Nuovi approcci immunoterapici nel trattamento del Melanoma: Background immunologico.

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1 Nuovi approcci immunoterapici nel trattamento del Melanoma: Background immunologico. Andrea Anichini Human Tumors Immunobiology Unit Dept. of Experimental Oncology and Molecular Medicine

2 Immune checkpoint inhibitors: a new age in melanoma immunotherapy Durable tumor regression and prolonged stabilization of disease by a-pd-l1 Objective responses by a-pd-1 in 1/4-1/5 patients A high rate of sustained tumor regression by a-pd-1 including patients with progressive disease after a-ctla4 Targeting of PD-1/PD-L1 a-pd-1 + a-ctla4: Rapid and deep tumor regression in a substantial proportion of patients BRAF-neg patients: OS at 1 year 72.9% vs 42.1% by chemotherapy 6 month PFS 47% by a-pd-1 vs 26.5% by a-ctla4. Response rate 33.7% by a-pd-1 vs 11.9% by a-ctla4 31.7% objective responses by a-pd-1 vs 10.6% by chemotherapy in patients progressing after a-ctla4 or a-ctla4 and a BRAF inhibitor Higher objective response rate, more frequent complete responses, and longer PFS by apd- 1 + a-ctla4 vs a- CTLA4 alone in previously untreated patients Improved survival by a-ctla4 compared to a vaccine Improved survival by a-ctla4 compared to chemotherapy 5-year survival rate 18.2% by a-ctla4 plus dacarbazine vs 8.8% by placebo plus dacarbazine Adjuvant a-ctla4 significantly improves recurrence-free survival for patients with completely resected high-risk stage III melanoma Targeting of CTLA-4

3 Functions of CTLA-4 vs. PD-1 CD80 or CD86 CD28 CD80 or CD86 Pardoll Nat Rev Cancer 2012 Clin Ther 2015

4 How anti-ctla-4 works 1-Promotes infiltration of neoplastic lesions by activated T cells. 2-Suppresses Tregs, thus increasing the Teff/Treg ratio. 3-Induces immune response to neoantigens generated by somatic mutations

5 Anti-CTLA4 therapy promotes infiltration of neoplastic lesions by activated T cells CVD IFN-a FTM anti-ctla4 mab PR (retroperitoneal nodes) anti-ctla4 mab Autoimmune colitis Regressing lesion Non-regressing lesion Del Vecchio, JCO 2011

6 Infiltration of activated T cells in the lesion responding to anti-ctla4 Pre-therapy lesion Regressing lesion Progressing lesion responding non responding

7 Enhanced infiltration of dendritic cells and reduced frequency of regulatory T cells in the lesion responding to Ipilimumab

8 A specific set of somatic neoepitopes associated with clinical benefit in response to ipilumumab Snyder A, NEJM 2014 DOI: /NEJMoa Ipilimumab promotes the generation of an effective T cell-mediated response directed to neoantigens generated by somatic mutations

9 Why anti-ctla-4 may not work T cell HLA Tumor

10 How anti-pd-1 works -counteracts an adaptive tumor resistance mechanism. -rescues the function of anti-tumor, differentiated T cells. -promotes the immune response to neoantigens generated by somatic mutations. B C 3 A D

11 PD-1 expression defines tumor-specific T cells at tumor site in melanoma 4-1BB= CD137 costimulatory molecule of the TNFR family that includes OX40 (CD134), GITR (CD137), CD40 and CD27. Gros A et al.

12 Correlation of PD-1, PD-L1 and TILs in different solid tumors Taube JM, Sc. Transl. Med Spranger S, Sc. Transl. Med Berghoff AF, Histopathology 2014

13 CD8 + lymphocytes and expression of PD-1/PD-L1 in pre-therapy lesions predict response to Pembrolizumab (anti-pd-1) in melanoma patients Responding patients Tumor Invasive margin Non responding patients Proximity of PD-1/PD-L1 expression Tumeh PC et al.

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15 Why combinatorial immune checkpoint blockade is so effective 2013 Ipilimumab, Nivolumab CTLA-4, PD-1 Rapid and deep melanoma regression in a substantial proportion of patients: 53% of patients had an objective response, all with tumor reduction of 80% or more Wolchok, NEJM Ipilimumab, Nivolumab CTLA-4, PD-1 objective response rate 61% by a-pd-1 +a-ctla-4 vs. 11% by a-ctla-4 and placebo. Postow, NEJM 2015 CD80 or CD86 CD28 CD80 or CD86 Pardoll Nat Rev Cancer 2012

16 Further developments in combinatorial immune checkpoint blockade PD-1 TIM-3 LAG-3 T cell TIGIT Gros A et al.

17 Acknowledgements Human Tumors Immunobiology Unit Roberta Mortarini Elena Tassi Valentina Perotti Giulia Grazia Ilaria Bersani Alessandra Molla Claudia Vegetti Gabriella Nicolini Paola Baldassari Medical Oncology Unit Michele Del Vecchio Lorenza di Guardo Filippo De Braud Dept. of Pathology Gabrina Tragni