229 Discovery of ganglioside GM2 activator as a novel proteomic biomarker associated with response to treatment in first-line melanoma subjects treated with PD-1 immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A247-A247
Author(s):  
Kristina Beeler ◽  
Jakob Vowinckel ◽  
Martin Soste ◽  
Domenico Mallardo ◽  
Mariaelena Capone ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Cell Function ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Statistical Testing ◽  
Response To Treatment ◽  
Protein Markers ◽  
First Line ◽  
Melanoma Tumor ◽  
Gm2 Activator

BackgroundImmune checkpoint inhibitors (ICI) have greatly improved the treatment options for patients with metastatic melanoma. Yet, a large percentage of melanoma patients do not respond to ICIs, there is a need for biomarkers that can predict patients‘ clinical benefit thereby identifying the patient population most likely to respond. Here, we apply unbiased discovery proteomics to deeply characterize global tumor proteomes and associate proteins and pathways at baseline with clinical response to anti-PD-1 immunotherapy.MethodsUnbiased, data-independent acquisition (DIA) mass spectrometry was used to analyze Formalin Fixed Paraffin Embedded (FFPE) tumor tissue from subjects with stage IIIc-IV melanoma which were resected prior to initiation of first-line anti-PD-1 therapy. The selected samples represent two distinct clinical subgroups; those who received clinical benefit (CR or PR by RECIST criteria or OS >1 year with SD by RECIST criteria, n = 13), and those with no clinical benefit (PD by RECIST criteria or OS <1 year with SD by RECIST criteria n = 9). Previously, the sample cohort had been analyzed by a 2-hour LC-MS/MS gradient setup operated in DIA mode. In this study, all samples were analysed with a longer gradient of 4-hours which enabled the quantification of 1’000 more proteins and enabled an updated analysis with a deeper level of characterization.Results8’548 proteins were quantified across all samples, with 7’416 quantified on average per sample. Univariate statistical testing between groups identified 285 proteins that were significantly regulated in subjects who received clinical benefit. Through partial least squares discriminant analysis (PLS-DA) a set of 25 proteins was identified that describe the variance between the two sample groups. Ganglioside GM2 activator (GM2A) and other members of its interaction network such as HEXB, HRNR and CPPED1 were identified to be upregulated in the non-responder group.ConclusionsGlobal profiling of the baseline tumor proteome provides a unique characterization of melanoma tumor biology. A signature of 25 protein markers was identified as a driver of separation between responder and non-responder patients to PD-1 blockade. Among the protein markers, GM2A and its interactors, were previously shown to perturb T cell function, which might explain their enrichment in the non-responder group and provide an attractive target for improving patient response to immunotherapy.

Efficacy and toxicity of immunotherapy with immune checkpoint inhibitors in gynecologic cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18092-e18092
Author(s):  
Michelle Kuznicki ◽  
Amy Joehlin-Price ◽  
Peter Graham Rose ◽  
Haider Mahdi
Keyword(s):  
Stable Disease ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gynecologic Cancer ◽  
Objective Response ◽  
Complete Response ◽  
Rank Test ◽  
First Line

