Clinical implication of autoimmunity in immune checkpoint blockade

Clinical implication of autoimmunity in immune checkpoint blockade therapy: with focus on autoimmune thyroiditis 핵의학과 서민석

History of cancer immunotherapy Nat Rev Cancer 2016; 16: 219

History of cancer immunotherapy Nat Rev Drug Discov 2011; 10: 591

Immune checkpoint blockades PD-1 inhibitor: Nivolumab, Pembrolizumab PD-L 1 inhibitor: Avelumab, Durvalumab CTLA-4 inhibitor: Ipililumab Nat Rev Cancer 2016; 16: 275

Immune checkpoint blockades Ipilimumab in untreated melanoma (Phase III trial) N Engl J Med 2011; 363: 2517

Immune checkpoint blockades Nivolumab in untreated melanoma without BRAF mutation (Phase III trial) N Engl J Med 2015; 372: 4 Eur J Cancer 2016; 54: 139

Side Effects (immune-related adverse events) Anti-PD-1 Ab in cancer, Phase I N Engl J

Side Effects (immune-related adverse events) immune-related adverse events (ir. AEs) Nat Rev Clin Oncol 2016; 13: 478

Side Effects (immune-related adverse events) Endocrinopathies Nat Rev Endocrinol 2017; 13: 195

Side Effects (immune-related adverse events) Clinical need for monitoring immune related thyroid disorder Masking of symptom Early treatment Broadening the indication Prognosis

Side Effects (immune-related adverse events) Mechanism: Unclear Hypothesis: polymorphic variants of PD-1 or CTLA-4 receptor gene Management J Endocrinol Diab. 2016; 3: 1

Side Effects (immune-related adverse events) Initial F/U Two weeks later, blood samples confirmed the diagnosis of hypophysitis After PD Clin Nucl Med. 2013; 38

Side Effects (immune-related adverse events) Clin Thyroidol 2016; 28: 299

Side Effects (immune-related adverse events) Study plan Pre-treatment risk stratification Post-treatment early evaluation

On the other hand… J Am Acad Dermatol 1983; 9: 689 Dermatologica 1991; 183: 239

Immune-related prognostication Interferon therapy Blood samples were obtained before treatment, after 1, 3, 6, 9, and 12 N Engl J Med 2006; 354: 7

Immune-related prognostication Prognostication N Engl J Med 2006; 354: 7

Immune-related prognostication J Endocrinol Invest 2007; 30: 734 Autoimmunity: US thyroid, Serum (f. T 4, TSH, anti-Tg Ab, TPO Ab) Positive (Goiter, Ab(+), and Echogenecity) TAb (+) ER (+), TAb (+) ER (-), TAb (+) ER (+), TAb (-) ER (-), TAb (-)

Immune-related prognostication Ann Hematol 2015; 94: 995 Autoimmunity: US thyroid (FNA), Serum (f. T 4, TSH, anti-Tg Ab, TPO Ab), and FDG PET Positive (Goiter, Ab(+), echogenicity, FNA, and diffuse thyroid FDG uptake)

Immune-related prognostication Ann Hematol 2015; 94: 995 J Nucl Med 2007; 48: 896

Immune-related prognostication On-going Study by F. SY Kang and Pf. SW Oh Clinical Significance of Diffuse Thyroid Uptake on FDG PET/CT in Triple Negative Breast Cancer Seo Young Kang, So Won Oh, Gi Jeong Cheon, and June-Key Chung Departments of Nuclear Medicine, Seoul National University Department of Nuclear Medicine, Seoul National University Boramae Medical Center Characteristics Age (year) TNM stage III stage IV Molecular subtype luminal HER 2 TN (triple negative) Surgical treatment QUA MRM Adjuvant treatment neoadj. CTx. Adj. CTx. RTx. DTU on FDG PET Antibodies Tab TPOab total (n=101) 46± 9 TNBC (n=23) 46± 9 non-TNBC (n=78) 47± 9 18 (18%) 41 (41%) 39 (39%) 3 (3%) 5 (22%) 13 (57%) 5 (22%) 13 (23%) 29 (37%) 34 (44%) 3 (3. 8%) 51 (50%) 50 (50%) 13 (57%) 10 (43%) 38 (49%) 40 (51%) 27 (27%) 98 (97%) 80 (79%) 45 (45%) 2 (8. 75) 22 (96%) 20 (87%) 12 (52%) 24 (31%) 75 (96%) 59 (76%) 33 (42%) 44 (44%) 43 (43%) 12 (52%) 11 (48%) 32 (41%) 54 (54%) 24 (24%) 23 (23%) p-value

Subgroup analysis TNBC patients (n=23) kappa p FDG*Tgab 0. 563 P = 0. 007 FDG*TPOab 0. 654 P = 0. 001 PFS P =0. 009 DTU P =0. 022 TPOab §DTU on FDG PET/CT showed agreements with thyroidrelated autoantibodies §Therapy-induced thyroid autoimmunity might mediate favorable outcome in TNBC patients.

Immune-related prognostication CTLA-4 therapy Autoimmunity Ophthalmologic examination Serum marker Anti-Tg Ab Rheumatoid factor Antinuclear antibody TSH f. T 4 Blood samples were obtained before treatment, after every 3 to 12 weeks, until the enrolled period J Clin Oncol 2005; 23: 6043

Immune-related prognostication Prognostication J Clin Oncol 2005; 23: 6043

Immune-related prognostication Nivolumab therapy Blood samples were obtained before treatment, after 7, 12, 19, 24 weeks and every 12 weeks up to 24 months of follow-up Clin Cancer Res 2016; 22: 886

Immune-related prognostication Abstract A 018: Onset of dysthyroidism during treatment with immune checkpoint inhibitors is increased in responder patients Diego Signorelli et al. Indication: 104 metastatic solid tumor patients who underwent immune checkpoint inhibitor therapy Dysthyroidism: According to CTCAE version 4. 0 Results: Dysthyroid 19/29 (65. 5%) achieved DCR No Dysthyroid 29/75 (38. 6%) achieved DCR Conclusions: In responding patients, we found a statistically significant increase of thyroiditis during treatment with ICI. CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16 -19, 2015; New York, NY

Summary Both CTLA-4 and PD-1/PD-L 1 targeted immunotherapy is associated with primary thyroid dysfunction, and has an elevated incidence when using combination therapy IRAEs, including thyroid dysfunction, might be associated with improved clinical response, but further studies are needed