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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 3500-3500
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 7_suppl ( 2017-03-01), p. 78-78
    Abstract: 78 Background: Recent publications support the emergence of predictive biomarkers for pembrolizomab in melanoma based on the expression of PD-L1 in the tumor microenvironment (Daud 2016a) or the frequency of PD-1 hi CTLA-4 hi on CD8 + TIL (Daud 2016b) whereby immunologically inactive tumors show poor response to immune checkpoint inhibition alone. Since intratumoral pIL-12 with electroporation (IT-pIL12-EP) increases TIL in both treated and untreated lesions, we hypothesize that non-response can be rescued with the combination of IT-pIL12-EP and anti-PD-1. Phase II clinical and immunological data are shown. Methods: Melanoma stage III/IV patients were enrolled with CD8 + TIL 〈 25% PD-1 hi CTLA-4 + measured by flow cytometry (NCT02493361). PD-L1 IHC (22C3 Ab) was also evaluated. Patients were treated with pembrolizumab (200mg every 3 weeks) and IT-pIL12-EP. Patients were evaluated for ORR every 12 weeks (RECISTv1.1). Pre- and post-treatment blood and tumor specimens were collected, and analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by IHC. Results: TIL assessment for evaluable enrolled patients were 〈 22% PD-1 hi CTLA-4 + , a value associated with anti-PD-1 non-response (Daud 2016b). Remarkably, although predicted to be an unresponsive population, the ORR was 40% (4CR/ 2PR) by RECISTv1.1. In patients with CR/PR, analysis of the tumor microenvironment revealed many significant immunological changes not seen in non-responders, including number and ratios of CD8 + :PD-L1 + by IHC, increased expression of NK, CD8 and ‘adaptive resistance’ markers by NanoString, as well as increased clonality and T cells by TCR sequencing. Conclusions: The excellent safety profile and striking 40% clinical response rate is encouraging as treated patients were predicted to be non-responsive to pembrolizumab. The correlative data shows an immune-directed mechanism that is differentiated between responders and non-responders suggesting the combination can effectively alter the tumor microenviroment to benefit patients otherwise unlikely to respond to anti-PD-1 monotherapy. Clinical trial information: NCT02493361.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 4_suppl ( 2019-02-01), p. 487-487
    Abstract: 487 Background: Immunoscore Colon is an IVD test predicting the risk of relapse in early-stage colon cancer (CC) patients, by measuring the host immune response at the tumor site. It is a risk-assessment tool providing independent and superior prognostic value than the usual tumor risk parameters and is intended to be used as an adjunct to the TNM classification. Risk assessment is particularly important to decide when to propose an adjuvant (adj.) treatment for stage (St) II CC patients. High-risk stage II patients defined as those with poor prognostic features including T4, lymph nodes 〈 12, poor differentiation, VELIPI, bowel obstruction/perforation can be considered for adj. chemotherapy (CT). However, additional risk factors are needed to guide treatment decisions. Methods: A subgroup analysis was performed on the St II untreated patients (n = 1130) from the Immunoscore international validation study (Pagès The Lancet 2018). The high-risk patients (with at least 1 clinico-pathological high-risk feature) were classified in 2 categories using pre-defined cutoffs: Low Immunoscore versus High Immunoscore and their five-year time to recurrence (5Y TTR) was compared to the TTR of the low-risk patients (without any clinico-pathological high-risk feature). Results: Among the patients with high-risk features (n = 630), 438 (69.5%) had a High Immunoscore with a corresponding 5Y TTR of 87.4 (95% CI 83.9-91.0), statistically similar (logrank pv not stratified p 〉 0.42, wald pv stratified by center p 〉 0.20) to the TTR 89.1 (95% CI 86.1-92.1) observed for the 500 low-risk patients (with no clinico-pathological feature). Furthermore, 5Y TTR for these patients were statistically similar to those of St II patients with high-risk features and a High Immunoscore (n = 438), who received adj. CT (n = 162) (5Y TTR of 83.4 (95% CI 77.6-89.9). Conclusions: These data show that despite the presence of high-risk features that usually trigger adj. treatment, when not treated with CT, a significant part of these patients (69.5%) have a recurrence risk similar to the low risk patients. Therefore, the Immunoscore test could be a good tool for adj. treatment decision in St II patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 4105-4105
