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Targeting Human T-Cell Leukemia Virus Type 1
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
An alternative approach to ATL therapy is to target cell-surface markers on the malignant cells with monoclonal antibodies. CC chemokine receptor 4 (CCR4) is expressed on leukemic cells from most ATL cases (Yoshie et al. 2002; Ishida et al. 2003). A humanized anti-CCR4 monoclonal antibody, mogamulizumab, with a defucosylated Fc region was developed and proved to markedly enhance antibody- dependent cellular cytotoxicity in ATL cells (Ishida et al. 2012). A clinical trial of mogamulizumab demonstrated significant response in relapsed ATL patients. Now, mogamulizumab is available in Japan as one of the treatment options for refractory ATL. An anti-CD25 (anti-Tac) monoclonal antibody was first administered to ATL patients in the late 1980s (Waldmann et al. 1988) and was reported to be effective in some patients (CR, 2/19; PR, 4/19) (Waldmann et al. 1993). It was reported that the anti-CD52 monoclonal antibody Campath-1H was effective in one patient with AZT/IFN-α-refractory ATL (Mone et al. 2005). A humanized anti-CD2 antibody (MEDI-507) has also been shown to be effective in a xenograft mouse model (Zhang et al. 2003).
Mouse Models in Personalized Cancer Medicine
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
M.E. Beaulieu, T. Jauset, D. Massó-Vallés, L. Soucek, J.R. Whitfield
In summary, there are a growing number of humanized mouse models that resemble more and more the behavior of human cancer and the crosstalk between the tumor and the immune system, although the use of these models for preclinical validation of immunotherapeutic approaches against cancer has not yet been generalized. Nevertheless, there are already a few examples that showcase the potential of humanized mice in the advancement of targeted therapies that can lead to personalized treatment for cancer. For instance, a chimeric defucosylated anti-CCR4 mAb displays potent antitumor activity in humanized mouse models of HL and CTCL that are transplanted with PBMCs from healthy donors. Tumor regression was mediated by robust antibody-dependent cellular cytotoxicity (ADCC), while no effect was observed in the absence of human immune cells (Ito et al., 2009). Importantly, the human version of the antibody (mogamulizumab) has already shown promising results in clinical trials (Remer et al., 2014). In addition, BRG mice engrafted with HSCs and vaccinated with human HER2+ SK-OV-3 ovarian cancer cells showed human immune anti-HER2 responses and reduced lung metastases after a subcutaneous SK-OV-3 cell challenge, when compared to nonvaccinated animals (De Giovanni et al., 2012). Finally, NSG mice engrafted with human PBMCs allowed in vivo validation of a new technique for DC-based immunotherapy in AML, consisting of antigen loading of DCs via electroporation with in vitro-transcribed mRNA encoding leukemia-associated antigens. This method showed efficient induction of antigen-specific T-cell immune responses and enabled the initiation of a clinical phase I/II trial to test its application in AML patients (reviewed by Subklewe et al., 2014).
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The pathogenesis of CTCL remained poorly understood until now, most of the therapies utilized have been empirical and not directed towards the malignant clone per se. Though targeted therapies are now being pursued, for the most part treatment for patients with limited-stage disease, include topical steroid creams, topical nitrogen mustard, topical bexarotene (retinoids), photochemotherapy and a specialized ultraviolet treatment called PUVA (psoralen and ultraviolet A-range) therapy. Some patients with the localized form of CTCL can achieve long-lasting remission with radiotherapy and IFN-α (Figure 11.23). The presence of several distinct malignant subpopulations in individual patients, with substantial single-cell heterogeneity and diverse sensitivity to treatment. Treatment of advanced-stage, including SS, and relapsed/refractory limited-stage disease is essentially palliative and requires a ‘risk-adapted’ multidisciplinary approach, often combining the licensed histone deacetylase inhibitors, romidepsin and vorinostat, initially at conventional doses and subsequently using a ‘dose-sparing’ strategy in order to minimize the drug is common side effects (Figure 11.24). Another recently licensed novel drug is mogamulizumab, a humanized CCR4-targeting monoclonal antibody, which demonstrated significant activity, and tolerance, in a cohort of heavily pretreated patients with MF and SS. The drug is now be tested in the first-line setting. Allo-SCT can induce durable remissions in a few patients with SS but TRM remains high, even with RIC. Clearly, the best treatment option is enrolment into a clinical trial assessing the potential therapeutic implications of the keynote driver mutations. In this regard, there is much interest to target the cytokine IL-13, a novel growth factor for CTCL, perhaps simultaneously with inhibition of IL-4.
