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Immuno Therapy
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Transcript of Immuno Therapy
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Immunotherapies currently in development for thetreatment of type 1 diabetes
Ian C Davis, Jacqueline Randell & Stephen N Davis
Expert Opinion on Investigational Drugs, 24:10, 1331-1341
Karthik Balachandran Immunotherapy in T1DM
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Background
Autoantigens released from cells prompt infiltration bymacrophages and dendritic cells
APCs present to CD4+ T cells which release cytokines
A cascade of immune attack follows which ultimately resultsin type 1 DM
Immunotherapies affect steps in this process
Karthik Balachandran Immunotherapy in T1DM
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Protective mechanisms
T cells have TCRs which recognize native and foreign antigenspresented by the APCs
Central tolerance in the thymus ensures apoptosis ofautoreactive T cells, but some T cells escape
Tregs control these escaped autoreactive T cells
Peripheral tolerance or defective central deletion ofdiabetogenic T cells can result in T1DM
Karthik Balachandran Immunotherapy in T1DM
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Immune Tolerance
Karthik Balachandran Immunotherapy in T1DM
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Tregs and CTLA4
Karthik Balachandran Immunotherapy in T1DM
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Tregs and CTLA4
Karthik Balachandran Immunotherapy in T1DM
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Challenges- Epitope Spreading
Karthik Balachandran Immunotherapy in T1DM
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Challenges- Timing
Karthik Balachandran Immunotherapy in T1DM
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Goals of immunotherapy
1 Slowing the progression of disease
2 Stopping the process of insulitis indefinitely
3 Restoring self tolerance
Karthik Balachandran Immunotherapy in T1DM
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Pharmacological immune suppression
Started with development of cyclosporine in 1980s
Pharmacologic strategies currently in use
Antigen specific therapiesMonoclonal antibodiesFusion proteinsAlternate Treg affectors
Karthik Balachandran Immunotherapy in T1DM
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Immunosuppression- How specific and how much?
Karthik Balachandran Immunotherapy in T1DM
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Antigen specific immunotherapies
Aims to achieve anergy in T cells
The same proteins that cause immune response result inanergy
Karthik Balachandran Immunotherapy in T1DM
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Glutamic acid decarboxylase
Triggers glutamate conversion to GABA
GAD65 vaccines potential to halt progression of diabetes
Moderate success in human trials
Phase II trial by Ludvigsson et al., 118 patients with recentonset T1DM received two, subcutaneous injections of 20 gof GAD-alum treatment or placebo
NO change in C peptide at 15 months, significantly differentfrom placebo at 30 months
Karthik Balachandran Immunotherapy in T1DM
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Glutamic acid decarboxylase
Could not be replicated in the phase III trial
No significant difference in glycated hemoglobin, daily insulindose or any other secondary outcomes
Karthik Balachandran Immunotherapy in T1DM
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Insulin
Skyler et al - DPT1
Low dose of oral insulin to first-degree relatives of T1DM
372 patients studied, 44 in the oral insulin group and 53 in theplacebo group developed T1DM
Post-hoc subgroup analysis revealed that oral insulin delayeddiabetes onset for up to 5 years in patients with high-titerinsulin antibodies
Karthik Balachandran Immunotherapy in T1DM
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Insulin
In phase I trial by Orban et al, oral insulin, despite inducingIL-10 producing Tregs, could not prevent progression ofdiabetes
Neither oral nor nasal administration of insulin had effect onprogression to type 1 diabetes
Karthik Balachandran Immunotherapy in T1DM
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Heat shock protein 60
HSP 60 is expressed in cells
Diapep277, which is a short 24 amino acid peptide that stemsfrom human HSP60, has been tested on both NOD mice andhumans as a potential ASI
Authors retracted the phase III trial and no further trial inpipeline
Karthik Balachandran Immunotherapy in T1DM
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CD3 and CD28-CD80/86 costimulation
Karthik Balachandran Immunotherapy in T1DM
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Monoclonal antibodies - Teplizumab
Humanized, anti-CD3 monoclonal antibody
Protege and Abate trials
Protege - 513 type 1 diabetes patient, primary end point-insulin use < 0.5u/kg/day and HbA1c < 6.5%
Four groups - 14 day high and low dose, 6 day high and lowdose
No significant difference between the groups
Karthik Balachandran Immunotherapy in T1DM
