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- Göran Jönsson (Lund, Sweden)
- Elin S. Gray (Perth, Australia)
131O - A composite biomarker for evaluation of homologous recombination repair deficiency in a pan-cancer cohort
- Marc Rübsam (Heidelberg, Germany)
Abstract
Background
Assessing the functional state of homologous recombination repair (HRR) is crucial to predict an effective response to
Methods
Whole-genome or -exome sequencing (WGS or WES) data from 739 patients including various rare cancers were evaluated for germline and somatic alterations in one of 183 genes related to HRR as well as for genomic patterns of HRR deficiency (HRD), i.e. exposure to single-base substitution signature 3, quantification of HRD-derived loss of heterozygosity (LOH-HRD), and the number of large-scale state transitions (LST). The individual markers were integrated into a composite biomarker, the TOP-ART score, with a scoring system (0-7) and compared to the other published HRR biomarkers. Currently, this biomarker is used to determine eligibility for the TOP-ART trial (ClinicalTrials.gov identifier: NCT03127215, olaparib/trabectedin vs. physician's choice, estimated study completion: December 2023).
Results
The occurrence and severity of HRD predicted by the TOP-ART score varies between entities. Strong associations were found between genomic patterns of HRD and mutations affecting several genes, including but not limited to
Conclusions
The TOP-ART score is a novel composite HRR biomarker developed and validated in an observational precision oncology cohort. It has the potential to broaden access to targeted treatments and is prospectively used to determine eligibility for the TOP-ART trial.
Clinical trial identification
NCT03127215 Study of Olaparib/Trabectedin vs. Doctor's Choice in Solid Tumors (NCT-PMO-1603) Estimated Primary Completion Date: December 2023 Estimated Study Completion Date: December 2023.
Legal entity responsible for the study
The authors.
Funding
German Cancer Consortium (DKTK).
Disclosure
C.E. Heilig: Financial Interests, Institutional, Research Funding: AstraZeneca, Pfizer, Roche, PharmaMar. M. Hlevnjak: Financial Interests, Personal, Stocks/Shares: Illumina, GSK, PharmaMar. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. R.F. Schlenk: Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pfizer, PharmaMar, Roche, Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, Pfizer; Financial Interests, Personal, Advisory Board: AbbVie, Daiichi Sankyo, Jazz, Pfizer. All other authors have declared no conflicts of interest.
1O - CircIGF1R_0001 mediates platinum resistance in ovarian cancer that sensitive to PARP inhibitors via promoting PARP1 binding to DNA damage sites
- Lei Ruilin (Guangzhou, China)
Abstract
Background
Clinical research indicated that some platinum-resistant ovarian cancer patients are sensitive to Poly (ADP-ribose) polymerase inhibitors(PARPi) and it is associated with high Poly(ADP-ribosyl)lation (PARylation) activity of PARP1. However, the specific mechanism remains unclear.
Methods
Key functional circRNAs that promote platinum resistance in epithelial ovarian cancer（EOC）were screened and identified through next-generation sequencing, quantitative real-time polymerase chain reaction (qRT-PCR), and comet assay methods. Experiments such as RNA immunoprecipitation (RIP), RNA pull-down, laser micro-irradiation, and fluorescence colonization were used to identify the proteins and domains that interact with target circRNA. The recruitment and trapping of PARP1 at DNA damage sites were detected through Chromatin extract isolation and Biotin-tagged Nicked DNA pulled down.
Results
The circIGF1R_0001 is highly expressed in some platinum-resistant tissues and cell lines, and its overexpression enhances DNA repair and platinum resistance in ovarian cancer cells. The circIGF1R_0001 binds to the DNA binding domain of PARP1 and can be recruited together to DNA damage sites. Silencing circIGF1R_0001 significantly reduces the PARylation of PARP1, weakens the recruitment of PARP1 at DNA damage sites, and inhibits the activation of downstream DNA liag3. Furthermore, EOC patients and cell lines with platinum resistance that overexpressing circIGF1R_0001 are more sensitive to PARP inhibitors; silencing circIGF1R_0001 increases the resistance to PARPi while weakening the DNA trapping effect of PARP1.
