Abstract
Association of common inherited NOD2 mutations with exceptional response to immune checkpoint inhibitors.
Author
person
Megan Babette Barnet
Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
info_outline
Megan Babette Barnet, Etienne Masle-Farquhar, Amanda Russell, Deborah Lilly Burnett, Katherine J.L Jackson, 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 Goodnow
Full text
Authors
person
Megan Babette Barnet
Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
info_outline
Megan Babette Barnet, Etienne Masle-Farquhar, Amanda Russell, Deborah Lilly Burnett, Katherine J.L Jackson, 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 Goodnow
Organizations
Garvan Institute of Medical Research, Darlinghurst, NSW, Australia, Garvan Institute of Medical Research, Darlinghurst, Australia, NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia, Princess Margaret Cancer Centre, Toronton, ON, Canada, Princess Margaret Cancer Centre, Toronto, ON, Canada, Olivia Newton-John Cancer Research Institute, Melbourne, Australia, Monash University and Eastern Health, Box Hill, Australia, Canberra Cancer Centre, Garran, Australia, Chris O'Brien Lifehouse, Camperdown, NSW, Australia, Peter McCallum Cancer Centre, Melbourne, Australia, Westmead Cancer Care Centre, Westmead, NSW, Australia, Westmead Hospital, Sydney, NSW, Australia, Concord Repatriation General Hospital, Concord NSW, Australia, Chris O'Brien Lifehouse, Camperdown, Australia, Austin Hospital, Heidelberg, Australia
Abstract Disclosures
Research Funding
No funding received
None.
Background:
Melanomas and lung cancers usually display a large burden of somatically mutated proteins, yet only a subset of individuals can be induced to mount a therapeutic immune response against tumours. Inherited mutations in immune regulatory genes may be one factor predisposing to a heightened immune response with addition of an immune stimulus.
Methods:
Germline whole genome sequencing (WGS) was performed in a patient with exceptional response (ExR) to targeted radiotherapy for metastatic melanoma (complete abscopal response). A target variant gene was identified, and interrogated within a prospectively recruited cohort of patients with ExR or non-response to anti-PD1 for non-small cell lung cancer (NSCLC). Results were experimentally tested in mice and validated in an independent mixed cancer clinical cohort.
Results:
Compound heterozygous variants in
NOD2
were found within the patient with abscopal response (expected genotype frequency 1.3 in 10,000), whose cancer regression occurred concurrently with a flare of pre-existing Crohn’s colitis (a
NOD2
-associated condition). Patients treated with anti-PD1 for NSCLC were prospectively recruited (n=144). Individuals with ExR to PD1 were selected, defined by progression-free survival (PFS) ≥2 years and ≥1 CTCAE grade 2 or higher immune-related adverse event (n=40). Median follow-up was 41 months (median PFS not reached). Patients with best response of progressive disease were selected for comparison (n=18, median PFS 2.76m, 95% CI, 2.1-3.81). WGS from blood was analysed for all human
NOD2
variants known to impair
NOD2
signalling. Of ExR patients, 25% carried 1 or more functional
NOD2
variants, totalling 11 of 80 alleles (13.8%); more than twice the expected allele frequency (6.58%, p=0.0199). Within non-responders, 1 patient carried a variant
NOD2
allele (1 of 36 alleles, 2.78%). The association between
NOD2
loss-of-function and heightened immune response to anti-PD1 was experimentally tested in
Nod2
-null C57BL/6J (
Nod2
fs
) mice.
Nod2
fs
mice transplanted with a syngeneic cell line and treated with anti-PD1 showed greater tumour response compared with
Nod2
wild-type
littermates (60-day OS 41.67% vs 0%, p<0.01). Flow cytometry of tumours showed greater proportion of (CD44
hi
CD62L
low
) CD8
+
and CD4
+
effector memory differentiated cells within
Nod2
fs
versus
Nod2
wild-type
animals (p<0.05). Results were validated within an independent clinical cohort (n=105). Overall response rate to PD1 in patients with mutant vs wild-type
NOD2
was 50% versus 15% (p=0.03).
Conclusions:
These results provide four complementary lines of evidence that common inherited defects in the immune regulatory gene
NOD2
promote exceptional immune response following acute triggers to control cancer.
NOD2
may be a biomarker for treatment stratification or a therapeutic target to enhance anti-PD1 response.
14 organizations
1 drug
1 target
Organization
Garvan Institute of Medical ResearchOrganization
Darlinghurst, NSW, AustraliaOrganization
NHMRC Clinical Trials CentreOrganization
The University of SydneyOrganization
Princess Margaret Cancer CentreOrganization
Monash University and Eastern HealthOrganization
Canberra Cancer CentreOrganization
Chris O'Brien LifehouseOrganization
Peter McCallum Cancer CentreOrganization
Westmead Cancer Care CentreOrganization
Westmead HospitalOrganization
Concord Repatriation General HospitalOrganization
Austin HospitalDrug
anti-PD1Target
PD-1