Association of common inherited NOD2 mutations with exceptional response to immune checkpoint inhibitors.

• DOI: 10.1200/jco.2023.41.16_suppl.2514
• Publication Date: 2023-06-04T15:12:10Z
• Authors: Megan Babette Barnet; Etienne Masle-Far...; Amanda Russell; Deborah Lilly Bur...; Katherine J.L Jac...; Robert Brink; Gillian Heller; Cindy Yang; Stephenie Prokopec; Andreas Behren; Ian D. Davis; Geoffrey D Peters; Michael J. Boyer; Tom John; Adnan Nagrial; Bo Gao; Prunella Blinman; Steven Chuan-Hao Kao; Jonathan S. Cebon; Christopher Carl ...
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

2514 Background: Melanomas and lung cancers usually display a large burden of somatically mutated proteins, yet only subset individuals can be induced to mount therapeutic immune response against tumours. Inherited mutations in regulatory genes may one factor predisposing heightened with addition an stimulus. Methods: Germline whole genome sequencing (WGS) was performed patient exceptional (ExR) targeted radiotherapy for metastatic melanoma (complete abscopal response). A target variant gene identified, interrogated within prospectively recruited cohort patients ExR or non-response anti-PD1 non-small cell cancer (NSCLC). Results were experimentally tested mice validated independent mixed clinical cohort. Results: Compound heterozygous variants NOD2 found the (expected genotype frequency 1.3 10,000), whose regression occurred concurrently flare pre-existing Crohn’s colitis (a NOD2-associated condition). Patients treated NSCLC (n=144). Individuals PD1 selected, defined by progression-free survival (PFS) ≥2 years ≥1 CTCAE grade 2 higher immune-related adverse event (n=40). Median follow-up 41 months (median PFS not reached). best progressive disease selected comparison (n=18, median 2.76m, 95% CI, 2.1-3.81). WGS from blood analysed all human known impair signalling. Of patients, 25% carried 1 more functional variants, totalling 11 80 alleles (13.8%); than twice expected allele (6.58%, p=0.0199). Within non-responders, (1 36 alleles, 2.78%). The association between loss-of-function Nod2-null C57BL/6J ( Nod2 fs ) mice. transplanted syngeneic line showed greater tumour compared wild-type littermates (60-day OS 41.67% vs 0%, p<0.01). Flow cytometry tumours proportion (CD44 hi CD62L low CD8 + CD4 effector memory differentiated cells versus animals (p<0.05). (n=105). Overall rate mutant 50% 15% (p=0.03). Conclusions: These results provide four complementary lines evidence that common inherited defects promote following acute triggers control cancer. biomarker treatment stratification enhance response.