Immunotherapy in type 1 Diabetes

download Immunotherapy in type 1 Diabetes

of 33

Embed Size (px)

Transcript of Immunotherapy in type 1 Diabetes

  • 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

  • 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

  • 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

  • Immune Tolerance

    Karthik Balachandran Immunotherapy in T1DM

  • Tregs and CTLA4

    Karthik Balachandran Immunotherapy in T1DM

  • Tregs and CTLA4

    Karthik Balachandran Immunotherapy in T1DM

  • Challenges- Epitope Spreading

    Karthik Balachandran Immunotherapy in T1DM

  • Challenges- Timing

    Karthik Balachandran Immunotherapy in T1DM

  • 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

  • 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

  • Immunosuppression- How specific and how much?

    Karthik Balachandran Immunotherapy in T1DM

  • Antigen specific immunotherapies

    Aims to achieve anergy in T cells

    The same proteins that cause immune response result inanergy

    Karthik Balachandran Immunotherapy in T1DM

  • 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

  • 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

  • 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

  • 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

  • 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

  • CD3 and CD28-CD80/86 costimulation

    Karthik Balachandran Immunotherapy in T1DM

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • Conclusion

    Currently immunotherapy has limited role in the management ofType 1 Diabetes

    Karthik Balachandran Immunotherapy in T1DM

  • Thank You

    Karthik Balachandran Immunotherapy in T1DM

  • Table: Someuseful caption

    One Two

    Three 1 Four

    1 The firstnote...

    Karthik Balachandran Immunotherapy in T1DM