Myelin proteolipid protein (PLP) peptide CAR T cells to target auto-reactive T cells for the treatment of Multiple Sclerosis

Background

Background

Multiple Sclerosis (MS) is a chronic and potentially disabling neurological disease that impacts millions of people world-wide.1

The signs and symptoms arise from the immune systems attacks on the CNS, particularly the myelin sheath which is a shielding surrounding nerves for protection.1

Proteolipid Protein (PLP) plays a critical function in maintaining the integrity of the myelin sheath and is often the target of autoimmune responses.2

Project Quality

Project Quality

Hypothesis: The administration of pMHCII-CAR T cells will result in the destruction of auto-reactive T cells (CD4+) responsible for causing Multiple Sclerosis.

Aim 1: Obtaining a MIGR1-based retroviral construct that drives the expression of MHC II receptors and PLP peptides for targeting the total population of self-reactive T cells.

Aim 2: Isolating the patients T-cells using leukapheresis and generating PLP pMHCII-CART cells by transducing the retroviral vector obtained.

Aim 3: Expanding the generated PLP pMHCII-CAR T cells for administration and monitoring patients over 18 months to track the progression of MS following treatment.

Potential Risks

Potential Risks

Cytokine Release Syndrome (CRS) 9

Immune effector cell-associated

neurotoxicity 10

Significance

Significance

Future directions

Quality of life 1

Prevalence 11

Communication of Results

Publishing

Conference presentations

Communication of Results

Social media

Talks at MS events

References

References

1. Dobson R, Giovannoni G. Multiple sclerosis – A Review. European Journal of Neurology. 2018 Nov 18;26(1):27–40. doi:10.1111/ene.13819

2. Greer JM, Trifilieff E, Pender MP. Correlation between anti-myelin proteolipid protein (PLP) antibodies and disease severity in multiple sclerosis patients with PLP responsepermissive HLA types. Frontiers in Immunology. 2020 Aug 21;11. doi:10.3389/fimmu.2020.01891

3. Rodríguez Murúa S, Farez MF, Quintana FJ. The immune response in multiple sclerosis. Annual Review of Pathology: Mechanisms of Disease. 2022 Oct 24;17(1):121–39. doi:10.1146/annurev-pathol-052920-040318

4. BioRender. Scientific Image and Illustration Software [Internet]. 2023 [cited 2023 Oct 7]. Available from: https://www.biorender.com/

5. NIH. Car T cells: Engineering immune cells to treat cancer [Internet]. 2022 [cited 2023 Oct 8]. Available from: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

6. Mackensen A, Müller F, Mougiakakos D, Böltz S, Wilhelm A, Aigner M, et al. Anti-cd19 car T cell therapy for refractory systemic lupus erythematosus. Nature Medicine. 2022 Sept 15;28(10):2124–32. doi:10.1038/s41591-022-02017-5

7. Yi J, Miller AT, Archambault AS, Jones AJ, Bradstreet TR, Bandla S, et al. Antigenspecific depletion of CD4+ T cells by car T cells reveals distinct roles of higher- and loweraffinity tcrs during autoimmunity. Science Immunology. 2022 Oct 14;7(76).doi:10.1126/sciimmunol.abo0777

8. Multiple Sclerosis Trust. Expanded disability status scale (EDSS) [Internet]. 2018 [cited 2023 Oct 7]. Available from: https://mstrust.org.uk/a-z/expanded-disability-status-scaleedss

9. Frey N, Porter D. Cytokine release syndrome with chimeric antigen receptor T cell therapy. Biology of Blood and Marrow Transplantation. 2019 Dec 23;25(4).

doi:10.1016/j.bbmt.2018.12.756

10. Sterner RC, Sterner RM. Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy. Frontiers in Immunology. 2022 Aug 23;13. doi:10.3389/fimmu.2022.879608

11. Tao C, Simpson S, van der Mei I, Blizzard L, Havrdova E, Horakova D, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.Journal of Neurology, Neurosurgery & Psychiatry. 2016 Apr 3;87(12):1343–9. doi:10.1136/jnnp-2016-314013