Immunotherapy Flashcards
Conventional Immunosuppressants
Relatively broad-acting (lack specificity):
- Corticosteroids: Inhibit inflammation
- Cytotoxic drugs (Azathioprine): Interfere with DNA synthesis
- Cyclosporin A: Suppress IL-2 and T cell proliferation (via NFAT inhibition)
- Rapamycin: inhibits mTOR pathway (proliferation/translation)
Immunotherapy mechanism and types
Treating disease via immune modulation (activation, suppression or skewing)
Types:
- Soluble mediators (cytokines, antagonists and adjuvants)
- Antibody therapy (receptor blocking, cell depletion, neutralising effectors)
- Cell based (DC vaccination, T cell adaptive transfer/engineering, vaccination)
- Skewing/suppression (preventing inappropriate immune response)
Soluble Mediator immunotherapy:
Recombinant Cytokines
GM-CSF treats neutropenia in cancer patients:
- recombinant proteins boost neutrophil production allowing for more rounds of chemotherapy
PEGylated IFNa: Hep B/C virus infection
- Type 1 IFNs are PEGylated to increase their biological half-life
- Treat viral infection (IFNg for bacteria)
Soluble Mediator immunotherapy:
Cytokine antagonists
Anakinra-soluble IL-1 receptor antagonists used to block inflammatory pathway
- Targets autoinflammatory diseases like RA, Gout, Muckle Wells syndrome
Rinocept IL-1R1-Fc fusion protein intercept IL-1 before it can bind to endogenous, pro-inflammatory IL-1 receptor
Soluble Mediator immunotherapy:
Adjuvants
1) CpG (hypomethylated DNA) triggers TLR9 for Th1 response
2) Yeast particles boost immune response: Beta glucans activate macrophage and innate immune system (boost innate immune memory - yes that exists!!)
3) Coley’s Toxins: early adjuvant - bacterial mixture injected into tumours
4) Alum promotes Th2 response
5) LPS promotes Th1 response
Antibody Immunotherapy:
Monoclonal Antibodies
1) Anti-TNFa (Infliximab) used in treating Crohn’s
- TNFa normally triggers inflammation/neutrophil influx/complement production
2) Anti-CD11a (Efalizumab) preventing influx of immune cells
- CD11a = integrin, responsible for recruitment of immune cells (TEM)
3) Anti-CD20 (Rituximab) for treating B-cell leukaemia
- CD20 highly expressed on B-cell surface
- IgG bind anti-CD20 to promote complement
4) Anti-HER2 receptor (Herceptin) for breast cancer treatment
- Inhibits HER2 receptor from signalling to block cell proliferation pathways
Problems with Monoclonal Antibodies
Repeat doses = immunogenic: resulting in neutralising anti-antibody antibodies
Overcome problem by producing Chimaeric Antibodies
- binding site = constant but constant region is replaced with mice/rat/human ones
- Can humanise antibodies, leaving just the specific mouse CDRs on the less immunogenic human Ab
Overcome problem by producing Bispecific Abs:
- 2 antibodies are combined (one target-specific, the other T-cell specific)
Preventing inappropriate immune responses:
IgE mediated allergies
Numerous inoculous particles cause inappropriate immune response (potentially life threatening):
- Normal Th2/IgE response activates Mast cell degranulation and inflammation/tissue damage
Immunotherapies target cause: skewing Th2 to a Th1/Treg response
Preventing inappropriate immune responses:
Suppression of Th2 response
Enhancing a Th1 response downregulates Th2 response.
1) Skewing therapy: CpG: TLR4 agonist + allergen leads to Th1 response. Mutated allergens might lead to IgG response
2) Tolerance therapy: Slowly increasing dosage of allergen to DCs increases Th1 response and Treg
- SLIT/SCIT may be used (SubLingual/SubCutaneous Immunotherapy
Potential risk of anaphylaxis with tolerance therapy overcome using anti-IgE therapy (Omalizumab reduces IgE impact)
Preventing inappropriate immune responses:
Suppression of Th1 response
Many autoimmune/autoinflammatory diseases are caused by excessive Th1/Th17 immunity (e.g. IBS, Type 1 diabetes, MS, RA). Th1 downregulated by enhancing Th2 response:
1) Helminth infection skews immune system away from Th1
- exact mechanisms unknown but supporting evidence from mice
- They decrease IFNg and increase IL-4
2) Tolerogenic DC therapy (possible transplant rejection therapy)
- In Vitro TolDCs made by treating with correct growth factors (IL-4, GM-CSF…)
- TolDCs produce a lot of inhibitory molecules (IL-10 and TGFb) to make Tregs switch off T cells
Preventing inappropriate immune responses:
Preventing Transplant Rejection
Short Course Immune Induction Therapy
- Induce T cell unresponsiveness to ‘reset’ tolerogenic mechanisms (re-educating T cells to approve donor antigens)
- -> Campath-1 monoclonal antibody depletes T cells
- -> Basiliximab prevents T cell activation (anti-IL-2 receptor)
Immunotherapy in Cancer
Used to activate immune system in cases of tumour immunosuppression
- Using monoclonal antibodies (Anti- CD20/erb2R/VEGF)
- Imiquimod TLR7/8 agonist triggers anti-viral response to remove tumour
Therapies for overcoming tumour suppression of immune system
Activating T cells (otherwise deactivated at checkpoint inhibitors)
- Blockading the inhibitory receptors (CTLA4, PD-1) on T cells allow their activation
- Blocking IL-10/TGFb
- Adoptive transfer of IL-2 treated cells
- Upregulate MHCI with IFNg treatment
- Engineer ‘super T cells’
Super T cells
- highly active
- don’t require MHCI (adding antigen)
- no checkpoint inhibitors
- Can add Activation domains, circumventing inhibitory cytokines
Host-directed therapy for infectious diseases:
Virus infection
Targeting host response rather than virus:
IFN therapies up-regulate anti-viral response and alter host-dependent life cycle
- e.g. altering CCR5 conformation prevents HIV entry into host cell