e18092 Background: There is limited data on outcomes for gynecologic cancer patients treated with immune checkpoint inhibitors (ICI) outside the scope of clinical trials. Here we present our Institutional experience with a cohort of endometrial (EC) and ovarian cancer (OC) treated with ICI. Methods: 59 patients who received ICI were included (23 OC and 36 EC). Progression-free (PFS) and Overall survivals (OS) were determined by Kaplan-Meier (KM) curve and log rank test. Comparison of duration of response (DOR) and stable disease (DOSD) was done with unpaired t-test or one-way ANOVA. Rates of objective response (ORR) including partial response (PR) and complete response (CR), and stable disease (SD) were compared by Fischer’s exact test. Results: Median age was 66 years. 23 patients were microsatellite stable (MSS), 23 microsatellite instability high (MSI-H). Median number of prior lines was 2 (0-11). PFS and OS for EC and OC were overlapping; therefore outcomes for both were combined [(PFS 6.4m OC vs 7.3 m EC, p = 0.61), (OS 15.9 m OC vs 14.2 m EC, p = 0.78)]. Response rates consisted of 20.3% PR, 8.5% CR, 37.3% SD. Differences in responses were noted for clear cell carcinoma (CC) (33.3% PR, 11.1% CR, 33.3% SD) and MSI-H (36.4% PR, 18.2% CR, 22.7% SD) compared to MSS (11.8% PR, 0% CR, 47% SD). MSI-H had higher ORR vs. MSS (54.1% vs 11.8%, p = 0.0078). CC trended toward improved ORR vs. MSS (44.4% vs 11.8%, p = 0.14). PFS was improved for MSI-H vs. MSS (10m v 5.0m, p = 0.03). OS for CC compared to any other histology was improved (NR vs 12.8m respectively, p = 0.009). 5 recurrent MSI-H EC patients received ICI as first line monotherapy. Responses included 4 PR and 1 SD (80% ORR, 100% clinical benefit). PFS was 9.2m (3.3-13.3). 80% remained progression-free at last follow up. Overall, 38.9% experienced toxicity: hypothyroidism (15%), dermatitis (5%), pneumonitis (10%), LFT elevation (2%), amylase/lipase elevation (3%), colitis or diarrhea (5%), uveitis (2%) or nephritis (5%). 10% of patients required discontinuation of ICI secondary to toxicity. Trends for PFS and OS favored improved outcomes in patients with toxicity vs. no toxicity [(PFS 12.9m vs 5.6m, p = 0.07), (OS 22.9m vs 13.1m, p = NS)] respectively. Conclusions: In this study, immunotherapy with ICI outcomes favor MSI-H and CC compared to MSS disease. CC had promising OS compared to other histology types. ICI showed promising efficacy in MSI-H EC with 100% clinical benefit rate in chemonaive patients. First line ICI should be investigated in these patients. Positive correlation between toxicity and outcome is noted and will be further investigated.

Treatment response in the intact primary renal mass (P-Rmass) and its relationship to the overall response to treatment in patients with metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 329-329
Author(s):  
Hamid Emamekhoo ◽  
Hameem I Kawsar ◽  
Jens C. Eickhoff ◽  
Danubia Hester ◽  
Tristan Bice ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Outcome Data ◽  
Response To Treatment ◽  
Second Line ◽  
First Line ◽  
Radiographic Response ◽  
Systemic Treatments ◽  
The Impact

329 Background: With the approval of more effective systemic treatments (syst Rx) such as tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI), the impact of cytoreductive nephrectomy (CN) on response to Rx and survival remains unknown. The majority of patients (pts) previously enrolled in clinical trials have had radical nephrectomy (RN) or CN prior to syst Rx. Therefore, the response of the P-Rmass to ICIs and the effect of intact P-Rmass on response to syst Rx is not well described. Methods: A retrospective review of 209 pts with mRCC who were treated with ICI in the first or second-line was conducted. Following the appropriate regulatory process, collaborators from 5 US sites collected clinical, pathological, and outcome data via chart review. The response was investigator-assessed for all pts with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Overall radiographic response (ORR) includes complete response (CR) and radiographic response (Rad-resp) to treatment. Disease control rate (DCR) includes CR, Rad-resp, and stable disease. Results: Median age at diagnosis was 63 yrs and 69% were male. 102 pts (49%) had localized disease at diagnosis and underwent radical or partial nephrectomy, 3 (1%) had ablation/radiation of P-Rmass, 26 (12%) had CN, 9 (4%) had CN after an excellent response to syst Rx, 12 (6%) had a previous nephrectomy but developed a new Rmass (measurable target lesion), and 57 (27%) did not have CN and had an intact P-Rmass. 176 (84%) pts had clear cell histology. 27 (14%) and 23 (12%) had known sarcomatoid and rhabdoid features, respectively. Overall, 77 (37%) pts had a measurable Rmass while receiving syst Rx. 84 (40%), 93 (45%), and 10 (5%) pts received ICI (Ipilimumab/Nivolumab or Nivo), TKI, or Pembrolizumab/Axitinib in the first-line. 143 (68%) and 70 (33%) pts received second- and third-line treatment. 103 (72%) and 28 (19%) pts received ICI and TKI in the second-line, respectively. The best ORR and the Rad-resp in the intact P-Rmass in evaluable pts are summarized in the table below. ORR to ICI in the first or second-line were numerically higher in pts with an intact P-Rmass compared to pts who had nephrectomy, but this difference was not statistically significant (p= .38 and .35 respectively). Conclusions: The intact P-Rmass had a good response (62-70%) to the first-line syst Rx. Although the overall Rad-resp rates to ICI are numerically higher in pts with intact P-Rmass, this difference was not statistically significant. [Table: see text]

