Association of homologous recombination deficiency in ovarian cancer with neoantigen load and expression of immune checkpoints.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5536-5536
Author(s):  
Kathleen Fenerty ◽  
Charlene Marie Fares ◽  
Gottfried E. Konecny
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Immune Checkpoint ◽  
Single Agent ◽  
Objective Response ◽  
Wilcoxon Test ◽  
Immune Checkpoints ◽  
Protein Abundance ◽  
Homologous Recombination Deficiency ◽  
L1 Protein

5536 Background: Immune checkpoint blockade (ICB) is being explored as a treatment option in ovarian cancer, but objective response rates for single agent ICB are modest at around 10-15%. Validated biomarkers are needed to predict which patients will respond to ICB. BRCA mutations and homologous recombination deficiency (HRD) status are the only validated integral biomarkers in ovarian cancer. HRD tumors exhibit defective DNA repair mechanisms that promote increased mutational burden, which we postulate may correlate with higher neoantigen load and increased expression of targetable immune checkpoints. Methods: The Cancer Genome Atlas (TCGA) ovarian cancer dataset was evaluated and previously published, well annotated samples were obtained for HRD status. HLA type was determined with OptiType. Nonsynonymous mutations were annotated with Ensembl VEP. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 amino acids in length for MHC class I, reporting only those with a predicted IC50 less than 500 nM. Immune checkpoint gene expression counts were normalized with TCGAbiolinks. Correlation between HRD status and neoantigen load was assessed by Wilcoxon test. After log2 transformation, Wilcoxon tests evaluated for association between HRD status and expression of immune checkpoints. The relationship between HRD status and PD-L1 protein abundance with reverse phase protein array was measured. Results: Data from 154 HRD positive and 198 HRD negative tumors were analyzed. HRD positive status correlated with higher neoantigen load (p = 0.038) and increased expression of the immune checkpoints CTLA4 (p = 0.024), TIGIT (p = 0.027), and PVR (p = 0.002), but not PD-L1 (p = 0.238), LAG3 (p = 0.583), HVEM (p = 0.805), GAL9 (p = 0.750), NECTIN2 (p = 0.874), VSIG3 (p = 0.438), PSGL1 (p = 0.205) or VISTA (p = 0.531). TIM3 (p = 0.064) and B7H3 (p = 0.052) both demonstrated a trend towards increased expression in HRD tumors. Interestingly, HRD status showed a negative association with PVRIG (p = 0.028). There was no association between PD-L1 protein abundance and HRD status. Conclusions: HRD positive ovarian tumors demonstrate higher neoantigen load than HRD negative tumors, as well as increased expression of certain immune checkpoints. This supports the hypothesis that increased neoantigen load leads to compensatory induction of immune checkpoints, and suggests that HRD status may predict response to ICB, particularly to drugs that target CTLA4, TIGIT, PVR, TIM3 and B7H4.

scholarly journals 261 A functional genetic screen uncovers regulators of intratumoral macrophage function and reveals CD24 as a novel target for cancer immunotherapy by macrophages

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A283-A283
Author(s):  
Amira Barkal ◽  
Rachel Brewer ◽  
Irving Weissman
Keyword(s):  
Ovarian Cancer ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Therapeutic Potential ◽  
Human Subjects ◽  
Tumor Model ◽  
Innate Immune ◽  
Immune Checkpoints ◽  
Human Subjects Research ◽  
Genetic Ablation

BackgroundCancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic, innate immune checkpoint molecules called ‘don’t eat me’ signals, including CD47,1 PD-L1,2 and MHC class I.3 Monoclonal antibodies that antagonize the interaction of ‘don’t eat me’ signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers. However, variability in the magnitude and durability of the responses to these agents has suggested the presence of additional, as yet unknown innate immune checkpoints. Here, we present a functional screening platform which identifies tumor-specific regulators of intratumoral macrophage function. We show that CD24 is a dominant innate immune checkpoint in many solid tumors, including ovarian cancer and breast cancer.4MethodsBy applying our screening method, we uncovered the novel innate immune checkpoint molecule, CD24. To characterize the role of CD24 as a macrophage checkpoint, we leveraged the MCF-7 human xenograft tumor model and the ID8 syngeneic ovarian cancer tumor model. We evaluated the anti-tumor effect of CD24 antagonism through genetic ablation experiments in addition to therapeutic CD24 monoclonal antibody (mAb) blockade. We also utilized primary human immune cells and tumor specimens to assess the effect of CD24 blockade either alone or in combination with additional tumor-targeting antibodies.ResultsWe demonstrate that CD24 promotes immune evasion through its interaction with the inhibitory macrophage receptor Siglec-10. Genetic ablation of either CD24 or Siglec-10, as well as blockade of the CD24–Siglec-10 interaction using monoclonal antibodies, robustly augmented the phagocytosis of all CD24-expressing human tumors that we tested. Therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumor growth in vivo and an increase in survival time. The therapeutic efficacy of anti-CD24 mAbs was enhanced when combined with a second anti-tumor antibody. In particular, dual treatment of HER2-positive breast cancers with anti-CD24 mAb and trastuzumab, augmented phagocytosis relative to either treatment alone, even among cancers with inherent trastuzumab resistance (figure 1).Abstract 261 Figure 1Macrophage checkpoints are therapeutic targets. (A) There are four defined innate immune checkpoint signaling axes which exist between macrophages and cancer cells, which all rely on ITIM or ITSM signaling on the cytoplasmic side of the macrophage. (B) Phagocytosis of BT-474 (n = 8 donors) in the presence of anti-CD24 mAb, anti-HER2 mAb or dual treatment, compared with IgG control.ConclusionsThese data reveal CD24 as a highly expressed, anti-phagocytic signal in several cancers, and demonstrate the therapeutic potential for CD24 blockade in cancer immunotherapy, either alone or in combination with existing anticancer treatments. Collectively, this work suggests a new paradigm that innate immune checkpoints are redundant and employed in a tissue-specific and even tumor-specific manner, and makes clear the need to measure the collective expression of these ‘don’t eat me’ signals in order to optimize patient responses to both innate and adaptive immunotherapies.ReferencesMajeti R, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138: 286–299. Gordon SR, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017;545:495–499.Barkal AA, et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat Immunol 2018;19:76–84.Barkal AA, Brewer RE, Markovic M, Kowarsky MA, Barkal SA, Zaro BW, Krishnan V, Hatakeyama J, Dorigo O, Barkal LJ, Weissman IL. CD24 signaling through macrophage siglec-10 is a new target for cancer immunotherapy. Nature 2019;572:392–396.Ethics ApprovalThe Human Immune Monitoring Center Biobank and the Stanford Tissue Bank all received IRB approval from the Stanford University Administrative Panels on Human Subjects Research and complied with all ethical guidelines for human subjects research to obtain samples from patients with ovarian cancer and breast cancer, and received informed consent from all patients.

scholarly journals Rucaparib in patients presenting a metastatic breast cancer with Homologous Recombination Deficiency, without germline BRCA1/2 mutation

2020 ◽  
Author(s):  
Anne Patsouris ◽  
M'boyba Khadija DIOP ◽  
Olivier Tredan ◽  
Daniel Nenciu ◽  
Anthony Goncalves ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Homologous Recombination ◽  
Statistical Significance ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Small Subset ◽  
Durable Response ◽  
Homologous Recombination Deficiency

Abstract Breast cancer may present genomic alterations leading to homologous recombination deficiency. PARP inhibitors have proved their efficacy in patients with HER2-negative metastatic breast cancer (mBC) harboring germline (g) BRCA1/2 mutations. We conducted the phase 2 RUBY trial to assess the efficacy of rucaparib in HER2-negative mBC with high genomic loss of heterozygosity (LOH) score or somatic, without gBRCA1/2 mutation. 220 of 711 patients with mBC screened for LOH presented high LOH score which was associated with a higher likelihood of death (HR = 1.39, 95% CI: 1.11-1.75, p = 0.005). The primary objective was not reached with a clinical benefit rate (objective response or SD>16 weeks) of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (14 and 32 months). HRDetect tended to be associated with response to rucaparib, whithout reaching statistical significance (median HRDetect responders versus non responders: 0.465 versus, 0.040, p = 0.2135). Our data suggests that a small subset of patients with high LOH score could derive benefit from PARP inhibitors.

Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17543-e17543
Author(s):  
Xiaoxiang Chen ◽  
Jing Ni ◽  
Xia Xu ◽  
Wenwen Guo ◽  
Xianzhong Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Regression Analysis ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Real World ◽  
Cox Regression ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Homologous Recombination Deficiency ◽  
Polymerase Inhibitors

e17543 Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p < 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p < 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p < 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.

