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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 -
Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin.Frontiers in Oncology 2021Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or... (Review)
Review
Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.
PubMed: 34976821
DOI: 10.3389/fonc.2021.781800 -
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 -
Cancer Science Jun 2021E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with...
E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.
Topics: Administration, Intravenous; Binding Sites; Diphtheria Toxin; Drug Administration Schedule; Female; Humans; Interleukin-2; Japan; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Neoplasm Recurrence, Local; Recombinant Fusion Proteins; Survival Analysis; Treatment Outcome
PubMed: 33792128
DOI: 10.1111/cas.14906 -
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 -
Experimental Gerontology May 2018Cancer immunotherapy has shown remarkable recent progress. Immune checkpoint blocking antibodies have become the most successful anti-cancer agent class ever developed,...
Cancer immunotherapy has shown remarkable recent progress. Immune checkpoint blocking antibodies have become the most successful anti-cancer agent class ever developed, with six distinct agents approved since 2011 for a wide variety of cancers. Although age is the biggest risk factor for cancer (aside from selected early-onset pediatric cancers), these agents were tested pre-clinically in young hosts, and there is remarkably little published on the effects of host age on treatment outcomes in pre-clinical studies or human clinical trials. The three principal immune checkpoints against which blocking antibodies have been FDA-approved for human use are CTLA-4, PD-1 and PD-L1. We used a mouse model of transplantable, orthotopic B16 melanoma to test age effects of treatments with anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies. All three agents were highly effective in treating young tumor-bearing hosts as expected. Anti-PD-L1 as a single agent had no effect on tumor growth in aged hosts, anti-CTLA-4 had detectable, modest effects and anti-PD-1 was essentially as effective in aged as in young hosts, the first single agent we have identified not to lose efficacy with age in this model. Other important differences in young versus aged hosts included lack of anti-CTLA-4-mediated depletion of intratumor regulatory T cells in aged hosts and poorer ability of all three agents to activate T cells in aged versus young hosts. Anti-CTLA-4 efficacy appeared to improve when combined with anti-PD-L1. Regulatory T cell depletion with FDA-approved denileukin diftitox did not improve treatment by any single agent. Aged mice tolerated treatments as well as young mice without obvious toxicities at equivalent doses.
Topics: Aging; Animals; B7-H1 Antigen; CTLA-4 Antigen; Diphtheria Toxin; Disease Models, Animal; Female; Immunotherapy; Interleukin-2; Male; Melanoma; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor; Recombinant Fusion Proteins; T-Lymphocytes, Regulatory
PubMed: 29326088
DOI: 10.1016/j.exger.2017.12.025 -
Proceedings of the National Academy of... Feb 2019Denileukin diftitox (DAB-IL-2, Ontak) is a diphtheria-toxin-based fusion protein that depletes CD25-positive cells including regulatory T cells and has been approved for...
Denileukin diftitox (DAB-IL-2, Ontak) is a diphtheria-toxin-based fusion protein that depletes CD25-positive cells including regulatory T cells and has been approved for the treatment of persistent or recurrent cutaneous T cell lymphoma. However, the clinical use of denileukin diftitox was limited by vascular leak toxicity and production issues related to drug aggregation and purity. We found that a single amino acid substitution (V6A) in a motif associated with vascular leak induction yields a fully active, second-generation biologic, s-DAB-IL-2(V6A), which elicits 50-fold less human umbilical vein endothelial cell monolayer permeation and is 3.7-fold less lethal to mice by LD analysis than s-DAB-IL-2. Additionally, to overcome aggregation problems, we developed a production method for the fusion toxin using that secretes fully folded, biologically active, monomeric s-DAB-IL-2 into the culture medium. Using the poorly immunogenic mouse B16F10 melanoma model, we initiated treatment 7 days after tumor challenge and observed that, while both s-DAB-IL-2(V6A) and s-DAB-IL-2 are inhibitors of tumor growth, the capacity to treat with higher doses of s-DAB-IL-2(V6A) could provide a superior activity window. In a sequential dual-therapy study in tumors that have progressed for 10 days, both s-DAB-IL-2(V6A) and s-DAB-IL-2 given before checkpoint inhibition with anti-programmed cell death-1 (anti-PD-1) antibodies inhibited tumor growth, while either drug given as monotherapy had less effect. s-DAB-IL-2(V6A), a fully monomeric protein with reduced vascular leak, is a second-generation diphtheria-toxin-based fusion protein with promise as a cancer immunotherapeutic both alone and in conjunction with PD-1 blockade.
Topics: Amino Acid Substitution; Antibodies; Cell Proliferation; Corynebacterium diphtheriae; Diphtheria Toxin; Human Umbilical Vein Endothelial Cells; Humans; Immunosuppressive Agents; Immunotoxins; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Melanoma, Experimental; Programmed Cell Death 1 Receptor; Receptors, Interleukin-2; Recombinant Fusion Proteins; T-Lymphocytes, Regulatory
PubMed: 30718426
DOI: 10.1073/pnas.1815087116 -
Molecular Oncology May 2020The majority of clinically diagnosed cutaneous T-cell lymphomas (CTCL) highly express the cell-surface markers CC chemokine receptor 4 (CCR4) and/or CD25. Recently, we...
The majority of clinically diagnosed cutaneous T-cell lymphomas (CTCL) highly express the cell-surface markers CC chemokine receptor 4 (CCR4) and/or CD25. Recently, we have developed diphtheria toxin-based recombinant Ontak®-like human IL2 fusion toxin (IL2 fusion toxin) and anti-human CCR4 immunotoxin (CCR4 IT). In this study, we first compared the efficacy of the CCR4 IT vs IL2 fusion toxin for targeting human CD25 CCR4 CTCL. We demonstrated that CCR4 IT was more effective than IL2 fusion toxin. We further constructed an IL2-CCR4 bispecific IT. The bispecific IT was significantly more effective than either IL2 fusion toxin or CCR4 IT alone. The bispecific IT is a promising novel targeted therapeutic drug candidate for the treatment of refractory and recurrent human CD25 and/or CCR4 CTCL.
Topics: Animals; Diphtheria Toxin; Flow Cytometry; Humans; Immunotoxins; Inhibitory Concentration 50; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphoma, T-Cell, Cutaneous; Mice; Receptors, CCR4; Recombinant Fusion Proteins; Recombinant Proteins; Skin Neoplasms; Xenograft Model Antitumor Assays
PubMed: 32107846
DOI: 10.1002/1878-0261.12653 -
JAAD Case Reports Nov 2017
PubMed: 29296637
DOI: 10.1016/j.jdcr.2017.06.031 -
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