scholarly journals What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy

2021 ◽  
Vol 11 (12) ◽  
pp. 1312
Author(s):  
Andrea Palicelli ◽  
Martina Bonacini ◽  
Stefania Croci ◽  
Alessandra Bisagni ◽  
Eleonora Zanetti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Literature Review ◽  
Systematic Literature Review ◽  
Liquid Biopsy ◽  
Cell Function ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Response To Treatment ◽  
Tumor Evolution ◽  
Liquid Biopsies

Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.

Melanoma: Prognostic Factors and Factors Predictive of Response to Therapy

2020 ◽  
Vol 27 (17) ◽  
pp. 2792-2813
Author(s):  
Martina Strudel ◽  
Lucia Festino ◽  
Vito Vanella ◽  
Massimiliano Beretta ◽  
Francesco M. Marincola ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Lactate Dehydrogenase ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Elevated Serum ◽  
Predictive Biomarkers ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Prognostic Features ◽  
Programmed Death

Background: A better understanding of prognostic factors and biomarkers that predict response to treatment is required in order to further improve survival rates in patients with melanoma. Predictive Biomarkers: The most important histopathological factors prognostic of worse outcomes in melanoma are sentinel lymph node involvement, increased tumor thickness, ulceration and higher mitotic rate. Poorer survival may also be related to several clinical factors, including male gender, older age, axial location of the melanoma, elevated serum levels of lactate dehydrogenase and S100B. Predictive Biomarkers: Several biomarkers have been investigated as being predictive of response to melanoma therapies. For anti-Programmed Death-1(PD-1)/Programmed Death-Ligand 1 (PD-L1) checkpoint inhibitors, PD-L1 tumor expression was initially proposed to have a predictive role in response to anti-PD-1/PD-L1 treatment. However, patients without PD-L1 expression also have a survival benefit with anti-PD-1/PD-L1 therapy, meaning it cannot be used alone to select patients for treatment, in order to affirm that it could be considered a correlative, but not a predictive marker. A range of other factors have shown an association with treatment outcomes and offer potential as predictive biomarkers for immunotherapy, including immune infiltration, chemokine signatures, and tumor mutational load. However, none of these have been clinically validated as a factor for patient selection. For combined targeted therapy (BRAF and MEK inhibition), lactate dehydrogenase level and tumor burden seem to have a role in patient outcomes. Conclusions: With increasing knowledge, the understanding of melanoma stage-specific prognostic features should further improve. Moreover, ongoing trials should provide increasing evidence on the best use of biomarkers to help select the most appropriate patients for tailored treatment with immunotherapies and targeted therapies.

scholarly journals Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer

Medicina ◽  
2021 ◽  
Vol 57 (5) ◽  
pp. 501
Author(s):  
Tadahiro Shoji ◽  
Chie Sato ◽  
Hidetoshi Tomabechi ◽  
Eriko Takatori ◽  
Yoshitaka Kaido ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Clinical Studies ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Ovarian Cancer ◽  
Targeted Drugs ◽  
First Line ◽  
Double Blind ◽  
Platinum Based Chemotherapy

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

scholarly journals First-Line Maintenance Treatment in Metastatic Colorectal Cancer (mCRC): Quality and Clinical Benefit Overview

2021 ◽  
Vol 10 (3) ◽  
pp. 470
Author(s):  
Marta Martín-Richard ◽  
Maria Tobeña
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Clinical Benefit ◽  
Maintenance Treatment ◽  
Randomized Clinical Trials ◽  
Line Treatment ◽  
First Line ◽  
Design Quality ◽  
Primary Endpoints ◽  
First Line Treatment

Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

scholarly journals Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide

2021 ◽  
Author(s):  
M. Del Re ◽  
V. Conteduca ◽  
S. Crucitta ◽  
G. Gurioli ◽  
C. Casadei ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Clinical Outcome ◽  
Liquid Biopsy ◽  
Response To Treatment ◽  
First Line ◽  
Primary Resistance ◽  
Circulating Free Dna ◽  
Free Dna ◽  
Signaling Inhibitors

Abstract Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001). Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

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