CANCER THERAPY BY TARGETING CO-INHIBITORY RECEPTORS TO STIMULATE ADAPTIVE IMMUNE RESPONSE: CTLA-4 AND PD-1

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Giulietta Sarti
6 anni fa
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1 CANCER THERAPY BY TARGETING CO-INHIBITORY RECEPTORS TO STIMULATE ADAPTIVE IMMUNE RESPONSE: CTLA-4 AND PD-1

3 CD28 ed il modello dei due segnali APC T cell MHC TCR B7 CD28 T cell NF-κB, survival (Bcl-xl) cytokine/chemokine (Tuosto Immunol. Letters 2011)

4 Costimulatory/coinhibitory signals

5 CD28

6 CD28

7 EFFICIENTE ATTIVAZIONE LINFOCITI T

8 CTLA4 MYPPPY PP2A: Ser/Thr fosfatasi SHP2: Tyr fosfatasi

9 INHIBITORY SIGNALLING - CTLA4

10 EFFETTI DELLA CO-STIMOLAZIONE DA PARTE DI CTLA4 Espresso su linfociti T attivati, T-memory e T-soppressorie Regola negativamente la risposta immunitaria, spegnendo le vie di segnalazione mediate da TcR e CD28 (due meccanismi possibili): Competition: il legame ad alta avidità tra CTLA4 e B7 compete per il legame a B7 da parte di CD28. Interference with rafts formation: il motivo YVKM recluta le fosfatasi PP2A e SHP2, che defosforilano le molecole coinvolte nella trasduzione del segnale (LAT, Vav) Non ha funzione inibitoria nei linfociti T CD8+ Protezione contro malattie autoimmuni (tolleranza periferica): topi ko fenotipo iperproliferante con infiltrazione e distruzione di organi e tessuti (morte entro le 3 sett) Polimorfismi di CTLA-4 identificati in molte malattie autoimmuni come diabete tipo 1 o morbo di Graves, recenti evidenze di polimorfismo anche nella SM

11 MECCANISMI DELL INIBIZIONE DA CTLA4

12 CTLA4 AND CANCER THERAPY

13 CTLA-4 BLOCKADE IN IMMUNOTHERAPY

PRECLINICAL STUDIES WITH ANTI-CTLA4 Ab Several preclinical studies in murine models of malignancy have provided evidences on the ability of anti-ctla-4 to enhance endogenous immune responses to

14 PRECLINICAL STUDIES WITH ANTI-CTLA4 Ab Several preclinical studies in murine models of malignancy have provided evidences on the ability of anti-ctla-4 to enhance endogenous immune responses to immunogenic tumors and to sinergize with other multiple therapies In murine models of melanoma (B16, poorly immunogenic), CTLA-4 blockade in association with tumor vaccination induced: 1. Rejection of tumors 2. Autoimmune responses: depigmentation 3. Interruption of peripheral tolerance against differentiation Ags

15 IPILIMUMAB (MDX-010): A fully human monoclonal antibody, an immunoglubulin IgG1κ antibody, genereted in transgenic mice with human immunoglobulin genes knocked-in, so it is a fully human antibody. It binds CTLA-4 and inhibits the binding of CTLA-4 to B7.1 and B7.2.

MELANOMA - Develops from the transformation of melanocytes (basal epidermal layer of skin) - Most common fatal skin cancer - In the last 40 yrs its incidence has increased 15-fold - Mortality rate:

16 MELANOMA - Develops from the transformation of melanocytes (basal epidermal layer of skin) - Most common fatal skin cancer - In the last 40 yrs its incidence has increased 15-fold - Mortality rate: second highest among all cancers for individuals 65 yrs age and older RGP (radial growth phase) melanoma: - Migration into the upper epidermis among the epithelial cells - Cytologic atypia, large abundant cytoplasm and increase overall size, large and hyperchromatic nuclei VGP (vertical growth phase) melanoma: - Penetrate the dermal-epidermal junction - Cytologic atypia - Cluster or individual invasion of dermis

