bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liquid biopsy using plasma proteomic profiling to reveal predictors of immunotherapy response.
Authors: Mehta Arnav , Kasumova Gyulnara , Rucevic Marijana , Sallman-Almen Markus , Hultin Rosenberg Lina , Kim Michelle S. , Lieb David , Bai Xue , Frederick Dennie T. , Sullivan Ryan J. , Flaherty Keith , Hacohen Nir , Boland Genevieve Marie 
Published: July 2019

130 Background: The response of metastatic melanoma to anti-PD1 is heterogeneous. We performed proteomic profiling of patient plasma samples to build a predictor of immunotherapy response and uncover biological insights underlying primary resistance. Methods: 58 metastatic melanoma patients receiving anti-PD1 (Pembrolizumab or Nivolumab) at MGH comprised the initial cohort, and 150 additional patients comprised a validation cohort. Plasma samples were collected (MGH IRB #11-181) at baseline and several on-treatment time-points. Samples were analyzed for 1102 proteins by a multiplex proximity extension assay (Olink Proteomics). A subset of patients had single-cell RNA-seq (Smart-Seq2 protocol) performed on tumor tissue. Group differences and treatment effects were evaluated using linear mixed models with maximum likelihood estimation for model parameters, and Benjamini and Hochberg multiple hypothesis correction. Results: 70 significantly differentially expressed (DE) proteins were identified across the treatment period, including markers of immune activation (PD1, CXCL9, CXCL10, CD25, IL-17a, among others). 38 significantly DE proteins were identified with on-treatment time points between anti-PD1 responders (R) and non-responders (NR), including several implicated in primary or acquired resistance (IL8, MIA, ERBB2, among others). Importantly, we demonstrate the relationship of these serum biomarkers to overall and progression-free survival, and employed statistical learning approaches to build classifiers of treatment response, leveraging early and late on-treatment time points. Analysis of single-cell RNA-seq data (Sade-Feldman et al, Cell, 2018) of tumor tissue from a subset of these patients revealed that gene expression of most proteins predictive of response were enriched among tumor myeloid cells, with the remainder of proteins being reflective of exhausted T cell states. Conclusions: Whole plasma proteomic profiling of anti-PD1 treated patients revealed DE proteins between R and NR that may enable a liquid biopsy to predict anti-PD1 response. These results unveil a putative role of myeloid cells within the tumor microenvironment in anti-PD1 response or primary resistance.
Biomarkers to predict immune-related adverse events with checkpoint inhibitors.
Authors: Head Lia , Gorden Nicholas , Van Gulick Robert , Amato Carol M. , Frazer-Abel Ashley , Robinson William , Holers V. Michael , Messersmith Wells A. , Davis S. Lindsey 
Published: July 2019

131 Background: Immune-related adverse events (IRAE) occur commonly with immune checkpoint inhibitor therapy for the treatment of cancer, although the specific event and severity can vary widely. Little is known regarding factors that may predict which patients will develop an IRAE. The goal of this study is to identify blood biomarkers predictive of IRAE associated with immune checkpoint inhibitor therapy. Methods: Blood samples collected from patients with melanoma prior to receiving therapy with immune checkpoint inhibitors were obtained from the University of Colorado Skin Cancer Biorepository. Testing for a panel of autoantibodies and cytokines (ANA, CCP 3.1, IL-1 beta, IL-2, IL-6, IL-10, IL-12, IP-10, MCP-1, TNF alpha, IFN alpha 2, IFN gamma) in serum samples from patients who had at least one documented IRAE was performed by Exsera BioLabs. Descriptive statistics were used to evaluate biomarker levels in relation to type, grade, and number of adverse events. Results: Pre-treatment samples from 45 patients were evaluated. Median age was 55; 26 were male and 19 were female. The most common IRAEs were colitis (n = 22), thyroid dysfunction (n = 21), and dermatitis (n = 20). Most IRAEs were grade 2 in severity, and the majority of patients (n = 36) experienced more than 1 IRAE. TNF alpha was elevated in 60% of patient samples, while IFN alpha 2 was elevated in 44%. Borderline ANA was detected in 27% of samples and ANA was positive in 11%. No samples had elevation of IL-2. Between 9% and 18% of samples had elevation of the other immune markers tested (IFN gamma, IL-1 beta, IL-6, IL-10, IL-12, and CCP 3.1). Elevation of TNF alpha and IFN alpha 2 were associated with higher grades of IRAEs. No associations between immune markers and the number or type of adverse events in an individual patient were noted. Results from 15 patients who did not have a documented IRAE on immune checkpoint inhibitor therapy are currently pending to confirm these findings are unique to patients developing IRAE. Conclusions: This preliminary data suggests that baseline elevations of TNF alpha and IFN alpha 2 may predict development of IRAEs with immune checkpoint inhibitor therapy. Results from samples from patients who did not develop an IRAE on therapy will be reported at the meeting.
Th17 responses to autologous dendritic cell vaccine.
Authors: Nistor Gabriel I. , Poole Aleksandra J. , Hsieh Candace , Keirstead Hans S. , Dillman Robert O. 
Published: July 2019