    Abstract: 4105 Background: Risk assessment is particularly important to decide when to propose an adjuvant treatment for Stage II Colon Cancer (CC) patients. However, the current tumor risk features are imperfect and additional risk factors are needed to guide treatment decisions. The consensus Immunoscore is an alternative and powerful approach that could be used in the T4N0 Stage II colon cancer population. Immunoscore is an in vitro diagnostic test that predicts the risk of relapse in patients with CC by measuring the host immune response at the tumor site. Methods: From the international Immunoscore consortium study (n = 2681) (Pagès et al. The Lancet 2018), a subgroup analysis was performed on T4N0 Stage II colon cancer patients (n = 208). Results: In stage II T4N0, Int+Hi Immunoscore represented 65.4% of the population and low-Immunoscore only 34.6%. T4N0 patients with Int+Hi Immunoscore presented a significantly prolonged survival for TTR compared to low Immunoscore patients (5 years recurrence rate Int+Hi: 84.6% (78.3-91.5), Lo: 46.3% (35.1-61); unadjusted HR [Int+Hi vs Lo] = 0.21; (95% CI 0.11-0.4); P 〈 0.0001), representing a restricted mean survival time (RMST) difference of 80.9 months (95% CI 51.1-110.6) ( P 〈 0.0001). The DFS was significantly different between Int+Hi and Low Immunoscore (5 years recurrence rate Int+Hi: 70.5% (95% CI 62.7-79.1), Lo: 38.5% (95% CI 28.2-52.5); unadjusted HR [Int+Hi vs Lo] = 0.31; (95% CI 0.19-0.49); P 〈 0.0001). Using restricted mean survival time (RMST) a significant ( P 〈 0.0001) difference of 60.4 months (95% CI 32.6-88.1) was observed between the 2 groups Importantly, Cox multivariate analysis in Stage II T4N0 colon cancer patients, revealed that Immunoscore was the only remaining significant parameter (HR [Int+Hi vs Lo] = 0.15; (95% CI 0.05-0.46); P= 0.0009). In contrast, all other parameters, gender, sidedness, mucinous, grade, T-stage, VELIPI, MSI were not significant in multivariate analysis. Finally, Immunoscore showed the highest relative contribution to predict relapse (76.2% chi2 relative contribution), stronger than all the other parameters, MSI (16.1%), Grade (5%), sidedness (2%), gender (2%), VELIPI (1%). Conclusions: Immunoscore is the most powerful parameter to predict the risk in T4N0 population, and could be a good tool for adjuvant treatment decision in Stage II patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e20071-e20071
    Abstract: e20071 Background: Malignant mesothelioma has been an incurable disease with few effective therapies. While PD-1 targeted therapies have elicited some patient responses, the overall response rate for mesothelioma is low. Since mesothelioma is derived from the mesothelium of the lung, we hypothesize that immune cells in the tumor microenvironment (TME) may behave differently than other solid tumors that are responsive to immunotherapy. Here we characterize prognostic immune gene signatures and spatial protein expression in the mesothelioma TME. Methods: 50 FFPE mesothelioma samples were analyzed using the NanoString PanCancer IO360 assay which measures expression of 770 genes, including the abundance of 14 immune cell types and of 32 IO signatures. All genes and signatures were correlated with overall survival (OS). GeoMx digital spatial profiling (DSP) was performed on 40 samples assessing the protein expression along 12 geometric circular regions-of-interest (ROI). Tissue slides were stained with a combination of fluorescent-labeled antibodies (pan-cytokeratin, CD3, CD68) and a panel of 38-antibodies each conjugated to a unique UV-photocleavable DNA barcode. UV light was applied to the defined ROI, which releases the DNA barcodes for quantitation on the nCounter platform. Results: Unsupervised clustering of samples based on gene signatures showed two distinct groups; one, with low expression of lymphocyte activation/exhaustion signatures and the second, with moderate expression of immune signatures. Two samples had high expression of all immune gene signatures, also confirmed by DSP had increased expression of T cell markers. Tumor proliferation (p 〈 0.001), hypoxia (p = 0.04), glycolysis (p 〈 0.001), B7-H3 (p = 0.007) and TGF-β (p = 0.001) signatures were significantly associated with shorter OS. Additional DSP profiling of these mesothelioma samples showed both T cell excluded and desert TMEs. Conclusions: We show that the mesothelioma TME has distinct immune biology associated with OS. Tumors from patients with poor survival had expression profiles previously described to be associated with immune excluded and desert phenotypes. We show that gene expression and DSP identifies unique targets for immunotherapy and we hypothesize that these findings may guide the development of combination trials that will be effective against mesothelioma.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 6622-6622
