John Bostock. Novel Immunotherapy Modalities. Catharrus aestivus. University Hospital Zürich. Thomas M. Kündig Dermatology Zurich University Hospital

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1 John Bostock University Hospital Zürich Novel Immunotherapy Modalities 1819 Catharrus aestivus Thomas M. Kündig Dermatology Zurich University Hospital

2 Charles Blackley William Dunbar 1873 Catarrhus aestivus 1903 Pollantin caused by pollen

3 John Freeman and Leonard Noon Lancet 1911

4 Allergen Immunotherapy High rate of success Insect venoms 80-95% Pollen 70-80% Tolerance dose Only causal treatment Stops progression of disease Long term effect As effective as pharmacotherapy

5 Subcutaneous Immunotherapy SLIT Only 4% Time consuming Allergic side effects Allergen dose 20 weeks 3-5 years (30-80 injections) Senna et al. JACI 2010

6 Understanding of Immunology von Behring Shibasaburo humoral theory Allergens = toxins Ehrlich antibody formation theory Allergies caused by IgE Gershon suppressor T cells Mosmann Coffman Th1 / Th2 Sakaguchi Treg What is the mechanism? Dunbar passive vaccination Noon / Freeman active vaccination Vaccination Cooke blocking antibodies Rocklin SIT induces suppressor T cells Varney SIT induces Th1 Akdis T cell tolerance Tolerance induction Bellinghausen SIT induces T reg Interpretation of SIT

7 Blocking Antibodies Understanding of Immunology Allergens = toxins Allergies caused by IgE von Behring Shibasaburo humoral theory Ehrlich antibody formation theory Ishizaka Johansson IgE Gershon suppressor T cells Mosmann Coffman Th1 / Th2 Sakaguchi Treg Dunbar passive vaccination Noon / Freeman active vaccination Vaccination Cooke blocking antibodies Rocklin SIT induces suppressor T cells Varney SIT induces Th1 Akdis T cell tolerance Tolerance induction Bellinghausen SIT induces T reg Cook JEM 1935 Interpretation of SIT

8 Dose Dependence How can this be improved? Symptoms Placebo Medium dose High dose UK Immunotherapy Study Group JACI 2006

9 Anti-PLA2 IgG2a Allergen Administration Route 0.01 µg 0.1 µg 10 µg intralymphatic (ILIT) subcutaneous (SCIT) intraperitoneal IFNg secretion (pg/ml) IL SC IL-4 secretion (pg/ml) IFNγ IL IL SC IL-2 secretion (pg/ml) IL-10 secretion (pg/ml) IL-2 IL SC IL-10 IL SC Matinez-Gómez et al. Int Arch Allergy Immunol 2009 Matinez-Gómez et al. Int Arch Allergy Immunol 2009

10 0.8 Adjuvants CpG dose (nmol) 10 nmole nmole nmole nmole into lymph node Subcutaneous i.ln. s.c. IgG2a (OD 405 nm) Anti-PLA 2 IgG2a (OD 405 nm) i.ln. s.c Serum dilution von Beust et al Eur J Immunol 2005

11 25 h Inguinal Lymph Nodes no large vessels little movement close to vessels leg movement Senti et al. Curr Opin Allergy Clin Immunol 2009

12 Intralymphatic Injection Pain? Pain score (VAS) Intralymphatic injection Venous puncture Senti et al. PNAS 2008

13 165 grass allergic pat treatment Patients 8 Senti et al. PNAS Allergen (SQ-U) Allergen (SQ-U) Cum. dose = SQ-U Pollen season baseline Cum. dose = SQ-U Pollen Pollen weeks season season baseline 4 months 1 year 3 years Evaluation Sept Jan Sept Sept visits Oct Feb Oct Oct B Maximum tolerated concentration (log10) Nasal Provocation Test intralymphatic subcutaneous Months Senti et al. PNAS 2008

14 Reproducible Hyalnder et al. JACI 2013

15 Antigen Presentation CAST-ELISA allergen IhC Fel d endolysosome allergen Tat Lysosom YYY slt (pg/ml) IhC MAT-Fel d 1 rfel d 1 Cat extract Golgi Golgi 500 Tat ER invariant chain (Ii) MHCII MHCII ER Leukotriens Fel d 1 Concentration (nm) Matinez-Gómez et al. Allergy 2009

16 Skin Prick Test MAT Fel d 1 IVN-CAT-001b 12 Alum + MAT-Fel d 1 Threshold concentration Cat hair extract P value IVN201 Cat hair extract MAT-Fel d 1 93x 8 Alum + placebo 1 µg 3 µg 10 µg 5d 28d 28d 28d V1a V1b V2a V2b V2c V3 V4 Screening Treatment Efficacy

17 IgG4 IL-10 a Titer (Post/Pre) 100 IgG4 10 p<0.05 ** Placebo Verum IL-10 (pg/ml) Placebo Verum p<0.05 p=n.s. Pre Post Pre Post

18 IL-10 Correlates with IgG4 Nasal Tolerance 100 p= p=n.s. 3 IgG4 (Post/Pre) 10 1 Improvement (Post/Pre log 1 0 ) 2 1 P< x IL-10 (Post/Pre) 0 Placebo Verum

19 ILIT vs. SCIT Low allergen doses Improved safety Enhanced immunogenicity Fewer injections Practically painless Enhanced compliance

20 Dogs with Atopic Dermatitis Horse Asthma 3 x ILIT better than 30 x s.c. Hatzmann et al. Vet Dermatol 2011

21 Horse Asthma

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

23 J Immunother 2008

24 Epicutaneous Immunotherapy (EPIT) Blamoutier 1959

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