132 Background: Dendritic cells (DC) loaded with autologous tumor antigens in vitro, can induce a Th17 phenotype preceding a Th1 type response. We examined this in patients with metastatic melanoma who had been treated in a randomized trial with either DC loaded with autologous tumor antigens (ATA) from self-renewing tumor cells (DCV) or irradiated tumor cells (TCV). Methods: Blood samples were obtained at baseline, one week before three weekly vaccinations (week-0), and at week-4, (one week after the third vaccination). They were analyzed for growth factors, tumor markers and biomarkers using a quantitative, multiplex ELISA. Monocytes, lymphocytes, loaded and unloaded DC were analyzed for cytokine production and intercellular responses using mixed lymphocyte co-cultures (MLC). Results: When compared to baseline or the TCV arm, DCV-treated patients showed reductions in tumor markers, inflammation and angiogenesis in parallel with Th17 pathway activation, IL12 p70 heterodimer expression was detected in monocytes and DC only after antigen loading. The IL12 p40 fraction was present after differentiation and was enhanced after antigen loading. Similarly, the p19 component of IL23 was expressed before DC loading and later enhanced. MLC showed induction of Th17, Th1 and CD8 subpopulations. In the presence of antigen-loaded DCs, the FOXp3 cells were reduced in number, an effect that was canceled by neutralizing the IL12p40 subunit or by the adding tumor cells alone in the MLC. Conclusions: DC produced ex vivo can activate multiple cytotoxic pathways depending on IL12 subunits. Expression of IL23p19 and the shared IL12p40 fraction are responsible for Th1 priming (IL12 incomplete) and Th17 induction (IL23 complete), determinants of the reactive phenotype of naïve DCs. IL12 p70 heterodimer expression after DC loading enables a targeted Th1 type response while neutralizing the IL12 subunit p40, enhances Foxp3 positive T-regs. DC vaccines produced ex vivo could induce a Th1/Th17 cytotoxic response against tumors. In the absence of antigens, however, The Th17 phenotype can become tolerizing in the microenvironment. The findings are important for applications in settings in which tumor infiltration with Th17 correlates with survival, such as in advanced ovarian cancer. Clinical trial information: NCT00436930.
Prognostic models for advanced melanoma patients treated with anti-PD-1 monotherapy.
Authors: Bai Xue , Kim Michelle S. , Kasumova Gyulnara G. , Cohen Justine Vanessa , Lawrence Donald P. , Freedman Christine , Fadden Riley , Rubin Krista M. , Sharova Tatyana , Flaherty Keith , Sullivan Ryan J. , Boland Genevieve Marie 
Published: July 2019