    Abstract: 6622 Background: An ever-increasing number of biomarker-guided therapies, some with pan-cancer indications have expanded the oncologist’s toolbox for fighting advanced cancer. Despite this, not all advanced cancer patients receive tumor genomic testing, or are tested for a limited number of targets. Still others are tested too late in their care journey to benefit from precision therapy. To assess the impact of removing testing barriers, we developed a reflex testing protocol where comprehensive genomic profiling (CGP) was routinely ordered by pathologists at time of diagnosis for advanced cancer patients. Methods: Reflex CGP testing was primarily initiated by the pathologist at the time of advanced cancer diagnosis. Testing was performed between 2019 and 2021 via CGP using the ProvSeq 523 lab-developed test, and testing was performed at no cost to the patient. Post-CGP, stage 4 patients were followed for ≥ 12 months. We assessed time to therapy, therapy selection, and overall survival (OS). Therapies were stratified by presence of biomarkers associated with approved targeted therapies (TT), presence of biomarkers for immunotherapies (IO), and/or therapies that were guideline based (GB) and not associated with a specific biomarker. As much key patient information is only consistently available in free-text medical charts, we implemented a novel natural-language processing (NLP) approach based on deep learning and large language models to accelerate abstraction. Results: A cohort of 1,423 advanced cancer patients met the study criteria. The median age was 66 years, 53% were female, and 82% white. The 3 most tested tumor types were 22% non-small cell lung cancer, 16% colorectal cancer, and 12% breast. Overall, 49% (N=704) of patients had a biomarker result considered actionable for an approved TT or IO. Median (IQR) time-to-treatment initiation post-CGP was 19 (2-70) days. In patients with no actionable TT or IO biomarkers (N=719), 63% were treated with chemotherapy-based regimens, 11% with GB, 17% with unmatched TT, and 8% with unmatched IO. Of patients who had only an actionable TT biomarker (N=287), 18% received matched TT and 13% received GB. 36% of patients with only an actionable IO biomarker (N=317) received matched IO monotherapy. 48% of patients with both actionable TT and IO biomarkers (N=100) received matched TT or IO monotherapy, and 5% received GB. Across all tumor types, patients receiving a TT had better OS compared to patients receiving chemotherapy with 12 months OS (%) of 70.1 (95% CI=64.4 - 76.3) for TT-treated patients, compared to 62.9 (95% CI=58.8 - 67.3) for chemotherapy only. Conclusions: CGP-guided precision therapy use is associated with significantly higher survival in a reflex testing population. A reflex protocol can overcome key barriers to the use and timing of genomic testing to improve access to these life-extending treatment modalities.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. e14639-e14639
    Abstract: e14639 Background: The DPV-001 DRibble is a dendritic cell-targeted microvesicle (proteasome blocked autophagosome) vaccine derived from an adenocarcinoma and a mixed histology cell line. It contains multiple TLR agonists and 〉 130 potential NSCLC antigens, many as prospective altered-peptide ligands. In preclinical studies, DRibble immunotherapy provided significant anti-cancer effects in a dozen models. We hypothesize that DRibble’ vaccination efficacy can be attributed to their capacity to present tumor-derived short-lived proteins (SLiPs) and defective ribosomal products (DRiPs) that are typically not processed and presented by professional antigen presenting cells and against which the host may be less tolerant. Methods: Pts received induction cyclophosphamide, 7 vaccines every 3-weeks, then every 6 weeks x 4 more doses. Pts were randomized to receive DRibble alone (A), or with I (B) or GM-CSF (C). PBMCs /serum were collected at baseline and at each vaccination to assess changes in antibodies (Ab) (ProtoArray and microsphere affinity proteomics), peripheral lymphocyte populations (flow cytometry) and T cell receptor (TCR) repertoires (Adaptive immunoSEQ). Results: 13 pts were enrolled (Arm A: 5; B: 4; C: 4). We previously reported that vaccination induced or increased IgG Ab responses against targets over-expressed by NSCLC. Patients receiving DPV-001 had a significant (p 〈 0.04) increase in total (CD4 + CD8) TCRs that increased 10 fold over baseline compared to normal controls (independent from trial, n = 3) and the increase in CD4 clones was similar to that seen following ipilimumab (melanoma pts, independent from trial, n = 9). Analysis of a resected metastasis (progressing on treatment), identified brisk infiltration of T cells and tumor that was strongly PD-L1+. Conclusions: Vaccination with DPV-001 expanded populations of T cells over that observed in controls and the increase in CD4 T cells was similar to that observed in patients receiving ipilimumab and may represent vaccine-reactive T cells. Clinical Trial Identifier: NCT01909752, Support: R44 CA121612 Clinical trial information: NCT01909752.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 9553-9553
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e15035-e15035
