 3 vaccinations for immunologic assessments.
RESULTS
In 17 treated subjects there were no drug-related G3-4 adverse events. One partial response and 8 stable disease were observed in 9 subjects (4 DD: 5 vaccine only) with no impact of denileukin diftitox on time to progression. Total peripheral Tregs were not significantly altered, and in 1 patient biopsy intra-tumoral FoxP3 transcripts were not reduced following denileukin diftitox. ELISA for IL2R-α demonstrated no impact on outcomes by soluble CD25 level. Immune monitoring suggested the development of modest vaccine-specific CD8(+) T cell responses in the control group, however immunization efficacy was actually reduced in the denileukin diftitox group.
CONCLUSION
Our results indicate that denileukin diftitox did not effectively deplete Tregs, augment T cell responses, or improve clinical activity in melanoma. Clinicaltrials.gov ID: NCT00515528; Registered August 9, 2007.
PubMed: 27330808
DOI: 10.1186/s40425-016-0140-2 -
Hematology. American Society of... 2015
Topics: Alemtuzumab; Aminopterin; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials as Topic; Deoxycytidine; Depsipeptides; Diphtheria Toxin; Disease Progression; Doxorubicin; Electrons; Humans; Hydroxamic Acids; Immunotherapy; Incidence; Interleukin-2; Lenalidomide; Lymphoma, T-Cell; Mycosis Fungoides; Pentostatin; Photopheresis; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Retinoids; Sezary Syndrome; Stem Cell Transplantation; Thalidomide; United States; Vorinostat; Gemcitabine
PubMed: 26637769
DOI: 10.1182/asheducation-2015.1.529 -
Drugs Nov 2015Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products... (Review)
Review
Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products have been vital for the development of multiagent treatment regimens currently employed in cancer chemotherapy, and are used in the treatment of a variety of malignancies. Therefore, this review catalogs recent advances in natural product-based drug discovery via the examination of mechanisms of action and available clinical data to highlight the utility of these novel compounds in the burgeoning age of precision medicine. The review also highlights the recent development of antibody-drug conjugates and other immunotoxins, which are capable of delivering highly cytotoxic agents previously deemed too toxic to elicit therapeutic benefit preferentially to neoplastic cells. Finally, the review examines natural products not currently used in the clinic that have novel mechanisms of action, and may serve to supplement current chemotherapeutic protocols.
Topics: Antineoplastic Agents; Biological Products; Cytochalasins; Dioxoles; Diphtheria Toxin; Drug Discovery; Epothilones; Furans; Harringtonines; Homoharringtonine; Humans; Immunoconjugates; Interleukin-2; Ketones; Recombinant Fusion Proteins; TOR Serine-Threonine Kinases; Tetrahydroisoquinolines; Trabectedin; Withanolides
PubMed: 26501980
DOI: 10.1007/s40265-015-0489-4 -
Dermatologic Clinics Oct 2015Use of monoclonal antibodies (mAbs) has revolutionized cancer therapy. Approaches targeting specific cellular targets on the malignant cells and in tumor... (Review)
Review
Use of monoclonal antibodies (mAbs) has revolutionized cancer therapy. Approaches targeting specific cellular targets on the malignant cells and in tumor microenvironment have been proved to be successful in hematologic malignancies, including cutaneous lymphomas. mAb-based therapy for cutaneous T-cell lymphoma has demonstrated high response rates and a favorable toxicity profile in clinical trials. Several antibodies and antibody-based conjugates are approved for use in clinical practice, and many more are in ongoing and planned clinical trials. In addition, these safe and effective drugs can be used as pillars for sequential therapies in a rational stepwise manner.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Clinical Trials as Topic; Diphtheria Toxin; Humans; Immunoconjugates; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Molecular Targeted Therapy; Recombinant Fusion Proteins; Skin Neoplasms
PubMed: 26433849
DOI: 10.1016/j.det.2015.05.015 -
Case Reports in Oncological Medicine 2015Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non-Hodgkin's lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach...
Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non-Hodgkin's lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach being generally ineffective. The most employed first-line treatment is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which still results in high rates of relapses. Denileukin diftitox is a fusion protein combining the cytotoxic portion of the diphtheria toxin and the receptor-binding domain of the interleukin-2 (IL-2) molecule, thereby targeting cells expressing the IL-2 receptor, including both T-cell and B-cell lymphomas. It has been approved for the treatment of cutaneous T-cell lymphomas, and it has documented activity in PTCL both as a single agent and as part of combination therapy. This report documents three cases of PTCL where denileukin diftitox has been used as long-term maintenance therapy after complete remission was achieved. While the overall survival rate of patients with advanced stage, refractory PTCL is generally poor (with median overall survival of 5.5 months), the three patients described in this report are all experiencing an ongoing complete remission for more than four years.
