synthetic live therapeutics Flashcards
Why live therapeutics?
- Adaptability to host environment
- Sustained therapeutic effects
- Targeted action
- Personalized medicine potential
- Reduced systemic side effects
CAR-T therapy
normal T-cell :
* Recognize specific antigens presented by Major Histocompatibility Complexes (MHCs)
* Tumours may escape immune surveillance due to downregulation or mutation of MHCs
* Specific TCR is required
CAR-T :
* Recombinant receptor with both tumour-antigen-binding and T-cell activating function
* Single-chain variable fragment (scFv) on extracellular domain recognizes and binds to specific tumour antigen
* Intracellular signal transduction region improve cell proliferation, survivor time and anti-tumour activity
* Unrestricted by MHCs
* More specific and more customizable as antigen-binding domain can be changed to various antigen target
Gut Microbiome
- Human intestinal microbiota is composed of 10^13 to 10^14 microorganisms
- The collective genome (“microbiome”) of intestinal microorganisms has at least 100 times as many genes as our own genome.
- Probiotics are recommended for gastric discomfort e.g. indigestion, abdominal bloating, constipation and diarrhoea
- Bacteria strains from Lactobacillus, Bifidobacterium, Streptococcus are commonly used in probiotics
Probiotics application
use of probiotics reported:
* Reduced gastrointestinal symptoms and severity score in patients with
irritable bowel syndrome (IBS)1
* Induction and maintenance of remission in patients with inflammatory bowel disease (IBD)2
However, there are currently no FDA-approved engineered live bacterial therapeutics
engineered bacteria applications
- obesity in children abd T2D has been linked to gut microbiota
Prevention of colorectal cancer
* E. coli Nissle was engineered to
* Specifically bind onto colorectal cancer cells
* Express myrosinase for conversion of glucosinolate into sulforaphane, an active anti-cancer compound
engineered bacteria benefits
- Non-invasive administration (Oral administration)
- Introduced in the form of probiotics that promote gut health
Transient effect
No rejection
Enhance survival
Target absorption sites
Limitations of CAR-T cell therapy
- Cytokine-release syndrome (CRS)
- Neurotoxicity
- On-target-off-tumour toxicity
- Exhaustion of CAR-T cells
- Tumour escape
CAR-T durability
- CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients
- CD4+ CAR T cells dominate at later time points
- Long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with
ongoing functional activation and proliferation.
CAR-T efficacy
Kymriah
In a group of 63 children and young adults with no response to standard treatment, 83 % (52/63) showed remission and 75% did not relapse after 6 months
Yescarta
- Slowed or stopped growth of cancer in 82% patients; 54% had the cancer disappeared completely; 40% showed no signs of cancer 15.4 months later
- At a median follow-up of 24.9 months, the median event-free survival is higher in patients receiving Axi-cel treatment compared to those receiving standard care
Clinical trial regulations
- Administrative and regulatory procedures e.g. submission for
investigational new drug (IND) - Chemistry, manufacturing and control information e.g. characterization of LBP, composition, method of manufacture and stability
- Non-clinical information:
Pharmacology, pharmacokinetic and toxicology - Clinical information:
Previous human experience, proposed study design and safety plan
-HSA and IRB regulate
benefits and risk of LBT
Benefit and risk balance for live therapeutics can be demonstrated through:
* Quality
* Safety
* Efficacy
Quality
Quality
* Batch to batch variation for LBPs
Identity and purity
Phenotypic characteristics of strain in terms of metabolic capabilities and pathogenicity
* Growth yield during upscaling process
Quantification of live microorganisms, beneficial metabolites and contaminants
* Stability of LBPs (shelf-life)
Viability and potency
Safety
- Pathogenic and allergenic potential
- Weakness of intended recipients
- Toxicology not always directly related to dosage
- Raw materials used for growth and maintenance, and potential residuals
- Transferability of antibiotic resistance gene to other bacteria
- Translocation (risk of infection)
Efficacy
- Intended effect/outcome
- Environmental factors e.g. transport and storage conditions
- Host-related factors e.g. diet, composition of recipient’s gut microbiota, stomach pH, ethnicity
- Viability and postbiotic concept
