Mogamulizumab for relapsed adult T‐cell leukemia–lymphoma: Updated follow‐up analysis of phase I and <scp>II</scp> studies

Ishida, Takashi; Utsunomiya, Atae; Jo, Tatsuro; Yamamoto, Kazuhito; Katô, Kôji; Yoshida, Shinichiro; Takemoto, Shigeki; Suzushima, Hitoshi; Kobayashi, Yasuhito; Imaizumi, Yoshitaka; Yoshimura, Kenichi; Kawamura, Kazushi; Takahashi, Takeshi; Tobinai, Kensei; Ueda, Ryuzo

doi:10.1111/cas.13343

Cited by 54 publications

(51 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The immunotherapy with Tax peptide-pulsed dendritic cells exhibited efficacy in some ATL patients and is currently under clinical trial (Suehiro et al, 2015). Furthermore, immunomodulatory agents, such as lenalidomide and anti-CCR4 antibodies, are now approved for the treatment of ATL patients (Ishida et al, 2016(Ishida et al, , 2017. Therefore, it will be useful to obtain information not only related to the host genome, but also to the HTLV-1 proviral genome to establish a standardized treatment strategy based on the molecular characteristics of ATL cells.…”

Section: Discussionmentioning

confidence: 99%

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

Katsuya¹,

Islam²,

Tan³

et al. 2019

Cell Reports

Self Cite

View full text Add to dashboard Cite

Graphical Abstract Highlights d A method for comprehensive analysis of HTLV-1 proviruses in infected individuals d The method provides viral sequence, integration site, and degree of cell expansion d Defective proviruses are present in asymptomatic carriers and HAM/TSP, as well as ATL d Infected cells with defective proviruses proliferate more than those with intact ones Correspondence y-satou@kumamoto-u.ac.jp In Brief Katsuya et al. demonstrate that HTLV-1 DNA-capture-seq provides comprehensive information, including the entire viral sequence, integration site, and clonal abundance of infected cells.Infected clones with defective-type proviruses are present in disease states and in asymptomatic carriers, and they proliferate more than full-length proviruses. SUMMARYThe retrovirus human T-cell leukemia virus type 1 (HTLV-1) integrates into the host DNA, achieves persistent infection, and induces human diseases.Here, we demonstrate that viral DNA-capture sequencing (DNA-capture-seq) is useful to characterize HTLV-1 proviruses in naturally virus-infected individuals, providing comprehensive information about the proviral structure and the viral integration site. We analyzed peripheral blood from 98 naturally HTLV-1-infected individuals and found that defective proviruses were present not only in patients with leukemia, but also in those with other clinical entities. We further demonstrated that clones with defective-type proviruses exhibited a higher degree of clonal abundance than those with full-length proviruses. The frequency of defective-type proviruses in HTLV-1-infected humanized mice was lower than that in infected individuals, indicating that defective proviruses were rare at the initial phase of infection but preferentially selected during persistent infection. These results demonstrate the robustness of viral DNA-captureseq for HTLV-1 infection and suggest potential applications for other virus-associated cancers in humans.

show abstract

Section: Discussionmentioning

confidence: 99%

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

Katsuya¹,

Islam²,

Tan³

et al. 2019

Cell Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…In detail, monoclonal antibodies against CD25 have been used to kill Treg cells by antibody‐dependent cell‐mediated cytotoxicity and complement‐mediated cytotoxicity in preclinical and clinical studies alone and in combination with dendritic cell vaccines . Additionally, a monoclonal antibody against the chemokine CCR4, which represents a main promoter of intratumoral Treg cell recruitment, has been tested in phase I/II clinical trials and achieved Treg cell depletion with well‐tolerated antitumor activity, although long‐term effects are unclear . In this context, Gyori et al .…”