PubMed: 26240767
DOI: 10.1155/2015/123756 -
Drug Safety May 2015Chimeric fusion proteins, produced by genetic engineering, are currently made up of effector peptides, for example, a ligand-binding portion of a cytokine or growth... (Review)
Review
Chimeric fusion proteins, produced by genetic engineering, are currently made up of effector peptides, for example, a ligand-binding portion of a cytokine or growth factor, extracellular domains of lymphocyte antigens, or a toxin linked to a suitable fusion partner. This review covers eight fusion proteins that have received regulatory approval for human therapy: etanercept, belatacept, abatacept, alefacept, rilonacept, romiplostim, aflibercept, and denileukin-diftitox. Important requirements for an effective fusion protein are effective targeting and binding, cytotoxicity, and a stable molecule with an extended half-life. The Fc region of human IgG1 is generally chosen as the fusion partner for the effector molecule(s) because it extends the fusion protein half-life by recycling via the salvage neonatal FcRn receptor and protects the molecule from lysosomal degradation. Each of the fusion proteins has IgG1 Fc as a fusion partner except denileukin-diftitox, which employs a modified diphtheria toxin effector peptide linked to interleukin-2. For six of the Fc fusion proteins, the effector peptide(s) is linked to the N-terminus of the Fc piece but for the thrombopoietin-mimetic romiplostim, linkage is through the C-terminus. Although some clear type I and IV hypersensitivities are known to be induced by fusion protein therapy, the pathomechanisms underlying many adverse hematologic, respiratory, renal, and cutaneous events have generally not been investigated. Assessment of immunogenicity risk is important because a number of immune-based, or influenced, adverse reactions such as anaphylaxis, cutaneous manifestations, infusion, and injection-site reactions, and cytokine release syndrome can occur. Features of many reactions, some autoimmune in nature, suggest type II, III, or IV hypersensitivities. Clinical findings with the anti-arthritis anti-psoriasis biologic etanercept provide the largest body of current knowledge of fusion protein-induced adverse events. For most fusion proteins, little information is available on appropriate diagnostic and desensitization procedures for hypersensitivity and other adverse responses, although skin test concentrations and some successful desensitization protocols have been published for etanercept.
Topics: Animals; Drug Eruptions; Drug Hypersensitivity; Drug Monitoring; Drug Stability; Glycoproteins; Humans; Protein Stability; Recombinant Fusion Proteins; Risk
PubMed: 25832756
DOI: 10.1007/s40264-015-0285-9 -
Cancer Treatment and Research 2015Peripheral T-cell lymphomas (PTCLs) are an uncommon group of lymphoproliferative disorders accounting for approximately 10-15 % of all non-Hodgkin lymphomas (NHL) in... (Review)
Review
Peripheral T-cell lymphomas (PTCLs) are an uncommon group of lymphoproliferative disorders accounting for approximately 10-15 % of all non-Hodgkin lymphomas (NHL) in Western countries. Although PTCLs are associated with poor prognosis, outcomes vary with disease subtype. The standard of care has been anthracycline-based induction combination chemotherapy, however, with the exception of low-risk ALK-positive anaplastic large cell lymphoma, relapse rates are high. Therefore, consolidation with autologous stem cell transplantation is usually recommended for patients deemed candidates, and with aggressive subtypes. In recent years, a number of novel agents including pralatrexate, histone deacetylase inhibitors, immunotoxins, proteasome inhibitors, aurora kinase inhibitors and the CD30 antibody-drug conjugate brentuximab vedotin, have shown promise in the treatment of PTCLs. Studies are underway to explore the activity of these newer agents used in the frontline setting.
Topics: Aminopterin; Antineoplastic Agents; Brentuximab Vedotin; Diphtheria Toxin; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lymphoma, T-Cell, Peripheral; Molecular Targeted Therapy; Protein Kinase Inhibitors; Recombinant Fusion Proteins; Stem Cell Transplantation
PubMed: 25655615
DOI: 10.1007/978-3-319-13150-4_12 -
Cancer Treatment Reviews Oct 2014Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on... (Review)
Review
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10-30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Cyclophosphamide; Depsipeptides; Diphtheria Toxin; Doxorubicin; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lenalidomide; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Peptides, Cyclic; Prednisolone; Recombinant Fusion Proteins; Stem Cell Transplantation; Thalidomide; Topoisomerase Inhibitors; Vincristine
PubMed: 25199959
DOI: 10.1016/j.ctrv.2014.08.001