Conclusions
1. Overexpression of circIGF1R_0001 promotes platinum resistance but also promotes sensitivity to PARPi in ovarian cancer. 2. The circIGF1R_ 0001 binds to and regulates the DBD domain of PARP1 to promote its PARylation and enhance its recruitment to DNA damage sites then enhanced the base excision repair pathway. Importantly, circIGF1R_ 0001 also enhances the DNA trapping of PARP1 by PARPi. 3. The circIGF1R_ 0001 acts as a potential biomarker for platinum resistance in ovarian cancer and a marker for screening patients who can benefit from PARPi after platinum resistance.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 131O and 1O
- Elin S. Gray (Perth, Australia)
Q&A
- All Speakers (Lugano, Switzerland)
2232O - Atezolizumab (atezo) and tumour microenvironment in early triple-negative breast cancer (eTNBC): Exploratory biomarker analysis from IMpassion031
- Carlos H. Barrios (Porto Alegre, Brazil)
Abstract
Background
IMpassion031 showed that neoadjuvant chemotherapy (CT) + atezo significantly increased pathological complete response (pCR) and numerically favoured event-free, disease-free and overall survival (EFS, DFS and OS) vs CT + placebo (Pla) in patients (pts) with eTNBC. This IMpassion031 substudy assessed potential predictive tumour immune biomarkers for atezo clinical benefit.
Methods
Biomarker evaluation was performed on baseline, on-treatment, surgery and disease recurrence matched formalin-fixed, paraffin-embedded tumour tissue samples. Samples were tested for tumour infiltrating lymphocytes (TILs) and with RNA sequencing to derive molecular subtypes (basal-like immune activated [BLIA], basal-like immune suppressed [BLIS], mesenchymal [MES], luminal androgen receptor [LAR]), biological pathways and cellular components (xCELL). Biomarkers were evaluated for their association with pCR, EFS, DFS and OS.
Results
In patients with TIL-low tumours, atezo numerically improved outcomes compared with Pla (ΔpCR =19.4%, EFS hazard ratio [HR] 0.57, DFS HR 0.64 and OS HR 0.31). Atezo had higher pCR than Pla in BLIA (75% vs 54%) and BLIS (54% vs 32%) subtypes but not in LAR (33% vs 33%). While atezo showed improved EFS (HR 0.38) and DFS (HR 0.24) only in pts with BLIA tumours, atezo OS improvement vs Pla was only seen in pts with BLIS tumours (HR 0.17). The LAR subtype had excellent EFS, DFS and OS regardless of treatment, in contrast to a relatively low pCR rate. Biological pathway and cell type analyses indicated that increased proliferation, γδ T cells and pro-B cells predict atezo pCR benefit, while epithelial-mesenchymal transition, pericytes and stromal biology (e.g. angiogenesis, TGFβ) are linked to lack of atezo pCR benefit. No biological pathway or cell type consistently predicted atezo EFS, DFS or OS benefit. Exposure to CT ± atezo promoted dynamic changes in molecular subtype, which return to baseline at disease recurrence.
Conclusions
Atezo provides benefit in eTNBC pts with proliferative basal tumours, but is less active in indolent LAR tumours. Atezo improves outcomes in pts with low TILs, a subgroup with poor prognosis in eTNBC. Further studies are needed to validate these findings.
Clinical trial identification
NCT03197935.
Editorial acknowledgement
Research support for third-party writing assistance for this abstract, furnished by Katie Wilson, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
N. Harbeck: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, Daiichi Sankyo, Exact Sciences, MSD, Novartis, Pierre Fabre, Pfizer, F. Hoffmann-La Roche Ltd., Seagen; Financial Interests, Personal, Other, Co-Director: West German Study Group (WSG); Financial Interests, Personal, Advisory Role: Comprehensive Cancer Center, Munich, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, F. Hoffmann-La Roche/Genentech, Inc., Sandoz, Seagen; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, MSD, F. Hoffmann-La Roche Ltd/Genentech, Inc. C. Duan: Non-Financial Interests, Personal, Funding, Research funding: Support for third party writing assistance from F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffman-La Roche Ltd., Bristol Myers Squibb. K. DuPree: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. C. Chang: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd. C.H. Barrios: Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: GSK, Novartis, Pfizer, Roche, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Lilly, Sanofi; Financial Interests, Personal, Advisory