Section: Introductionmentioning

confidence: 99%

“…8,24,25 Additionally, a monoclonal antibody against the chemokine CCR4, which represents a main promoter of intratumoral Treg cell recruitment, has been tested in phase I/II clinical trials and achieved Treg cell depletion with well-tolerated antitumor activity, 26 although long-term effects are unclear. 27 In this context, Gyori et al 28 obtained Treg cell depletion in a preclinical in vivo model with a specific Treg deletion of PI3K. They found that isolated disruption of Treg activity had only a limited antitumoral effect and was accompanied by increased numbers of immunosuppressive CSF1R + tumor-associated macrophages within tumor; in contrast, co-depletion of Foxp3 + Treg cells and CSF1R + tumor-associated macrophages increased the recruitment and activity of CD8 + Tconv cells and achieved almost complete tumor rejection.…”

Section: Introductionmentioning

confidence: 99%

Blocking inflammation to improve immunotherapy of advanced cancer

Macciò

Madeddu

2019

Immunology

View full text Add to dashboard Cite

The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T‐cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

show abstract

“…Although this antibody offers clinical benefit to patients with ATL (9-11), skin-related adverse events (AE) such as erythema multiforme are frequent, and severe AEs including Stevens-Johnson Syndrome/toxic epidermal necrolysis are occasionally observed (12). On the other hand, moderate skin-related AEs after mogamulizumab may be associated with a favorable prognosis (9,13). The skin-related AE may be due to regulatory T (Treg) cell depletion by mogamulizumab (9,12,(14)(15)(16), but the detailed mechanisms have not been fully established.…”

Section: Introductionmentioning

confidence: 99%

Mogamulizumab Treatment Elicits Autoantibodies Attacking the Skin in Patients with Adult T-Cell Leukemia-Lymphoma

Suzuki

Saito

Ishii

et al. 2019

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: The anti-CCR4 mAb, mogamulizumab, offers therapeutic benefit to patients with adult T-cell leukemialymphoma (ATL), but skin-related adverse events (AE) such as erythema multiforme occur frequently. The purpose of this study was to determine the mechanisms by which mogamulizumab causes skin-related AEs in patients with ATL. Experimental Design: We investigated whether autoantibodies were present in patients' sera using flow cytometry to determine binding to keratinocytes and melanocytes (n ¼ 17), and immunofluorescence analysis of tissue sections. We analyzed the IgM heavy chain repertoire in peripheral blood mononuclear cells before and after mogamulizumab or other chemotherapy by next-generation sequencing (NGS; n ¼ 16). Results: Autoantibodies recognizing human keratinocytes or melanocytes were found in the sera of 6 of 8 patients suffering from mogamulizumab-induced erythema multiforme. In one patient, complement-dependent cytotoxicity (CDC) mediated by autoantibodies against keratinocytes or melanocytes was proportionally related to the severity of the erythema multiforme. The presence of autoantibodies in the epidermis was confirmed in all biopsy specimens of mogamulizumab-induced erythema multiforme (n ¼ 12). Furthermore, colocalization of autoantibodies and C1q, suggesting the activation of CDC, was observed in 67% (8/12). In contrast, no autoantibody or C1q was found in ATL tumor skin lesions (n ¼ 13). Consistent with these findings, NGS demonstrated that IgM germline genes had newly emerged and expanded, resulting in IgM repertoire skewing at the time of erythema multiforme. Conclusions: Mogamulizumab elicits autoantibodies playing an important role in skin-related AEs, possibly associated with regulatory T-cell depletion. This is the first report demonstrating the presence of skin-directed autoantibodies after mogamulizumab treatment.

show abstract

Mogamulizumab for relapsed adult T‐cell leukemia–lymphoma: Updated follow‐up analysis of phase I and II studies

Cited by 54 publications

References 48 publications

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach

Blocking inflammation to improve immunotherapy of advanced cancer

Mogamulizumab Treatment Elicits Autoantibodies Attacking the Skin in Patients with Adult T-Cell Leukemia-Lymphoma

Contact Info

Product

Resources

About