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CD3-epsilon(CD3e) immunotoxins (IT), a promising precision reagent for various clinical conditions requiring effective depletion of T cells, often shows limited treatment efficacy for largely unknown reasons. Tissueresident T cells that persist in peripheral tissues have been shown to play pivotal roles in local and systemic immunity, as well as transplant rejection, autoimmunity and cancers. The impact of CD3e-IT treatment on these local cells, however, remains poorly understood. Here, using a new murine testing model, we demonstrate a substantial enrichment of tissue-resident Foxp3+ Tregs following CD3e-IT treatment. Differential surface expression of CD3e among T-cell subsets appears to be a main driver of Treg enrichment in CD3e-IT treatment. The surviving Tregs in CD3e-IT-treated mice were mostly the CD3edimCD62Llo effector phenotype, but the levels of this phenotype markedly varied among different lymphoid and nonlymphoid organs. We also found notable variations in surface CD3e levels among tissue-resident T cells of different organs, and these variations drive CD3e-IT to uniquely reshape T-cell compositions in local organs. The functions of organs and anatomic locations (lymph nodes) also affected the efficacy of CD3e-IT. The multi-organ pharmacodynamics of CD3e-IT and potential treatment resistance mechanisms identified in this study may generate new opportunities to further improve this promising treatment. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous lymphomas with poor overall prognosis, particularly in the setting of relapsed/refractory PTCL. Given the limited efficacy of current therapies, several different novel therapies encompassing multiple different mechanisms of action have been evaluated for relapsed and refractory PTCLs. In this review, we explore the current standard of care for relapsed/refractory PTCL, and evaluate in depth novel and emerging therapies, their scientific basis, and current trials for relapsed/refractory PTCL. [ABSTRACT FROM AUTHOR]

Anti-CD3-epsilon (CD3e) monoclonal antibodies (mAbs) and CD3e immunotoxins (ITs) are promising targeted therapy options for various T-cell disorders. Despite significant advances in mAb and IT engineering, vascular leakage syndrome (VLS) remains a major dose-limiting toxicity for ITs and has been poorly characterized for recent "engineered" mAbs. This study undertakes a direct comparison of non-mitogenic CD3e-mAb (145-2C11 with Fc-silentTM murine IgG1: S-CD3e-mAb) and a new murine-version CD3e-IT (saporin–streptavidin (sZAP) conjugated with S-CD3e-mAb: S-CD3e-IT) and identifies their distinct toxicity profiles in mice. As expected, the two agents showed different modes of action on T cells, with S-CD3e-mAb inducing nearly complete modulation of CD3e on the cell surface, while S-CD3e-IT depleted the cells. S-CD3e-IT significantly increased the infiltration of polymorphonuclear leukocytes (PMNs) into the tissue parenchyma of the spleen and lungs, a sign of increased vascular permeability. By contrast, S-CD3e-mAbs-treated mice showed no notable signs of vascular leakage. Treatment with control ITs (sZAP conjugated with Fc-silent isotype antibodies) induced significant vascular leakage without causing T-cell deaths. These results demonstrate that the toxin portion of S-CD3e-IT, not the CD3e-binding portion (S-CD3e-mAb), is the main driver of vascular leakage, thus clarifying the molecular target for improving safety profiles in CD3e-IT therapy. [ABSTRACT FROM AUTHOR]

T-Cell malignancies are a group of heterogeneous disorders composed of primary cutaneous T-cell lymphomas (CTCLs), peripheral T-cell lymphomas (PTCLs), and T-cell leukemias, including T-cell large granular lymphocytic leukemia (T-LGLL). Cases of patients with combined T-cell malignancies and plasma cell dyscrasias (PCD) are reported in the literature, but these are mostly limited to case reports or small case series with <10 patients. Here, we described the clinical course of 26 patients and report baseline characteristics and clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs) in this unique population. There was no survival difference in patients with CTCL or T-LGLL and concomitant PCD when treated with standard therapy directed at the T-cell malignancy when compared to historical controls. However, patients with PTCL and concomitant PCD had significantly inferior outcomes with rapid progression and worse OS and PFS at 1.7 years (p=0.006) and 4.8 months (p=0.08), respectively, when compared to historical controls for patients with PTCL, although the limited number of patients included in this analysis precludes drawing definitive conclusions. Treatment directed at the T-cell malignancy resulted in the eradication of the PCD clone in multiple patients (15.4%) including one with multiple myeloma (MM) who experienced a complete response after starting therapy directed at the T-cell malignancy. For patients with T-cell malignancies and concomitant PCD, treatment with standard T-cell-directed therapies is recommended based on this analysis with continued follow-up and monitoring of the concomitant PCD. Further studies are needed to definitively elucidate the increased risk of relapse in patients with PTCL and concomitant PCD, and larger, multi-center cohorts are needed to validate these findings across T-cell malignancies and PCDs. [ABSTRACT FROM AUTHOR]