Board, Consultation: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board, Scientific Presentations Consulting AD Board: Daiichi Sankyo; Financial Interests, Personal, Ownership Interest, Virtual APP: Thummi; Financial Interests, Personal, Stocks/Shares, Clinical Research Company: MedSIR; Financial Interests, Institutional, Research Grant, Research Funding To The Institution: Pfizer, Amgen, GSK, Lilly, Sanofi, Merck, BioMarin, BMS, Medivation, Exelixis, Merck KGaA, Shanghai Henlius Biotech, Polyphor, PharmaMar; Financial Interests, Institutional, Research Grant, Research Funding to the Institution Steering Committee: Novartis, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Research Grant, Research Funding to the Institution Steering committee: Roche; Financial Interests, Institutional, Local PI, Research Funding to the institution: Nektar, Regeneron, Janssen, OBI Pharma, Seagen, Checkpoint Therapeutics, Novocure, Aveo Oncology, Takeda, Celgene, TRIO, PPD, Syneos health, DOCS, Labcorp, IQIVIA, Parexel, Nuvisan, PSI, Medplace; Financial Interests, Institutional, Local PI, Research funding to the institution Steering Committee: Myovant; Non-Financial Interests, Member of Board of Directors, Member of Executive Board: BIG International Group; Non-Financial Interests, Leadership Role, Latin American Cooperative Oncology Group: LACOG; Non-Financial Interests, Other, Chair, International Educational Steering Group: ASCO; Non-Financial Interests, Advisory Role, Member Compliance Committee: ESMO. H.A. Zhang: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd. S. Saji: Financial Interests, Personal, Invited Speaker: Eli Lilly, Chugai, AstraZeneca, Kyowa Kirin, Daiichi Sankyo, Taiho, Pfizer, MSD, Novartis, Eisai, Ono, Takeda, Exact Sciences; Financial Interests, Institutional, Research Grant: Taiho, Chugai, Daiichi Sankyo; Financial Interests, Institutional, Local PI: MSD, Daiichi Sankyo, Chugai, AstraZeneca, Sanofi; Non-Financial Interests, Member of Board of Directors: Japanese Breast Cancer Society, Japanese Society of Medical Oncology, Japan Breast Cancer Research Group, Breast International Group. K.H. Jung: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F Hoffmann-La Roche Ltd.; Financial Interests, Personal, Advisory Role: AstraZeneca, Bixink, Celgene, Daiichi Sankyo, Eisai, Everest Medicine, MSD, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: F. Hoffmann-La Roche Ltd., Takeda Pharmaceuticals. M.L. Telli: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.; Financial Interests, Institutional, Research Grant: AbbVie, Arvinas, Bayer, Biothera, Calithera Biosciences, EMD Serono, Genentech, Inc., GSK, Hummingbird Biosciences, Medivation, Merck, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro, Vertex; Financial Interests, Personal, Advisory Role: AbbVie, Aduro Biotech, AstraZeneca, Blueprint Medicines, Celgene, Daiichi Sankyo, Genentech/Roche, Gilead, GSK, G1 Therapeutics, Guardant, Immunomedics, Lilly, Merck, Natera, Novartis, OncoSec, Pfizer, RefleXion, Sanofi. M. Liste Hermoso: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche, Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche, Ltd. S. Chui: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. M. Dieterich: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Coordinating PI, Gilead provides clinical trial support to my institution for a study that I am the PI on: Gilead; Financial Interests, Personal, Steering Committee Member: Roche/Genentech, BMS; Non-Financial Interests, Member of Board of Directors: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. L. Molinero: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: Roche/Genentech.
2O - PD-1 defines a distinct, functional, tissue-adapted state in V-delta-1+ T cells with implications for cancer immunotherapy
- Yin Wu (London, United Kingdom)
Abstract
Background
Checkpoint inhibition (CPI), particularly that targeting the inhibitory co-receptor, programmed cell death protein (PD-1), has transformed cancer care. Although CPI can de-repress cancer antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition through loss of MHC or low mutational burdens. In such settings, tissue-associated Vδ1+ γδ T cells have been implicated as these cells are not classically peptide-MHC dependent. Despite some evidence for association of Vδ1+ T cells to CPI response, the immunological significance of PD-1 expression by human Vδ1+ T cells remains uncharacterised.
