Intralymphatic immunotherapy (ILIT) renders allergen-specific immunotherapy (AIT) faster and safer

Transcription

1 Intralymphatic immunotherapy (ILIT) renders allergen-specific immunotherapy (AIT) faster and safer Pål Johansen Department of Dermatology, University Hospital Zurich

2 AIT in 1911 & in 2013 Dose Maintenance phase Time (3-5 yrs) Disease-modifying therapy Long-lasting effect Stops the atopic march Costs: 1,500-10,000 Allergic side effects Long-lasting treatment (>50 doctor visits) Poor willingness (<10%) Poor compliance

3 The influence of the past Edward Jenner ( ) Louis Pasteur ( ) William Dunbar ( ) John Freedman ( ) Leonard Noon ( ) Disease caused by microbial toxins Protection by antiserum Vaccination = 3 injections Allergy caused by toxins Protection by antiserum AIT = 50 injections

4 What causes allergy? Allergy is caused by toxins von Behring & Shibasaburo Humoral theory Ehrlich Antibody formation theory Ishizaka & Johansson: IgE discovery Allergy is caused by IgE Gershon Suppressor T cells Mosmann & Coffman Th1 / Th2 Sakaguchi Treg Ibellinghausen AIT induces T reg Dunbar Passive vaccination of allergic animals Cooke Blocking antibodies Noon and Freeman: Active vaccination (AIT) Loveless Blocking correlate with efficacy of AIT Varney AIT induces Th1 Rocklin AIT induces suppressor T cells Akdis T cell tolerance Vaccination Tolerance induction

5 Vaccination or Tolerance? Flu symptoms Rhinitis, conjunctivitis, bronchitis Hay fever symptoms Rhinitis, conjunctivitis, bronchitis

6 Vaccination or Tolerance? Antigen + Alum = Vaccine Allergen + Alum = AIT Vaccinated! Tolerant! Treg Th1 Treg Th1 Goal & result Goal & result

7 Basic concepts of immunogenicity Signal 0 (adjuvant) Signal 1 (antigen-mhc) Signal 2 (co-stimulation) Bystander affects (neighbouring cells, inflammation, etc) Antigen persistency (depot)

8 Immunological mechanisms of immunotherapy Natural exposure (low-dose allergen) Immunotherapy (high-dose allergen) Shamji and Durham, Clin Exp Allergy, 41, (2011)

9 Allergen immunotherapy a practical approach Route of administration? The geography of human lymphatics ILIT is a strike at the roots

10 The target of all vaccines is the lymph node X Viral infection Live attenuated vaccine Non-replicating vaccine (needs adjuvant)

11 The road to immunity Nature Immunology 7, (2006)

12 Allergy vaccines a model kit of intralymphatic immunotherapy Feasibility testing and mice-man transitions Johansen et al. Eur J Immunol 2005, 35, 3591 Senti et al PNAS U.S.A. 2008, 105, 17908

13 ILIT in mice Plasmid DNA vaccines improved cytotoxicity (CD8 T cells) Maloy et al. PNAS DNA dose (μg) Intradermal Intramuscular Into spleen Into lymph node Specific Lysis (%) E:T ratio

14 ILIT in mice Peptide vaccines improved tumour protection (CD4 T cells) Johansen et al. Eur J Immunol Survival (%) (%) i.ln. i.v. i.v. i.ln. s.c. untr Days Days

15 ILIT in mice Protein vaccines improved antibody responses (B cells) Matinez-Gómez et al. Int Arch Allergy Immunol 2009 Anti-PLA2 IgG2a (titer) μg 0.1 μg 10 μg Time (weeks) intralymphatic (i.ln.) subcutaneous (s.c.) Δ intraperitoneal (i.p.)

16 ILIT improves allergen immunotherapy in mice More Th1 (IFNγ and IL-2) & less anaphylaxis Matinez-Gómez et al. Int Arch Allergy Immunol 2009 IFN-γ production (Th1) CD8 CD4 SCIT ILIT SCIT ILIT Body temp drop Anaphylaxis SCIT ILIT

17 ILIT in man Needle Lymph node

18 Clinical trial with bee venom ILIT (ZU-BV-001) n=12 Open label 3 injections, 14d interval Cum. dose = 30 μg Sting provocation and serology 4 wks post ILIT BV aqueous BV + alum Be e venom dose (μg) Day 0 Day 14 Day 28 Allergen Conventional SCIT injections, 3-5 years 100 μg, maintenance dose

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20 Transient swelling of lymph nodes after ILIT LN swelling (relative) Time (days)

21 ILIT stimulates IgG1 but not IgE Analysed 4 weeks after end of ILIT (8 weeks after start ILIT) IgE p=0.168 IgE p= IgG1 p=0.045 IgG1 p= Anti-PLA2 IgE (U/ml) Anti-PLA2 IgG1 (U/ml)

22 Bee venom sting challenge the ultimate answer to treatment efficacy

23 Increased sting tolerance in 7 out of 8 (87.5%) patients 4 p= BV sting challenge score Baseline After ILIT (week 8)

24 Clinical Trial with bee venom ILIT (ZU-BV-002) n=65 (multicenter) Open label, dose finding 3 injections, 14d interval Dose = 10 vs. 20 μg (+ alum) 1 Endpoint: improvement of 2 grades 82% No. of patients % 10 μg 20 μg Grade improvement Grade improvement