133 Background: Anti-PD-1 monotherapy has dramatically improved the outcomes of patients with advanced melanoma, yet the majority of patients develop therapeutic resistance. A prognostic model is needed to optimally select patients who are most and least likely to benefit. Methods: We performed a retrospective analysis of 141 advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital from Sept 2009 to Dec 2017. Demographic and clinical characteristics, baseline and early-on-treatment (median 3 weeks after anti-PD-1 monotherapy initiation) routine laboratory variables, and prognostic data were collected and correlated in both univariate and multivariate analyses. Results: Median progression free survival (PFS) and overall survival (OS) were 7.6 months (95% CI 2.3-12.9) and 57.3 months (95% CI 33.3-81.3), respectively. In multivariate analyses, significant independent prognostic variables ( P < 0.05) in favor of longer PFS included cutaneous subtype, low baseline lactic acid dehydrogenase (LDH); low early-on-treatment derived neutrophil-to-lymphocyte ratio (dNLR); high early-on-treatment albumin, basophil, and red blood cell counts (RBCs); those in favor of longer OS included BRAF V600 mutation; low baseline LDH and neutrophil-to-lymphocyte ratio (NLR); low early-on-treatment LDH; high early-on-treatment total protein, basophil, and lymphocyte counts. Prognostic scoring models (total scale: 0-6) were established based on these independent prognostic factors as dichotomous variables, for both PFS (HR 0.555, 95% CI 0.481-0.641, P<0.001) and OS (HR 0.411, 95% CI 0.326-0.519, P<0.001), respectively. For patients with PFS scores of ≤ 2, 3, 4, 5, and 6, rates without progression at 6 months were 0%, 9.4%, 31.0%, 67.3%, and 80.0%, respectively. For patients with OS scores of ≤ 2, 3, 4, 5, and 6, survival rates at 12 months were 25.0%, 68.4%, 79.3%, 97.1%, and 100% ; at 24 months were, 0%, 45.6%, 69.1%, 82.6%, and 100%, respectively. Conclusions: A scoring system based on clinical characteristics and easily accessible routinely tested biomarkers may be used to help predict outcomes of anti-PD-1 monotherapy treated advanced melanoma patients.
Real-world time to next treatment (TTNT) for first-line (1L) targeted and immuno-oncology therapies for BRAF-mutated metastatic melanoma (MM) by lactate dehydrogenase (LDH) level.
Authors: Luke Jason J. , Ghate Sameer R. , Kish Jonathan , Lee Choo Hyung , Ndife Briana , McAllister Lindsay , Mehta Sonam , Nakasato Antonio Reis , Feinberg Bruce A. 
Published: July 2019

141 Background: Dabrafenib plus trametinib (D+T), ipilimumab plus nivolumab (I+N), and both nivolumab and pembrolizumab (“PD-1 mono”) are approved for the 1L treatment of MM. This study reports real world 1L TTNT for patients receiving these therapies by LDH status. Methods: This was a retrospective, observational study. MM patients initiating 1L treatment with D+T, I+N, or PD-1 monotherapy from Jan-2014 through Jun-2017 were identified from community oncology practices in the U.S. Patients treating oncologist abstracted patient date into case report forms. LDH at initiation of treatment was classified by the provider as normal or abnormal ( > 1x and < 2x ULN or ≥ 2x ULN) according to the reference laboratory. TTNT was calculated from 1L initiation to initiation of second-line (2L). Cox proportional hazard models estimated the risk of initiating 2L (proxy for progression) between groups adjusted for age, gender, brain/liver metastases (mets), number of mets and ECOG-PS. Results: Data for 332 patients were submitted by 53 providers including 51.6% who initiated 2L. Abnormal LDH: D+T = 60.3%, ipi/nivo = 53.0%, PD-1 mono = 35.4%. No differences in the frequency of patients with stage IV M1c, brain mets, ECOG, or discontinuation due to toxicity (8.4% of all patients) were noted between cohorts. TTNT was significantly longer in both normal and abnormal LDH cohorts for D+T (14.1 and 11.6 mo.) vs. ipi/nivo (10.1 and 10.2 mo.) but not PD-1 mono (13.3 and 10.6). Adjusted for confounding variables in the abnormal LDH cohort the hazard ratio (HR) for risk of 2L initiation was significantly higher (2.08, p < 0.01) for ipi/nivo vs. D+T but not significant different among normal LDH patients (HR = 1.89, p = 0.054). No significant difference in the risk of 2L initiation between D+T and ipi/nivo were noted in either the normal or abnormal cohorts. Conclusions: For normal and abnormal LDH cohorts 1L TTNT was longer for patients receiving D+T vs. ipi/nivo (but not vs. PD-1 mono). Using the multivariate model we observed the risk of 2L initiation, a proxy for progression, was higher for ipi/nivo treated vs. D+T adjusted for clinical factors for abnormal LDH patients.
Use of TMB and PD-L1 to predict outcomes of checkpoint inhibitor treatment.
Authors: Robbins Paul B. , Krieger Tina , Pearson Isobel , Bell Judith , Doherty Jim P. 
Published: July 2019