Methods
As Vδ1+ T can operate independent of neoantigen load, we looked for a transcriptomic signature of Vδ1+ T cells in a public dataset of patients with melanoma receiving anti-PD-1 therapy and correlated this signature to response in the context of neoantigen load. Alongside this, we developed a protocol which enabled the extraction of substantial numbers of human skin γδ T cells to permit transcriptomic and functional studies of these rare cells. Skin-derived PD-1+ and PD-1- Vδ1+ T cells were sorted and analysed by NanoString using the nCounter Immune Exhaustion Panel. The cells were also activated
Results
We found that a transcriptional signature of intratumoral Vδ1+ T cells predicts response to anti-PD-1 in patients with melanoma, particularly in the context of low neoantigen load. Moreover, we found that skin-derived PD-1+ Vδ1+ T cells display a transcriptomic programme of tissue-residence, survival/self-renewal, and functional competence distinct from the canonical exhaustion programme of co-located PD-1+ CD8+ αβ T cells. Indeed, PD-1+ Vδ1+ T cells retained effector responses to T cell receptor signalling that were inhibitable by PD-1 engagement and partially derepressed by CPI.
Conclusions
Our formal demonstration that Vδ1+ T cells can be suppressed by PD-1 engagement and de-repressed by anti-PD-(L)1 CPI therapy supports their utility as a predictive biomarker for therapy.
Legal entity responsible for the study
The authors.
Funding
Wellcome Trust, Francis Crick Institute, Takeda Pharmaceutical Company.
Disclosure
Y. Wu: Non-Financial Interests, Personal and Institutional, Research Grant: Wellcome Trust; Financial Interests, Personal, Advisory Board: PersonGen Biotherapeutics. A. Hayday: Non-Financial Interests, Personal and Institutional, Funding: Takeda Pharmaceutical Company; Financial Interests, Personal, Advisory Board: eGenesis, Prokarium. All other authors have declared no conflicts of interest.
3O - IGSF8 is an innate immune checkpoint and cancer immunotherapy target
- Karim Benhadji (Cambridge, United States of America)
Abstract
Background
Loss of MHC-I antigen presentation is often associated with T cell excluded tumors, and represents a common mechanism of both primary and acquired resistance to immune checkpoint blockade (ICB) treatment. MHC-I normally acts as a marker of “self” and cells that lack MHC-I are recognized and killed by innate immunity. A major puzzle in cancer immunology remains as to how T cell excluded tumors with MHC-I antigen presentation defects evade innate immune killing.
Methods
Integrating functional genomics, big data, and artificial intelligence, we discovered that IGSF8 expressed on cancer cells is a conserved innate immune checkpoint. IGSF8 is normally expressed in neuronal tissues and is not essential
Results
IGSF8 has receptors on both natural killer (NK) cells and dendritic cells (DC) to strongly suppress NK cytotoxicity and antigen presentation. In many cancer types across TCGA, IGSF8 is frequently DNA copy number amplified and overexpressed, and IGSF8 expression is associated with low antigen presentation, low immune infiltration, and worse overall survival in patients with low MHC class I expression. We developed a cross-species reactive antibody against IGSF8 (GV20-0251) which blocks IGSF8 interaction with NK and DC. This antibody enhances NK killing of cancer cells
Conclusions
IGSF8 is a novel innate immune checkpoint and cancer immunotherapy target. Given the ability for anti-IGSF8 to activate innate immunity, a phase 1 study has been initiated to explore the IGSF8 inhibitor GV20-0251 in patients with advanced or metastatic solid tumors (NCT05669430).
Legal entity responsible for the study
GV20 Therapeutics.
Funding
GV20 Therapeutics.
Disclosure
K. Benhadji: Financial Interests, Personal, Officer: GV20 Therapeutics; Financial Interests, Personal, Stocks/Shares: Lilly; Other, Employment: Taiho Oncology. Y. Li, H. Liu, X. Xiao, H. Liu: Financial Interests, Personal, Full or part-time Employment, Stock options: GV20 Therapeutics. X. Wu, B. Xie, R. Zheng, Q.Yu: Financial Interests, Personal, Full or part-time Employment: GV20 Therapeutics. Q. Ding: Financial Interests, Personal, Full or part-time Employment, Stock Ownership: GV20 Therapeutics. C. Sheng: Financial Interests, Personal, Financially compensated role, Stock options: GV20 Therapeutics; Financial Interests, Personal, Full or part-time Employment: Novartis. X. Hu: Financial Interests, Personal, Officer, Stock Options: GV20 Therapeutics. X.S. Liu, T.Xiao: Financial Interests, Personal, Officer, Director, Stock ownership: GV20 Therapeutics.
Invited Discussant 2232O, 2O and 3O
- Göran Jönsson (Lund, Sweden)
Q&A
- All Speakers (Lugano, Switzerland)