Erik Yusko

Adaptive Biotechnologies (United States)

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Harlan Robins

Adaptive Biotechnologies (United States)

Catherine Sanders

Adaptive Biotechnologies (United States)

Ryan Emerson

Adaptive Biotechnologies (United States)

Marissa Vignali

Adaptive Biotechnologies (United States)

Rachel Gittelman

Guardant (United States)

Sharon Benzeno

Adaptive Biotechnologies (United States)

Eleanor J. Cheadle

University of Manchester

Simon J. Dovedi

AstraZeneca (United Kingdom)

Tom B. Davidson

Children's Hospital of Los Angeles

Robert W. Wilkinson

University of Bath

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The University of Texas MD Anderson Cancer Center

207

National Institutes of Health

169

National Cancer Institute

163

Dana-Farber Cancer Institute

153

Center for Cancer Research

143

Memorial Sloan Kettering Cancer Center

134

Harvard University

123

Johns Hopkins University

109

Cornell University

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Data from TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence

Alexandre Reuben Rachel Gittelman Jianjun Gao Jiexin Zhang Erik Yusko

<div>AbstractGenomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088–97. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047</div>

10.1158/2159-8290.c.6546671.v1

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894 Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence

Journal of Investigative Dermatology (2020)

W. Pruessmann Julie Rytlewski James S. Wilmott Martín C. Mihm Grace H. Attrill

Histopathology

Primary tumor

Mitotic index

10.1016/j.jid.2020.03.910

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T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis

Cell Reports (2019)

Caren Ramien Erik Yusko Jan Broder Engler Stefanie Gamradt Kostas Patas

Identifying T cell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the T cell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the T cell repertoire becomes less dominated by expanded clones. However, only a few T cell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated T cell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the T cell repertoire during pregnancy could serve as a tool to discover and track "private" T cell clones associated with disease activity in autoimmunity.

clone (Java method)

10.1016/j.celrep.2019.09.025

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Baseline tumor T cell receptor (TcR) sequencing analysis and neo antigen load is associated with benefit in melanoma patients receiving sequential nivolumab and ipilimumab

Annals of Oncology (2016)

Jeffrey S. Weber Christine E. Horak F. Stephen Hodi Han Chang David M. Woods

10.1093/annonc/mdw378.01

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Citations (12)

Circulating tumor DNA predicts therapeutic outcome in mantle cell lymphoma

Blood Advances (2022)

Rahul Lakhotia Christopher Melani Kieron Dunleavy Stefania Pittaluga Nakhle S. Saba

Mantle cell lymphoma (MCL) is biologically and clinically heterogeneous and would benefit from prognostic biomarkers to guide management. Circulating tumor DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma that may have applicability in MCL. We analyzed ctDNA dynamics in previously untreated patients with MCL who received induction therapy with bortezomib and DA-EPOCH-R for 6 cycles followed by random assignment to observation or bortezomib maintenance in responding patients in a prospective phase 2 study. Most patients also underwent initial treatment window of bortezomib alone prior to induction. Serum was collected pretreatment, after the window, after cycles 1 and 2, at the end of induction, and at each follow-up visit along with restaging computed tomography scans. Next-generation sequencing was used to identify and quantify ctDNA encoding the immunoglobulin receptor sequences in serum as markers of minimal residual disease. Fifty-three patients were enrolled, with a median follow-up of 12.7 years. Patients without detectable ctDNA after 2 cycles of induction had longer progression-free survival (PFS) and overall survival (OS) compared with those with detectable ctDNA (median PFS, 2.7 vs 1.8 years; overall P = .005; median OS, 13.8 vs 7.4 years; overall P = .03). Notably, in vivo assessment of ctDNA dynamics during the bortezomib window was not prognostic, and there was no difference in PFS or OS with bortezomib maintenance. ctDNA monitoring after induction showed that molecular relapse preceded clinical relapse in some cases. In conclusion, interim ctDNA negativity strongly correlates with improved survival and supports the investigation of response-adapted strategies. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

Minimal Residual Disease

Circulating tumor DNA

10.1182/bloodadvances.2021006397

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Hybrid capture-based next-generation sequencing (HC NGS) in melanoma to identify markers of response to anti-PD-1/PD-L1.