150 Background: Medical practice is moving toward a more tailored, patient-centric one with precision medicine (biomarker)-guided therapies. Studies have evaluated ways of applying precision medicine to cancer therapies, and the use of several biomarkers has shown promise. The potential value of tumor mutational burden (TMB) and/or programmed death-ligand 1 (PD-L1) biomarkers to enhance the prediction of which patients are most likely to respond to checkpoint inhibitors has been explored in many studies. The objective of this literature review was to identify and summarize these studies. Methods: Literature searches were performed using electronic medical databases (MEDLINE, Embase, and BIOSIS) and internet searches of specified sites. Bibliographies of key systematic literature reviews and meta-analyses were reviewed for studies of interest. Due to the volume of literature for various cancer types, studies with a sample size of <50 patients were excluded. Results: The review identified 27 trials in non-small cell lung cancer (NSCLC), 39 trials in melanoma, 10 trials in urothelial cancer, and 5 trials in renal cell cancer indications. Studies also were identified in other cancer types (eg, colorectal, breast, and gastric cancer and Merkel cell carcinoma [MCC]). TMB as a predictor of outcomes was evaluated in 12 trials, including 6 in NSCLC. A TMB of ≥10 mutations per megabase was shown to be an effective biomarker in the CheckMate 227 study. PD-L1 was found to predict response in melanoma and all types of NSCLC other than squamous (Checkmate-017). However, prediction of response was not a prespecified analysis in some PD-L1 studies; other studies had small sample sizes and wide CIs. A clear predictive trend for PD-L1 was not identified in renal, breast, or gastric cancer or MCC. Conclusions: On the basis of the data in this review, assessment of TMB and PD-L1 biomarker expression may enhance the prediction of response to checkpoint inhibition in some tumors, such as NSCLC and melanoma. In this rapidly growing area of research, further exploratory biomarkers are being investigated, such as tumor-infiltrating lymphocytes and KRAS and BRAF mutations, that may provide insight on the potential efficacy of a treatment in a given patient.
RRx-001 is a phase III aerospace-derived small molecule that immunonormalizes the tumor microenvironment.
Authors: Cabrales Pedro 
Published: July 2019

156 Background: Tumor associated macrophages (TAMs) with M2-like phenotypes produce angiogenic factors and cytokines which lead to vascular immaturity. M2 cytokines also impair immune cell activity. CD47 and SIRP⍺ are innate immune checkpoints which inhibit macrophage phagocytosis and enhance M2 polarization. Disruption of the CD47/SIRP⍺ axis polarize TAMs away from an M2-like phenotype to normalize tumor vessels and stimulate antitumor immunity. Normalized vessels facilitate delivery of drugs and immune cells and also sensitizes tumors to therapy and promotes M1-like TAM phenotype. RRx-001 modulates TAM infiltration and phenotype via CD47/SIRP⍺ downregulation, which normalizes both the tumor vasculature, and the immune cell milieu. Methods: The effect of RRx-001 on intratumoral blood flow was evaluated both preclinically and clinically with dynamic contrast MRI. An in vitro phagocytotic assay was used to determine whether RRx-001 promoted engulfment of A549 tumor cells by macrophages. Transcriptional mRNA profiling in murine tumor associated macrophages (TAMs) was performed to analyze the cytokine profile of TAMs in the presence or absence of RRx-001. Athymic mice with intracranial GBM43 were administered RRx-001 (10 mg/kg) followed 4 hours later by 0.4 mg of irinotecan by tail vein on days 12, 18, 24 and 30 after implantation of tumor cells. Mice were euthanized 24 hours after last irinotecan administration, with brains immediately resected and tumor tissue dissected prior to snap-freezing by immersion in liquid nitrogen. Results: RRx-001 was shown to induce: vascular normalization with increased intratumoral perfusion, dual downregulation of CD47 and SIRP⍺, increased phagocytosis, improved delivery of chemotherapy and increased T cell infiltration. Conclusions: RRx-001 leads to vascular normalization and enhanced delivery of chemotherapy and immune cell infiltration. The increase in tumor perfusion diminishes hypoxia and also serves to polarize TAMs away from an M2-like state. These results also suggest and are borne out by clinical biopsies that the effect of RRx-001 depends on the number of TAMs present in the tumor microenvironment with higher numbers leading to better activity.
Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced-stage ovarian cancer.
Authors: Thaker Premal H. , Bradley William Hampton , Leath Charles A. , Gunderson Camille Catherine , Borys Nicholas , Musso Lauren , Anwer Khursheed , Alvarez Ronald David 
Published: July 2019