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Teplizumab
AbATE study showed a significant preservation in C-peptidefor up to 2 years
Two courses of teplizumab or placebo were administeredshortly after diagnosis and again after 1 year to 52 T1DMpatients
Patients treated with teplizumab had a 75% reduced declinein C-peptide at 2 years (-0.28 nmol/l vs control -0.46 nmol/l,p = 0.002)
Karthik Balachandran Immunotherapy in T1DM
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Otelixuzumab
anti-CD3 monoclonal antibody
In a large randomized Phase III trial Defend 1, a cumulative3.1 mg dose of otelixizumab did not preserve C-peptide orother markers of metabolic control in 281 recent onsetpatients
Distinct risk/benefit profile for anti-CD3 therapeutics withgreater doses providing a longer slowing of the autoimmuneattack for up to 4 years but at the price of more severe sideeffects
Karthik Balachandran Immunotherapy in T1DM
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Rituximab
anti CD20 antibody, depletes B cells
A 1-year study of 87 patients with recent onset T1DM hadthe defined primary end point of mean Cpeptide, which wassignificantly better in the rituximab group vs placebo: 0.56and 0.47 nmol/l, respectively (percentage difference 20%; p =0.03)
At 2 years difference had vanished
Karthik Balachandran Immunotherapy in T1DM
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Canakinumab (and Anakinra)
IL-1 causes -cell dysfunction and destruction via the NFkBand MAPK pathways
IL-1 is released locally by the cells during hyperglycemia,which then inhibits insulin synthesis and release and causesapoptosis of cells via the Fas receptor
Canakinumab is a human monoclonal anti-IL-1 antibody
Phase II trials showed neither Anakinra nor Canakinumab areuseful for halting the immune attack on cells
Karthik Balachandran Immunotherapy in T1DM
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Gevokizumab
Antibody against IL-1
Shown in type 2 diabetes to be well tolerated and efficacious
IL-1 has role in both type 1 and type 2 diabetes
None of the antibodies have shown durable reduction inautoimmune attack on the cells
Karthik Balachandran Immunotherapy in T1DM
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Fusion proteins
Fusion proteins are composed of an immunoglobulin Fcdomain directly linked to another protein
The fused peptide can serve as a ligand that activates whenreceived by a cellsurface receptor, an antigen (Ag) or as abinding protein
Karthik Balachandran Immunotherapy in T1DM
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Abatacept
Fusion protein created to curb T cells co-stimulatory signalinterceded through the CD28-CD80/86 pathway
Obstructs the early stages of T-cell activation, production andcontinued existence
Phase II trial involving 103 patients
Defers immune attack for an average of 9.6 months
Well tolerated, no increased risk of EBV infection orneutropenia
Return to inexorable decline in cell function
Karthik Balachandran Immunotherapy in T1DM
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Alefacept
Dimeric fusion protein blocking T cell costimulation
alefacept had a positive effect on preserving b-cell function,which investigators attribute to the depletion of highlypathogenic effecter and memory T cells (CD4+ Tcm cellsdecreased by 25 30% and CD4+ Tem cells decreased by 40 60%)
Promising treatment due to its demonstrated preservation ofTreg/Teff balance
Karthik Balachandran Immunotherapy in T1DM
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Other T reg affectors
IL2 improves Tregs
Low dose IL2 prevents and treats type 1 DM in NOD mice
Adult patients tolerate IL2 at tested dose levels of3IU/day(max)
Persistent increase in IL2 at 60 days and improvement inTreg/Teff balance
Karthik Balachandran Immunotherapy in T1DM
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Lessons . . .
No single therapeutic gent provides a lasting halt of theimmune attack and remission of the T1DM phenotype
Responders in Abate and Protege trials
Younger (8-17 years)HbA1c < 7.5%Used < 0.4U/kg/d of insulinEnrolled within 6 weeks of diagnosis of T1DMC-peptide mean AUC > 0.2 nmol/l
Karthik Balachandran Immunotherapy in T1DM
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Lessons . . .
High cumulative doses of monoclonal antibodies can have cell protective effects upto 4 years
Combination therapies to be evaluated, but caution to bemaintained
Combination of rapamycin(mTOR inhibitor) which decreasesTeffs and IL2 which increases Tregs resulted in transientdecline in cell function
Ideal timing and dosing are not known
Karthik Balachandran Immunotherapy in T1DM
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Conclusion
Currently immunotherapy has limited role in the management ofType 1 Diabetes
Karthik Balachandran Immunotherapy in T1DM
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Thank You
Karthik Balachandran Immunotherapy in T1DM
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Table: Someuseful caption
One Two
Three 1 Four
1 The firstnote...
Karthik Balachandran Immunotherapy in T1DM