17 MELANOMA Stage 0 Stage I and II Stage III Stage IV Epidermis without underlying dermis invasion Ulceration, no lymph node and no distant metastasis Lymph node metastasis, no distal metastasis Distal metastasis high level of lactate dehydrogenase

18 Studio di Maker et al., 2005: si propone che l inibizione delle Treg (CTLA-4 + ) possa permettere il rilascio di cellule T autoreattive, incluse le cellule tumore-reattive, dai meccanismi di soppressione periferici. 2 IPOTESI: 1)Blocco del CTLA-4 determina la deplezione o il blocco delle Treg (NO) 2)Blocco del CTLA-4 agisce direttamente su T CD4 + e T CD8 + per rimuovere influenze inibitorie ed aumentare le loro funzioni effettrici (SI) Queste ipotesi esplorate sugli umani attraverso l analisi dei cambiamenti cellulari in seguito alla somministrazione dell anti CTLA-4 Ab a pazienti con melanoma metastatico (stadio IV).

19 CLINICAL TRIALS (M. Maio) PHASE I/II: advanced metastatic melanoma mg/kg ipilimumab in monotherapy or in combination with IL-2 or gp100 peptide vaccine - Anti-tumor activity: reactivation of tumor-specific immune response in patients - Extensive tumor necrosis with infiltration of lymphocytes and granulocytes - Some immune-related reactions: no serious toxicities

20 PHASE I/II: ipilimumab

21 PHASE III: ipilimumb 1. The median overall survival (OS) increase from 6.4 months to 10.1 either in combination with gp100 (a protein involved in the maturation of melanocytes and over-expressed in melanoma) or alone 2. The median overall survival (OS) increase from 9.1 months to 11.2 in combination with dacarbazine (chemotherapeutic agent - alkylating agent) Approved at 3 mg/kg by FDA and EMA in 2011

5-years follow up: ipilimumab -1861 patients with a OS of 11.

22 5-years follow up: ipilimumab patients with a OS of 11.4 months, stable for 10 yrs with a survival rate of 20% Strong long-term benefit of ipilimumab

23 SAFETY AND QUALITY OF LIFE Toxicity: immune-related adverse effects that resolve in 6-8 weeks - Intestinal, liver, skin and endocrine organs - Rash, diarrhea, colitis, thyroiditis and hepatitis Use of corticosteroid for improving ipilimumab safety Quality of life: - No negative or positive impact reported

24 SUMMARY I

25 PD-1 - Recettore inibitorio della famiglia CD28 espresso sui linfociti effettori attivati in presenza di infezioni croniche persistenti o tumori, che riconosce i ligandi PD-L1 e PD-L2 - PD-L1 espresso su APC e cellule tissutali, mentre PD-L2 è espresso solo sulle APC - Stimolazione di PD-1 porta all inattivazione dei linfociti T - Espressione di PD-L1 o 2 è un meccanismo attraverso il quale i tumori evadono la risposta immune adattativa

26 INHIBITORY SIGNALLING- PD-1 ITIM and ITSM : - Recruitment of 5 phosphatidyl inositol phosphatese SHIP - Recruitment of tyrosine phosphatases (SHP1/2) Inhibiton of TCR signalling and PI3K pathway

27 ROLE OF PD-1 IN TOLERANCE

28 ANTI-PD-1/PD-L IMMUNOTHERAPY FOR CANCER

29 PD-1/PD-L Abs in melanoma therapy PD-1 Abs: - Nivolumab (approved in Japan 2014), pembrolizumab (approved by FDA in 2014) e pidilizumab (in phase II and III) PD-L Abs: in phase II and III

30 PRELIMINARY CLINICAL TRIAL DATA Pembrolizumab: phase I (2 mg/kg) - 26% overal response - 62% 1-year survival rate Nivolumab: phase III ( 3 mg/kg) - 40% overall response - 73% 1-year survival rate

31 ADVERSE EFFECTS

32 SUMMARY II

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