Poly (ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer

2021 ◽  
Author(s):  
Olivia Le Saux ◽  
Hélène Vanacker ◽  
Fatma Guermazi ◽  
Mélodie Carbonnaux ◽  
Clémence Roméo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Advanced Ovarian Cancer ◽  
Cost Effective ◽  
Preclinical Study ◽  
The Body ◽  
Synergistic Activity ◽  
High Grade ◽  
First Line ◽  
Homologous Recombination Deficiency

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Comparison of molecular signatures in small cell lung cancer with or without homologous recombination associated gene mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20580-e20580
Author(s):  
Lili Fu ◽  
Feifei Li ◽  
Dandan Ren ◽  
Beibei Mao ◽  
Huan Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Homologous Recombination ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Gene Mutations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Homologous Recombination Deficiency

e20580 Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. Recently, Immune checkpoint inhibitors (ICIs) have been shown to have the potential to improve the prognosis of SCLC, but little is known about immunotherapeutic biomarkers. Homologous recombination deficiency (HRD) is demonstrated to be a response predictor to immunotherapies in gynecologic cancers, while limited studies were reported in small cell lung cancer. Herein, we analyze the mutational pattern of HRR related genes in a Chinese SCLC cohort and further analyze the relationship between HRR-gene mutations and tumor mutational burden. Methods: Target gene sequencing (543 genes) was performed in 133 Genecast cohort with small cell lung cancer. PD-L1 expression were evaluated for 90 among 133 patients using the SP142 PD-L1 immunohistochemistry assay. Results: Among 133 patients, 47 (35.3%) had HRR-gene mutations. ATM (8.3%), NBN (4.5%) and BRCA2 (4.5%) were the top 3 mutated HRR-gene in the cohort，followed by ATR (3.8%), BARD1 (3.8%), BRCA1 (3.8%), PALB2 (3.8%), RAD50 (3.8%), CHEK2 (3.0%), BLM (3.0%), BRIP1(2.3%), CHEK1(1.5%), RAD52(1.5%), and MRE11A (0.8%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (11/47, 23.4%) and 3 (3/47, 6.4%) patients, respectively. 1 (1/47, 2.1%) patient carried both germline and somatic variants. Genomic landscape revealed that TP53 and RB1 were commonly mutated genes in SCLC cohort. Mutations in KMT2D, AR and RTK-RAS pathway occurred more frequently in the HRR-Mut group, compared with the wildtype ones. Furthermore, we found that mutations in HRR-gene were associated with high TMB (Wilcoxon, p = 0.048), and patients with high TMB (≥median) showed a higher proportion of positive PD-L1 expression in 90 SCLC patients. Conclusions: Our data indicated that genomic alterations associated with HRR-genes have a positive correlation with high TMB, and detection of HRR-gene mutation status probably could help identify patients who might benefit from immune checkpoint blockade therapy. Keywords: Small cell lung cancer, Homologous recombination deficiency, Immunotherapy.

scholarly journals Recent Findings in the Posttranslational Modifications of PD-L1

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Shu-Man Li ◽  
Jie Zhou ◽  
Yun Wang ◽  
Run-Cong Nie ◽  
Jie-Wei Chen ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Immune Checkpoint ◽  
Protein Modification ◽  
Immune Cell ◽  
Response Rate ◽  
Malignant Tumors ◽  
Objective Response ◽  
Cell Activity ◽  
Patients With Cancer ◽  
L1 Protein

Immune checkpoint therapy, such as the reactivation of T-cell activity by targeting programmed cell death 1 (PD-1) and its ligand PD-L1 (also called B7-H1 and CD274) has been found pivotal in changing the historically dim prognoses of malignant tumors by causing durable objective responses. However, the response rate of immune checkpoint therapy required huge improvements. It has been shown that the expression of PD-L1 on cancer cells and immune cell membranes is correlated with a more durable objective response rate to PD-L1 antibodies, which highlights the importance of deeply understanding how this protein is regulated. Posttranslational modifications such as phosphorylation, N-glycosylation, and ubiquitination of PD-L1 have emerged as important regulatory mechanisms that modulate immunosuppression in patients with cancer. In this review, we summarized the latest findings of PD-L1 protein modification and their clinical applications.

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