2 Background: This study evaluated weekly intraperitoneal (IP) GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine-cholesterol lipopolymer, with intravenous (IV) weekly taxane (T) and carboplatinum (C) every 3 weeks in epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives included objective clinical response and pathological response at interval debulking surgery (IDS). Methods: Newly diagnosed EOC patients with no prior therapies were eligible. The trial utilized a 3+3 design with dose escalation in ~30% increments at GEN-1 IP dose levels of 36 mg/m2, 47 mg/m2, 61 mg/m2, and 79 mg/m2 weekly for 8 treatments with concurrent IV T/C. Dose-limiting toxicity (DLT) was based on the first 4 doses of GEN-1 administered. Results: 18 patients were enrolled into the study and 12 of those patients received all 8 treatments with no DLTs. 14 patients underwent IDS. Most common related toxicities were Gr 1 nausea, abdominal pain and fatigue. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. Conclusions: Adding GEN-1 to T/C is safe and appears to be active in EOC patients receiving NAC. Dose limiting toxicity was not reached and further dose escalation and safety and activity is being evaluated in an ongoing phase I/II study. Clinical trial information: NCT02480374. [Table: see text]
Phase Ib: Preliminary clinical activity and immune activation for NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] in patients (pts) with locally advanced or metastatic solid tumors (REVEAL Phase Ib/II Trial).
Authors: Diab Adi , Marcondes Mario , Kotzin Brian , Tagliaferri Mary Ann , Hoch Ute , Li Yunfeng , Cattaruzza Fiore , Zalevsky Jonathan , Brohl Andrew Scott , Brugarolas James , Bilen Mehmet Asim , Gupta Shilpa , Domingo Musibay Evidio , Conley Anthony Paul , Borazanci Erkut Hasan , D'Angelo Sandra P. , Curti Brendan D. 
Published: July 2019

26 Background: NKTR-262 is a novel intratumoral prodrug designed to promote tumor antigen release, an immune stimulatory environment, and antigen presentation. NKTR-214 increases CD8+ T cells and NK cells in the tumor microenvironment. The combination of NKTR-262 with NKTR-214 accesses innate and adaptive immunity to provide an abscopal response and systemic tumor immunity. The Phase 1b/2 REVEAL trial is enrolling. Methods: In a 3+3 Phase 1 design, pts who are relapsed/refractory to ≥1 CPI receive escalating doses of intratumoral (IT) NKTR-262 followed by combined q3w treatment of IT NKTR-262 and fixed-dose intravenous (IV) NKTR-214 (0.006 mg/kg). Phase 1 will evaluate PK, safety, efficacy, and determine recommended Phase 2 dose. Scans are conducted every 9 wks (± 1 wk). Peripheral blood (PB) and tumor tissue are collected to measure biomarkers of immune activation. In Phase 2 expansion, NKTR-262 + NKTR-214 ± IV nivolumab (360 mg) will be assessed in specific tumor cohorts of IO-naïve and experienced pts. Results: As of 06 Nov 2018, 11 pts had received at least one cycle of NKTR-262 + NKTR-214 therapy. 7/11 pts were efficacy evaluable with at least one on-treatment scan (4 MEL, 2 SARC, 1 CRC). 2/4 R/R melanoma pts had uPRs with 100% (scan 2) and 40% (scan 1) reductions in target lesions per RECIST 1.1, respectively. Both patients remain on treatment. Two SARC pts had stable disease at scan 1. No pts experienced G3 or higher TRAEs or immune-related adverse events (AEs). Most common G1-2 AEs were transient flu-like symptoms. Gene expression analysis of tumor and PB show dose-dependent induction (4 to 16-fold) of TLR target genes. Consistent with the mechanism of action for NKTR-214, PB flow cytometry shows an average 13-fold increase from baseline in Ki67+ CD8+T cells in 6 pts. Conclusions: NKTR-262 + NKTR-214 engage the immune activation cascade from local tumor antigen production to anti-tumor T cell response. Initial dose levels of NKTR-262 with fixed-dose NKTR-214 were well-tolerated with early evidence of clinical activity. These data support continued evaluation of the combination +/- nivolumab. Clinical trial information: NCT03435640.