Advanced Therapeutics MSc Lecture Notes PDF

Advanced Therapeutics  Topics to cover: Gene editing Genome modification CAR-T cells Stem cell therapy Unexplored therapeutic opportunities GARV-AAV2-A20 Rituximab (anti-CD20) >50% efficacy in patients with CD20+ non-Hodgkin’s l...

Advanced Therapeutics  Topics to cover: Gene editing Genome modification CAR-T cells Stem cell therapy Unexplored therapeutic opportunities GARV-AAV2-A20 Rituximab (anti-CD20) >50% efficacy in patients with CD20+ non-Hodgkin’s lymphoma Weekly administrations Not curative Nat Clin Prac Rheum, 2007 JAK (tyrosine kinase) Inhibitors Furumoto et al, Biodrugs, 2013  Immune checkpoint blockade - an example of the success of monoclonal therapies Nivolumab/Pembrolizumab (anti-PD1) Ipilimumab (anti-CTLA4) The next step? Gene & cell therapy drugs that have gained regulatory approved Glybera lipoprotein lipase deficiency. AAV1 viral vector delivering an intact copy of the human lipoprotein lipase (LPL) gene to muscle cells. Strimvelis ADA-SCID (Combined Immunodeficiency) hematopoietic stem cell extracted from the patient, CD34-purified. Transduced with a gammaretrovirus containing the human adenosine deaminase gene Luxturna Leber's congenital amaurosis AAV2 vector containing human RPE65 cDNA Kymriah B-cell acute lymphoblastic leukemia (ALL) Autologous CAR-T cells Yescarta large B-cell lymphoma Autologous CAR-T cells  Disease categories being targeted by gene therapies e.g. ADA-SCID e.g. Dermatitis/eczema e.g. Neoantigens, CAR-T etc. e.g. Diabetes e.g. COVID19 e.g. β-thalassemia e.g. IBD – ETS2 in 95% of patients e.g. DMD Gene therapies pricing and reimbursement HSC transplants: The Origins of Cell Therapy Severe combined immunodeficiency David Vetter SCID-X1 SCID-X1; The most common immunodeficiency SCID-X1; Impaired T cell development due to lack of γc Defective JAK signalling No help to B cells Animal models of Severe combined immunodeficiency Foxn1nu Nude, athymic Lack T cells Prkdcscid Non-obese diabetic (not diabetic) Impaired T/B cell Reduced NK cell Complement deficient (C5) Macrophage immature PrkdcscidIl2rg No B cells, T cells or NK cells or complement Defective DCs and Macrophage Rag1nullIL2rgnull No B cells, T cells NK cells deficient How to treat SCID? Autologous or allogeneic bone marrow transplants from immune-competent HLA-matched donors E. Donnall Thomas Nobel Prize in Medicine 1990 In 1956 performed the first successful syngeneic (genetically identical) bone marrow transplant between two humans. In 1969 these refinements enabled Thomas to perform the first successful bone marrow transplant in a leukemia patient from a relative who was not an identical twin. Timothy Ray Brown – “The Berlin Patient” 1995- diagnosed with HIV Successfully treated with anti-retroviral therapy (ART) 2006- diagnosed with acute myeloid leukemia (AML) 2007- underwent allogenic stem cell transplant and ART stopped Donor harbored a genetic mutation of the CCR5 gene (CCR5-delta-32) – cell surface receptor for HIV 2008- relapse and second transplant from same donor March 2008- diagnosed as “cured” from HIV, virus completely undetectable and HIV- specific antibodies in decline 2010- waived right to anonymity and became advocate for HIV research 2012- Timothy Ray Brown Foundation for HIV research and vaccines founded 2019- Adam Castillejo “The London Patient” becomes 2nd person cured of HIV using the same transplantation regime 2020- NIH supported 241 individual research projects focused on HIV cure with a total investment of over $130,000,000. September 29th 2020- Timothy Ray Brown dies of AML Modifying HSC gives permanent expression Advantage is autologous cells can be used to circumvent need for HLA-matched donor Mechanisms of transplant rejection; Graft versus host disease Host immune system central to all this whether it be monoclonal therapies, mRNA therapeutic approaches, CAR-T etc.. Innate and adaptive immune responses are interdependent Innate immunity primes antigen uptake and priming of adaptive immunity within lymphoid organs APC-T cell communication: Signal 1, 2 and 3 APC-derived cytokines influence T cell differentiation Campe and Ullrich, Front Imm, 2022 T cell receptors and the Class I, Class II MHC Exogenous vs endogenous antigen processing and presentation Thermo Fisher Scientific T cell receptor diversity The human HLA locus Peptide presentation by the MHC receptor to the T cell receptor Gene therapy - Introduction Methods to deliver gene therapies Viral Non-viral The pros and cons of non-viral versus viral vectors Non-viral gene therapy is an area of intense focus Antigen uptake and adaptive priming in the gastrointestinal tract Non-viral gene therapy mRNA Therapy COVID has accelerated nucleic acid based therapeutic research Nance, K.D. and Meier, J.L., 2021. Modifications in an emergency: the role of N1-methylpseudouridine in COVID-19 vaccines. ACS Central Science, 7(5), pp.748-756. Structure and nucleotide modification of therapeutic mRNA  mRNA vaccines, how good are they really? Benefits over traditional vaccines include rapid production and roll-out at scale Good safety profile Two-dose vaccine effectiveness against COVID-19–related death was 69.8% (95% CI, 65.9%‒73.3%) during the pre-Delta period and 55.7% (49.5%‒61.1%) during the high Delta period Three doses provided 88.7% (73.5%‒95.2%) vaccine effectiveness against death, and the incremental benefit of 3 vs 2 doses was 74.6% (40.4%‒89.2%) during high Delta. Substantial waning of effectiveness from 65.1% (54.2%‒73.5%) within 6 months from second-dose vaccination to 45.2% (30.6%‒56.7%) ≥6 months after second-dose vaccination in the high Delta period. Efficacy rates lower for less severe outcomes i.e. infection not resulting in death Fail to prevent transmission Lu et al, Open Forum Infectious Diseases, Volume 11, Issue 3, March 2024 Mongin et al, Nat Comms, 14, Article number: 5452 (2023) Moderna is developing a vast array of mRNA-based therapies Pfizer found its “candidate demonstrated non- inferiority and superiority to a licensed flu vaccine at the time of the primary analysis.” The trial met its secondary immunogenicity endpoints for A strains but missed for B strains. Different forms of mRNA therapeutics Fang, E., Liu, X., Li, M., Zhang, Z., Song, L., Zhu, B., Wu, X., Liu, J., Zhao, D. and Li, Y., 2022. Advances in COVID-19 mRNA vaccine development. Signal Transduction and Targeted Therapy, 7(1), pp.1-31. Potential mRNA therapeutics in cancer