CCL22-based peptide vaccines induce anti-cancer immunity by modulating tumor microenvironment
Published in OncoImmunology, 2022
Inés Lecoq, Katharina L. Kopp, Marion Chapellier, Panagiotis Mantas, Evelina Martinenaite, Maria Perez-Penco, Lars Rønn Olsen, Mai-Britt Zocca, Ayako Wakatsuki Pedersen, Mads Hald Andersen
The CCL22:CCR4 axis has been shown to function as an immune checkpoint; this axis is crucial for controlling T-cell immunity, particularly in the TME context, where a CCL22 deficiency was correlated with prolonged survival.43 Consequently, different approaches to disrupt this axis are currently under investigation. A CCR4 antagonist (mogamulizumab), was recently developed to disrupt CCL22:CCR4-mediated Treg recruitment to the tumor.44 Anti-CCR4 antibodies showed promising results in vivo. These antibodies effectively inhibited chemotactic Treg recruitment to the tumor in a CCL22-dependent manner, which led to the restoration of anti-tumor immunity in a humanized murine model.17 Furthermore, those findings were reproduced in a clinical setting, and in 2018, mogamulizumab was approved by the FDA for the treatment of cutaneous T-cell lymphoma. Subsequently, a phase Ia trial tested a combination therapy of mogalinumab and nivolumab (anti-PDL1) in multicancer solid tumors and found that effector Tregs were depleted in peripheral blood and in the TME.45 In some cases, the Treg depletion induced by mogamulizumab was associated with serious autoimmune side effects.46,47 Its application in combination with checkpoint inhibitors was tested in a phase I48 and a phaseI/II49 study. However, the combination did not results in a potent antitumor efficacy in patients with advanced solid tumors therefore, leaving an open door for other approaches aiming at targeting Treg recruitment through the CCL22:CCR4 axis.
New nonchemotherapy treatment options for cutaneous T-cell lymphomas
Published in Expert Review of Anticancer Therapy, 2021
Mogamulizumab is another targeted agent directed against a chemokine receptor, CCR4, which is expressed on MF/SS cells as well as on normal T-regs. This unconjugated antibody requires intact immune function for its activity as it depends on ADCC to eradicate tumor cells. A secondary mechanism may be its effects on T-regs in the tumor microenvironment. Mogamulizumab has shown significant activity in the circulating blood compartment with more modest activity in patients with skin only disease and is a treatment of choice for patients with B1 or B2 blood involvement. Skin flare has occurred but is managed with topical and systemic corticosteroids. Similarly, IPH4102 is an unconjugated antibody dependent on ADCC for efficacy which has shown activity in Sézary syndrome and is under further investigation. Because of their acceptable toxicity profiles, these antibodies may be useful for long-term maintenance or in conjunction with skin directed approaches. Studies with alternate dosing schedules of mogamulizumab are underway.
Mogamulizumab in the treatment of advanced mycosis fungoides and Sézary syndrome: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2020
Daniel J. Lewis, Alain H. Rook
Mogamulizumab is a novel targeted therapy that has improved the current treatment landscape for advanced MF/SS since its approval by the FDA in 2018. Although its response rate of 28% in the pivotal MAVORIC trial is similar to that of alternative agents for advanced disease, many of these agents were studied in smaller trials with different study populations [3–5,49]. For example, romidepsin is used to treat MF/SS primarily based on the results of a smaller phase II trial [4]. Moreover, brentuximab vedotin was studied in the phase III ALCANZA trial, which excluded patients with high Sézary cell counts and included patients with primary cutaneous anaplastic large-cell lymphoma [4,49]. Conversely, the phase III MAVORIC trial enrolled a significant proportion of patients with advanced or relapsed/refractory disease and also represents the largest randomized controlled trial in CTCL to date [18]. Mogamulizumab also offers specific advantages over other therapies for advanced MF/SS: a prolonged duration of response, a high response rate within the blood compartment, and a favorable safety profile.