Therapeutic Approaches for Targeting T Regulatory Cells in Autoimmunity

Regulatory T cells (Tregs) are a specialized CD4+ subpopulation of lymphocytes with regulatory functions that suppress excessive and uncontrolled immune responses, which inhibit adaptive and innate immune cells such as conventional T cells, B cells, antigen-presenting cells (APCs), natural killer (NK) cells, and so forth.

The most specific marker for these cells is FoxP3, which is localized intracellularly. Selected surface markers such as CD25high (high molecular density) and CD127low (low molecular density) could serve as surrogate markers to detect Tregs in routine clinical practice. Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease.

Regulatory T (Treg) cells maintain immune homeostasis by inhibiting abnormal/overactive immune responses to both autogenic and nonautogenic antigens. Treg cells play an important role in immune tolerance, autoimmune diseases, infectious diseases, organ transplantation, and tumor diseases.

  • Organ transplantation is the gold standard therapy for end-stage organ failure. Although, the results of organ transplantation have been ameliorated in recent decades, chronic rejection and the side effects of immunosuppressants are still an ongoing serious issue. None of the present immunosuppressive medications (in contrast to Tregs) have the potential to specifically suppress immune mechanisms. Various strategies are currently underway to avoid or minimize the use of immunosuppressive drugs. In this case, it may be possible that Tregs represent a promising solution to induce transplantation tolerance and control the immune response.
  • Autoimmune diseases as lifelong disorders are one of the major causes of mortality. The main etiology of autoimmune diseases is not fully understood; however, failure of immunological tolerance is a common cause of each autoimmune condition.
    • Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to the development of diverse pathologies including autoimmunity and cancer. Consistently recent studies have highlighted that Treg dysfunction is a common denominator in autoimmunity, with reduced Treg cell frequencies and impaired suppressive function identified in a wide range of autoimmune diseases, including multiple sclerosis, SLE, type 1 diabetes, thyroiditis, and inflammatory bowel disease. Thus, it is becoming apparent that Treg cells possess a unique power in supervising autoimmune reactions and the re-establishment of self-tolerance.
  • Two main strategies have been developed to augment the numbers and/or increase the functional activity of Tregs. In vivo Treg therapies focus on the administration of immunomodulatory agents that enhance the number and/or function of Treg cells in vivo, and the adoptive Treg therapies transfer in vitro expanded Treg cells. Interventions that increase polyclonal endogenous Treg cells in vivo involve low-dose interleukin-2 (IL-2), mutant IL-2, IL2/Anti-IL-2 Ab complexes. In contrast, applications of antigen-based treatments could lead to the enhancement of antigen-specific Treg subsets. On the other hand, adoptive Treg cell therapies rely on the optimal isolation and expansion of Treg cells in vitro. Thus far, clinical trials in autoimmunity have only utilized expanded polyclonal Treg cell populations. However, antigen-specific Treg cells can be generated in vitro by genetic insertion of synthetic receptors (including engineered T cell receptors (TCR), chimeric antigen receptors (CAR) or B cell antibody receptors (BAR)), or by transformation of antigen-specific effector T (Teff) cells into induced Treg (iTreg) cells via stimulation in the presence of transforming growth factor beta (TGF-ß) and IL-2, transgenic FOXP3 overexpression, blockade of cyclin-dependent kinase 8 (CDK8) and CDK19 signaling, or a combination of cytotoxic T lymphocyte antigen 4 (CTLA-4) overexpression, IL-2 ablation and antigenic stimulation.
  • Therapeutical Treg modulation is considered to be a promising therapeutical approach to treat some selected disorders, such as allergies, autoimmune disorders, and to prevent allograft rejection. Multiple approaches such as adoptive Treg cell therapies as well as targeting mediators that can enhance the action of endogenous Treg cells are under evaluation, both in academia and industry.

Cutaneous T-cell Lymphoma (CTCL): Market Size & Forecast

Cutaneous T-cell Lymphoma (CTCL): Market Size & Forecast

Disease Overview

Cutaneous T-cell Lymphoma (CTCL) is the most common type of skin lymphoma. CTCL is rare cancer that begins in white blood cells called T cells (T lymphocytes) and these the T cells develop abnormalities that make them attack the skin. It appears as an eczema-like skin rashes and can affect widespread parts of the body.

There are different types of Cutaneous T-cell Lymphoma (CTCL). Mycosis Fungoides and Sezary syndrome are the most frequent type of Cutaneous T-cell Lymphoma (CTCL). The other forms of cutaneous lymphoma include the CD30 positive lymphoproliferative disorders (CD30+ LPDs), subcutaneous panniculitis-like T-cell lymphoma, Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma, Primary cutaneous gamma/delta T-cell lymphoma, Extranodal natural killer/T-cell lymphoma, nasal type, and others.

The World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) Classification

Indolent Clinical Behavior Aggressive Clinical Behavior
Mycosis fungoides Sézary syndrome  
Subcutaneous panniculitis-like T-cell lymphoma Primary cutaneous CD8+ aggressive epidermotopic T-cell lymphoma  
Primary cutaneous CD4+ small/medium pleomorphic T-Cell lymphoma   Primary cutaneous gamma/delta T-cell lymphoma  
CD30+ Lymphproliferative Disorders Primary cutaneous anaplastic large cell lymphomaLymphomatoid papulosis   Extranodal natural killer/T-cell lymphoma, nasal type  

Epidemiology

According to the CmaxInsight, the total incident cases of Cutaneous T-cell lymphoma (CTCL) were calculated to be around 9,000 in 2018 in 7MM including the United States, EU5 countries (the United Kingdom, France, Italy, Spain, and Germany) and Japan. The United States accounts for the highest incident cases of 3,430  in 2018 followed by EU5 countries, and Japan According to the National Organization for Rare Disorders (NORD), the Cutaneous T-cell lymphoma (CTCL) affects males twice as often as females. The majority of the CTCL cases are diagnosed between the age-group of 40 to 60 years. Further, it is expected that the incident cases of the CTCL would increase over the forecasted period.

Market Size

According to the Cmaxinsight, the market size of Cutaneous T-cell Lymphoma (CTCL) is growing at a CAGR of 5.54% for the forecasted period 2018-2028 in 7MM including the United States, EU5 countries (the United Kingdom, France, Italy, Spain, and Germany) and Japan. The United States accounts for the highest market share of around 40% in 2018 followed by EU5 countries, and Japan. The market is dominated by the availability of topical therapies, including corticosteroids, retinoids, different chemotherapy regimens, and others. The market is driven by rising incident cases, the expected launch of emerging therapies, technological advancement, and improving healthcare facilities.

Competitive Analysis

The market is dominated by the availability of the marketed drugs such as Istodax (Celgene Corporation), Poteligeo (Kyowa Hakko Kirin Co. Ltd), Valchlor/ Ledaga (Actelion), Uvadex (Mallinckrodt Pharmaceuticals), Targretin (Eisai Co., Ltd.), and Zolinza (Merck Sharp & Dohme Corp), and others. The expected launch of emerging therapies such as Quisinostat (Janssen), Remetinostat (Medivir AB), denileukin diftitox (Eisai Co., Ltd) and others shall have a positive impact on the market.

The companies are entering into the mergers, acquisitions, collaborations and other activities for increasing their market penetration. In January 2020, the Almirall had entered into an option agreement to acquire Bioniz Therapeutics and to establish a broad research agreement to further expand its innovative pipeline in medical dermatology. This collaboration would allow Almirall to executes its strategy to develop and expand its R&D pipeline with new treatment modalities with the objective to address highly underserved diseases within oncodermatology and immunodermatology.