Intralymphatic Immunotherapy ILIT. Gabriela Senti Center for Clinical Research University and University Hospital Zurich

Transcription

1 Intralymphatic Immunotherapy ILIT Gabriela Senti Center for Clinical Research University and University Hospital Zurich

2 Subcutaneous Immunotherapy Problems

3 Intralymphatic Immunotherapy

4 Protein Vaccines into lymph node IgG? subcutaneous

5 Allergen Administration Route g 0.1 g 10 g Anti-PLA2 IgG2a IgE intralymphatic (ILIT) subcutaneous (SCIT) Δ intraperitoneal

6 Injection into Lymph Nodes

7 Inguinal Lymph Nodes no large vessels little movement close to vessels leg movement

8 into lymph node Subcutaneous

9 20 Min

10 25 h Senti et al. Curr Opin Allergy Clin Immunol 2009

11 Allergen Allergen Clinical Trial ZU-BV g 5 years (~80 injections) 10 g 3 injections 2 wk intervals

12 BV sting challenge score Sting Provocation 4 p= Before After Vaccination

13 Allergen (SQ-U) Allergen (SQ-U) igibility luded n=18 t meeting inclusion eria n=18 Allocated to Subcutaneous SIT n= grass allergic pat. Received treatment n=54 (Tree=19) Baseline n=54 (Tree=19) 4 months n=54 (Tree=19) Patients 1 year n=53 (Tree=16) 3 years n=32 (Tree=12) Pollen season baseline 54 Cum. dose = SQ-U Cum. dose = SQ-U Pollen Pollen weeks season season baseline 4 months 1 year 3 years Evaluation Sept Jan Sept Sept Evaluation visits visits Oct Feb Oct Oct Senti et al. PNAS 2008

14 Pain? Pain score (VAS) Intralymphatic injection Venous puncture Route of administration

15 Nasal Provocation Test us B 6.0 intralymphatic subcutaneous Maximum tolerated concentration (log10) Time Months (months) Senti et al. PNAS 2008

16 Antigen Presentation allergen allergen IhC Tat Molecular targeting : MAT Antigen (Modular antigen transporter) - Tat protein for cytoplamic update - IC for targeting MHC II Receptor endolysosome Lysosom Golgi Golgi ER invariant chain (Ii) ER MHCII MHCII Matinez-Gómez et al. Allergy 2009

17 IVN-CAT-001b 12 Alum + MAT-Fel d 1 8 Alum + placebo 1 g 3 g 10 g 5d 28d 28d 28d V1a V1b V2a V2b V2c V3 V4 Screening Treatment Efficacy Senti et al. JACI 2012

18 Adverse Events No SAE Possibly drug related AE Placebo Verum Severity mild moderate mild moderate Local reactions temporary lymphnode swelling Systemic reactions rhinorea sneezing pruritus nausea rash dyspnoe headache cough Total Senti et al. JACI 2012

19 IL-10 Correlates with IgG4 IgG4 (Post/Pre) p= p=n.s IL-10 (Post/Pre) Senti et al. JACI 2012

20 Fold improvement Allergen (log 10 ) Fold improvement Prick Test and Intradermal Test SPT n.s. SPT Improvment Factor 3.16 p<0.05 ** n.s. IPT IDT Improvment Factor 4.64 ** p< Placebo Verum -3 Placebo Verum Treatment group Treatment group Senti et al. JACI 2012

21 Improvement (Post/Pre log 10 ) Nasal Tolerance NPT 3 2 P< x 0 Placebo Verum Treatment group Senti et al. JACI 2012

22 More data will be published soon From Kopenhagen From Stockholm Interest from China Low efficacy? Weekly intervall too short? Very positive results We can relax again Drug Development is not easy

23 Is intralymphatic specific immunotherapy with grass pollen allergen ready for clinical use? Malling, H; Blom, L; Poulsen, B; Poulsen, L; Witten, M IgG4 IgE VAS RQLQ IgG4 IgE ICT VAS RQLQ 4wk IgG4 IgE SPT NPT VAS JACI 2013, 07/033

24 JACI 2013, 07/033

25

26 JACI 2013 Feb;131(2):412-20

27 JACI 2013 Feb;131(2):412-20

28 JACI 2013 Feb;131(2):412-20

29

30

31

32

33

34 Practicability and safety of intralymphatic allergenspecific immunotherapy in dogs with atopic dermatitis. Hatzmann K, Mueller RS. 3 low dose i.ln. vs. 30 high dose s.c. intralymphatic allergen-specific immunotherapy is an interesting and safe alternative to subcutaneous administration. A more prominent decrease of pruritus score, CADESI (Canine Atopic Dermatitis Extent and Severity Index) and total score was noted in the trial group Vet Dermatol 2011

35

36

37 Antibodies of all four isotypes, IgG 1, IgG 2, IgA, and IgM, increased in dry secretions following immunization via lymph node.

38 Conclusions ILIT vs SCIT Low allergen doses Improved safety Enhanced immunogenicity Fewer injections Practically painless Enhanced compliance

39 Epicutaneous Immunotherapy 1911 prophylactic hypodermic inoculation 1929 into the substance of the skin

40 ZU-Skin-SIT 001 P = 0.04 P = 0.002

41 Improvement (%) ZU-Skin-SIT e of hay fever symptoms Placebo Allergen dose 30% better than placebo

42 EPIT is «en vogue» From Paris From Osaka From Salzburg DVB /VIASKIN Preclinical Data Dissolving Microneedles Infectious Disease Data Generated micropores using Laser Technologies Preclinical Data

43 Summary EPIT SLIT SCIT ILIT Allergen dose Efficacy Convenience Convenience

44 Senti G, Crameri R, Kuster D, Johansen P, Martinez-Gomez JM, Graf N, Steiner M, Hothorn LA, Grönlund H, Tivig C, Zaleska A, Soyer O, van Hage M, Akdis CA, Akdis M, Rose H & Kündig TM. (2012) Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. JACI / The Journal of allergy and clinical immunology 129: Senti G, von Moos S, Tay F, Graf N, Sonderegger T, Johansen P & Kündig TM. (2012) Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: Adouble-blind, placebo-controlled dose escalation study. JACI / The Journal of allergy and clinical immunology 129: Senti G, Graf N, Haug S, Ruedi N, von Moos S, Sonderegger T, Johansen P & Kündig TM. (2009) Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy. JACI / The Journal of allergy and clinical immunology 124: Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, McCormack SJ, Simard JJ, Wüthrich B, Crameri R, Graf N, Johansen P & Kündig TM. (2008) Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. PNAS / Proceedings of the National Academy of Sciences of the United States of America 105: More Senti & Kündig Stories will follow

45 You will hear about «Hypo Pet» soon