    Abstract: e15035 Background: Precision therapies and immunotherapies have revolutionized cancer care, with novel genomic biomarker-associated therapies being introduced into clinical practice rapidly. We assessed the utility of comprehensive genomic profiling (CGP)-based testing for identifying biomarkers associated with approved therapies, and therapies in precision medicine basket clinical trials (CT) across a large cohort of advanced cancer patients in the Providence health system. Methods: Advanced cancer patients were tested utilizing the Providence CGP workflow between 2019-2021. Clinical actionability was assessed for CGP and compared with results from an in silico 50-gene panel based on a previously utilized lab-developed test at Providence. Clinical actionability was assessed based on OncoKB and alterations were assigned as: FDA recognized (Level 1), standard of care (Level 2), FDA approved/investigational drug in another indication or having compelling clinical evidence (Level 3). CT matching was assessed based on enrollment criteria for ASCO-TAPUR, NCI-MATCH and My Pathway CTs at time of testing. Pooled electronic medical record and genomic data were curated and standardized. Results: Of the 3,218 advanced cancer patients tested with CGP, 52% were female, 80% were white, and median age was 67 years. Across 31 tumor types, the most commonly tested were lung (26%), bowel/colon (16%), and breast (9%). Overall, 48% of patients tested with CGP harbored at least one actionable biomarker (OncoKB Levels1/2/3). Clinical actionability was significantly higher in the CGP cohort compared to the in silico cohort based on presence of at least one Level 1 biomarker (45% vs. 19%, p 〈 0.001). CGP cohort had higher proportion of patients with multiple/co-occurring Level 1 biomarkers compared to in silico cohort (20% vs. 9%, p 〈 0.001). Of the most prevalent tumor types, 57% lung, 94% bowel/colon, and 37% breast had Level 1 alterations with CGP testing. Notably, 49% of CGP cohort vs. 23% in silico cohort (p 〈 0.001) harbored a biomarker matching to one or more arms of the three basket CTs. Conclusions: CGP and small panel testing can both identify patients eligible for approved therapies and/or basket CTs with CGP having significantly higher clinical actionability and CT eligibility. We expect value of CGP to increase as biomarker actionability transforms clinical practice.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3078-3078
    Abstract: 3078 Background: Gene fusions caused by chromosomal rearrangements comprise a key category of oncogenic driver mutations. However, given the diverse array of potentially novel loci where each proto-oncogene can translocate, many assays including DNA-based CGP have technical limitations that disallow the detection of all relevant fusion partners potentially leading to false negatives. Hybrid Capture RNA sequencing renders a more comprehensive evaluation of genes and allows detection of novel and known fusion partners. Here we assessed the impact of utilizing in-house CGP testing with a paired RNA-DNA hybrid assay in the identification of pathogenic fusions and their potential clinical actionability for patients with solid tumors across a large US health system. Methods: Patients in the Providence health system diagnosed with advanced solid tumor malignancies over a two-year period (2019-2021) received reflex CGP testing at the time of diagnosis utilizing an internally validated workflow. DNA/RNA sequencing results as well as histology and staging information were curated from deidentified electronic medical records and in-house databases, and tumor types were mapped to OncoTree tissue categories. Potential clinical actionability was assessed based on OncoKB therapeutic levels 1-3 and clinical trial eligibility matched to the biomarker inclusion criteria for ASCO TAPUR, NCI-MATCH and MyPathway studies (both without time limits and at time of testing). Results: The median patient age at diagnosis was 67 years, 52% of patients were female, and the majority (80%) were white. Across all tested advanced solid tumors, 6.7% (217/3218) were found to harbor a pathogenic fusion. The tumor types most enriched in this set of pathogenic fusions were prostate (30%), lung (27%), CUP (10%) and breast (9%). 29% (n = 64) of the identified pathogenic fusions were identified as actionable based on OncoKB criteria (levels 1-3), and 31% (n = 69) matched to one or more arms in the ASCO TAPUR, NCI-MATCH or MyPathway basket clinical trials. The most frequent actionable fusion driver genes identified were ALK (12%), FGFR 1-3 (12%), RET (7%) NTRK 1-3 (3%), and ROS1 (2%) and a subset of these key drivers were fused with novel gene pairs. A subset of fusions co-occurred with other targetable biomarkers, with the most common comprising tumor mutational burden high (TMB-H) (13%), PIK3CA (7%) and high microsatellite instability (MSI-H) (2%). Conclusions: In-house CGP testing utilizing an RNA-DNA based assay identified actionable fusion targets across tumor types, with many novel fusion partners that may be undetectable by prior generation sequencing assays. While many of these actionable targets are rare individually, the expanding totality of actionable gene alterations supports the growing utility of CGP for identifying patients who are candidates for approved targeted therapies and clinical trials.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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