New T1D Immune Targeted Therapies on the Horizon

New T1D Immune Targeted Therapies on the Horizon

By: Tiffany Richardson 

Summary: Type 1 Diabetes (T1D) occurs after a targeted attack on insulin-producing beta cells by inappropriately activated immune cells (T cells). New therapies seek to take back control of the immune system in T1D by manipulating defective Tregs. Given the immune nature of the pathophysiology of T1D, Treg therapy has the inherent potential for directly targeting the root cause of this disease. There are multiple studies attempting to expand Tregs ex vivo for later transplantation. Furthermore, engineered CAR Treg technology may provide a more specific disease pertinent population of therapeutic immune cells.

 Type 1 Diabetes (T1D) occurs after a targeted attack on insulin-producing beta cells by inappropriately activated immune cells (T cells). Defects in immunosuppressive T regulatory cells (Tregs) and T cells that are triggered by beta cell specific autoantigens lead to a precipitous drop in beta cell numbers in T1D. It is hypothesized that clinical presentation of T1D occurs while this autoimmune attack occurs asynchronously on various pancreatic islets. New therapies seek to take back control of the immune system in T1D by manipulating defective Tregs. Currently, T1D is treated with insulin but there is growing promise for immune mediated treatment of T1D.

 In vivo Tregs to the Ex vivo Rescue

 T cell therapies have the potential to not just treat but cure T1D by re-establishing appropriately functioning immune cell populations. Typically, T cells provide immune surveillance by migrating between the bloodstream and lymphoid tissue (i.e. tissues responsible for lymphocyte and antibody production). Binding to an antigen can cause the T cell to proliferate and differentiate into more T cells that can further recognize and remove this antigen [1]. Generally, these therapies attempt to 1) amplify the amount of Tregs outside of the body (ex vivo) before transplantation or 2) enhance Treg performance in vivo by stimulating, re-activating, or converting them to a more protective phenotype. Below is a description of these new therapies [2,3,4,5]:

Study ID Clinical Phase & Status Therapeutic Agent Study Outcomes Summary
ISRCTN06128462

NCT01210664

Completed Ex vivo expanded Tregs Effects on beta cell secretion were variable between patients. Butt beta cell secretion did not decline over time given the nature of decreasing beta cell function during T1D. Two years after post-infusion some patients required reduced daily insulin use per day.
NCT02691247 II 

Completed

Ex vivo expanded Tregs No results reported as of yet.
NCT02772679 I

Active, not recruiting

Ex vivo expanded Tregs + Interleukin-2 (IL-2) Evaluation of infusion of ex vivo Tregs in conjunction with interleukin-2 (IL-2) in an attempt to enhance Treg survival and performance. In 2019, early study results detailed beta cell function was still declining in these patients. Thus, IL-2 may not increase the benefit of this therapy.
NCT02932826 I, II

Recruiting

Ex vivo expanded CB Tregs Evaluation of the safety and efficacy of ex vivo Tregs into recently diagnosed patients with T1D. The infusions were safe, but the patients did not show improvements in beta cell function.
NCT03011021 I, II

Recruiting

Ex vivo expanded Tregs + Liraglutide dose escalation No results reported as of yet.
TregVAC2.0EudraCT: 2014-004319-35 II Recruiting Ex vivo expanded Tregs + anti-CD-20 antibody Evaluation of infusion of ex vivo Tregs in combination with anti-CD-20 antibody (B-cell immune marker).

These studies represent a new frontier for T1D immune treatment. Disadvantages to these ex vivo therapies include general difficulties in ex vivo Treg expansion and low frequency of the infused cells in circulation over time. Scientists are working to convert other T cell types into Tregs which may increase the starting material for the generation of transferable Tregs. Ex vivo expansion can result in contamination by other T cell populations before and after differentiation. These cells also have low survival ability after transplantation. These pitfalls need to be overcome before these therapies are able to be regularly used in the clinic.

Antigen Specific Tregs for T1D Specific Therapy

Studies of T1D animal models have shown even further promise for antigen specific Tregs over ex vivo expansion. Most Tregs that are antigen specific for T1D associated antigens are located within these cells’ target tissue, the pancreas. Because of the pancreas’s low accessibility, it is difficult to isolate a sufficient quantity of this type of Tregs. To circumvent this challenge, chimeric antigen receptor (CAR) Treg technology has been employed. Tenspolde and colleagues have generated insulin-specific CAR Tregs [5]. These Tregs were able to proliferate in the presence of insulin and reduced the proliferation of populations of T cells that have been implicated in T1D progression. These CAR Tregs were not able to prevent T1D development in mice but were still detectable long after transfer. This study shows a proof of principle for the potential of this technology in T1D.

The Takeaway: Given the immune nature of the pathophysiology of T1D, Treg therapy has inherent potential for directly targeting the root cause of this disease. There are multiple studies that are attempting to expand Tregs ex vivo for later transplantation. Furthermore, engineered CAR Treg technology may provide a more specific disease pertinent population of therapeutic immune cells. It is yet to be completely seen how these therapies will optimally perform in patients, but further innovation could result in successful T1D treatment.

 Sources

  1. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Chapter 8, T Cell-Mediated Immunity. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10762/
  2. Volfson-Sedletsky Victoria, Jones Albert, Hernandez-Escalante Jaileene, et al. (2021). Emerging Therapeutic Strategies to Restore Regulatory T Cell Control of Islet Autoimmunity in Type 1 Diabetes. Frontiers in Immunology. 12. https://doi.org/10.3389/fimmu.2021.635767.
  3. Trzonkowski, P., Bacchetta, R., Battaglia, M., et al. (2015). Hurdles in therapy with regulatory T cells. Science translational medicine, 7(304), 304ps18. https://doi.org/10.1126/scitranslmed.aaa7721.
  4. Gliwiński, M., Iwaszkiewicz-Grześ, D., & Trzonkowski, P. (2017). Cell-Based Therapies with T Regulatory Cells. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, 31(4), 335–347. https://doi.org/10.1007/s40259-017-0228-3.
  5. Tenspolde, M., Zimmermann, K., Weber, et al. (2019). Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes. Journal of autoimmunity, 103, 102289. https://doi.org/10.1016/j.jaut.2019.05.017.

 

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