25 Phase I/IIa clinical trial with hay fever 165 patients (grass pollen) Senti et al., PNAS USA, 2008 Allergen Allergen SCIT ILIT ILIT (n=66) 3 injections, 1 month intervals Cum. dose = SQ-U 12% drop-outs SCIT (n=99) 54 injections, 3 years Cum. dose = SQ-U 45% drop-outs

26 1 Endpoint: Nasal Provocation Test Earlier tolerance with ILIT and comparable final efficacy Senti et al., PNAS USA, 2008 NPT at 4 months NPT over 3 years ILIT SCIT ILIT SCIT Symptom score Baseline 4 mo Max tolerated allergen conc. (log10) Patients (%) 3 Grass pollen extract (SQ-U) Years Years

27 ILIT (3x) and SCIT (54x) stimulate comparable symptom amelioration Senti et al., PNAS USA, 2008 Symptom score Symptoms recorded during 3 yrs (VAS) SCIT ILIT Patients (%) Rescue medication ILIT SCIT Years

28 Safety of SCIT and ILIT ILIT with less AE and none SAE Senti et al., PNAS USA, 2008 Allergic reactions SCIT ILIT None Milde (Grade 1+2) Severe (Grade 3) Anaphylactic (Grade 4)

29 ILIT with cat fur allergen Modular antigen transporter (MAT)-Feld1 Senti et al, JACI, 2012 n=20 (12 verum, 8 placebo) DB RCT 3 injections, 1 month intervals Dose = 1, 3 and 10 μg (+ alum) 1 Endpoint: NPT Increased uptake in APC (Tat) Increase MHC affinity (Il) Martinez-Gómez et al. Allergy,2009 rfeld1 Invariant chain Tat 1 μg 3 μg 10 μg 5d 28d 28d 28d Screening Treatment Efficacy

30 Reduced reactivity of MAT-Feld1 in SPT and CAST Senti et al, JACI, 2012 Skin-Prick Test 2500 CAST ELISA MAT Feld1 Thresshold conc (log10) 1 p< SPT -3-4 Extract MAT-Feld1 slt (pg/ml) 2000 Extract 1500 Feld MAT-Feld Allergen Fel d 1 Concentration (nm)

31 No SAEs after ILIT with MAT-Feld1 Senti et al, JACI, 2012 Placebo ILIT/Severity of AE Verum mild moderate severe mild moderate severe Local reactions temporary lymphnode swelling Systemic reactions 0 rhinorea sneezing pruritus nausea rash dyspnoe headache cough Total

32 Increased IgG4 production after MAT-Feld1 ILIT Senti et al, JACI, 2012 a Titer (Post/Pre) IgG4 p<0.05 ** Placebo Verum

33 Feld1-specific IL-10 secretion Increased secretion of IL-10 in PBMCs after MAT-Feld1 ILIT Senti et al, JACI, p<0.05 IL-10 (pg/ml) IL-10 (pg/ml) p=n.s. Pre Post Pre Post Placebo Verum

34 Nasal tolerance allergen challenge (NPT) Allergen specific nasal tolerance is increased after MAT-Feld1 ILIT Senti et al, JACI, P<0.001 Post / pre (log10) x 0 Placebo Verum

35 Grass and birch pollen ILIT in Sweden (I)

36 Grass and birch pollen ILIT in Sweden (I) L.O. Cardell & co-workers: reduced nasal allergic symptoms without safety problems Hylander et al, JACI, 2013 ILIT (n=7) Placebo (n=8) Complete recovery No improvement

37 Grass and birch pollen ILIT in Sweden (II) Lennart Nilsson & co-workers: ILIT-1-Linköping Source: EU Clinical trial registry n= 10 (rhinoconjunctivitis due to birch/grass allergy) 3x ALK-Alutard SQ Betula or SQ 5-grasses with 1 month interval, open label 1 objective: Subjective symptoms following CPT before and after treatment 2 objective: QoL over 3 yrs, symptoms, medication, SPT, serology,

38 Grass and birch pollen ILIT in Denmark H. Malling & co-workers: no clinical efficacy of grass pollen ILIT Allergy 67. Suppl. 96 (2012) DB Placebo controlled RCT n=45 3 or 6 weekly injections Dose 1000 SQ-U

39 Is there are mechanism of ILIT?

40 Das Bild kann zurzeit nicht angezeigt werden. Das Bild kann zurzeit nicht angezeigt werden. Biodistribution of conventional and intranodal injected vaccines ( 99 mtc-labelled protein) Subcutaneous Intralymphatic (IL or i.ln.)

41 Subcutaneous proteins remain at injection site 20 Min 4 h 25 h

42 ILIT versus SCIT ILIT provides lower allergen doses in skin and circulation ILIT provides higher allergen doses to the lymphatics ILIT is practically painless Improved safety Enhanced immunogenicity Compliance Compliance Fewer injections Compliance

43 Relative properties of SIT methods SLIT SCIT ILIT Allergen dose administered U U 1 U LN drainage (Immunogenicity) Allergen delivered to immune system Clinical efficacy

44 University Hospital Zurich Julia M. Martínez-Gómez Seraina von Moos Mareike Prinz Gabriela Senti Thomas M. Kündig University of Zurich Regine Hofmann-Lehmann Barbara Riond Swiss Asthma and Allergy Institute Reto Crameri Cezmi Akdis Karolinska Institutet Marinanne van Hage Hans Grönlund MannKind Corp. Kent Smith Adrian Bot