Journal of Clinical Oncology (2016)

Douglas B. Johnson Garrett M. Frampton Matthew J. Rioth Erik Yusko Riley Ennis

105 Background: Agents blocking programmed death-1/ligand (aPD1) induce durable responses in many melanoma patients (pts). Greater numbers of somatic mutations have been linked to high aPD1 response rates (RR) in other cancers. We assessed whether number and/or type of mutations (mut) using HC NGS correlated with outcomes to aPD1 in melanoma. Methods: HC NGS on 236-315 genes was performed on archival samples from pts who received aPD1 (comprising ~1.25 megabases [MB]). A novel algorithm extrapolated genomic mutational load (ML) from this panel. Intratumoral T cell clonal expansion was determined by T cell receptor (TCR) sequencing. ML and TCR clonality were correlated with with aPD1 outcomes. Results: Responders to aPD1 had higher ML compared to non-responders in discovery (median 45.6 vs. 3.9 mut/MB; p=0.003, n=32), and validation cohorts (37.1 vs. 12.8 mut/MB; p=0.002, n=33). RR was superior in high ML pts compared to intermediate/low (Table) as was progression-free survival (PFS) (median not reached [MNR] vs. 89 days vs. 86 days, p<0.001) and overall survival (OS) (MNR vs. 300 days vs. 375 days, p<0.001). Responders had more C>T transitions than non-responders (median 33.5 vs. 3.0, p<0.001). Melanomas with NF1 mutations had high ML (median 62.7 mut/MB) and high RR (74%); whereas BRAF mutant (12.0 mut/MB), NRAS mutant (17.6 mut/MB), and BRAF/NRAS/NF1wild-type (2.2 mut/MB) melanomas had lower median ML. TCR clonality did not correlate with response in these archival samples, nor did PD-L1 gene amplification (<1% incidence). Conclusions: ML as determined by HC NGS effectively stratified patients by likelihood of response. This approach may provide a widely available, clinically feasible predictor of response to aPD1. Cohort Mutational load group Response No Response P value Discovery High (n=11) 9 (82%) 2 (18%) 0.003 Intermediate (n=11) 4 (36%) 7 (64%) Low (n=10) 1 (10%) 9 (90%) Validation High (n=16) 14 (88%) 2 (12%) 0.001 Intermediate (n=13) 3 (23%) 10 (77%) Low (n=4) 1 (25%) 3 (75%) Combined High (n=27) 23 (85%) 4 (15%) <0.001 Intermediate (n=24) 7 (29%) 17 (71%) Low (n=14) 2 (14%) 12 (86%) High ML: >23.1 mut/MB; Intermediate: 3.2 – 23.1 mut/MB; Low: <3.2 mut/MB

10.1200/jco.2016.34.15_suppl.105

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Data from Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade

Douglas B. Johnson Garrett M. Frampton Matthew J. Rioth Erik Yusko Yaomin Xu

<div>AbstractTherapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti–PD-1 in melanoma. Using archival melanoma samples from anti–PD-1/PD-L1-treated patients, we performed hybrid capture–based NGS on 236–315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti–PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti–PD-1/PD-L1. Cancer Immunol Res; 4(11); 959–67. ©2016 AACR.</div>

10.1158/2326-6066.c.6548372

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Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade

Cancer Immunology Research (2016)

Douglas B. Johnson Garrett M. Frampton Matthew J. Rioth Erik Yusko Yaomin Xu

Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti-PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1. Cancer Immunol Res; 4(11); 959-67. ©2016 AACR.

Exome

10.1158/2326-6066.cir-16-0143

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Citations (442)

Circulating Tumor DNA Dynamics during Therapy Predict Outcomes in Mantle Cell Lymphoma

Blood (2018)

Rahul Lakhotia Christopher Melani Stefania Pittaluga Kieron Dunleavy Nakhle S. Saba

Induction chemotherapy

Circulating tumor DNA

10.1182/blood-2018-99-112573

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Citations (13)

Supplemental Figures S1-S11 from TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence

Alexandre Reuben Rachel Gittelman Jianjun Gao Jiexin Zhang Erik Yusko

Supplemental Figure S1. Number of predicted neoantigens. Supplemental Figure S2. Association between expressed branch predicted neoantigens and relapse. Supplemental Figure S3. Substantial ITH in the number of unique T cell rearrangements. Supplemental Figure S4. Substantial ITH in tumor-enriched T cell repertoire in 8 patients whose blood samples were available. Supplemental Figure S5. A minority of T cell clones are shared between different regions within a tumor. Supplemental Figure S6. The top 5 clones within each tumor are conserved across all regions of that given tumor. Supplemental Figure S7. Tumor-enriched MOI in patients with available paired blood. Supplemental Figure S8. CD4-dominant T cell infiltrate in localized lung adenocarcinomas by immunohistochemical (IHC) staining. Supplemental Figure S9. Correlation between predicted neoantigen burden and TCR metrics. Supplemental Figure S10. Association between intratumor TCR heterogeneity and patient relapse. Supplemental Figure S11. Follow up time (months) in patients who recurred and those who have not. n.s., not significant.

10.1158/2159-8290.22532243.v1

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