bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of state policies on telehealth use among the privately insured with newly diagnosed cancer.
Authors: Shih Ya-Chen Tina , Pan I-Wen , Yen Tina W.F.
Published: June 2023

1607

Background: The COVID-19 public health emergency (PHE), declared on January 31, 2020, relaxed many telemedicine restrictions. Yet there remains wide variation across states on the coverage and reimbursement of telemedicine services and rules to permit practicing across state lines. Research has shown expanded access to telemedicine is beneficial to cancer patients, making it important to understand the relationship between state policies and the use of telemedicine. Methods: We identified privately insured non-elderly patients newly diagnosed with any of five common cancers (female breast, prostate, lung, colorectal, and lymphoma) between March 2019 and March 2021 from Optum Clinformatics Data Mart. We characterized state telehealth policies by parity status (coverage & payment parity, coverage parity only, and none) and rules for cross-state practice (allowed with vs. without limitations). We applied interrupted time series analysis to examine the trend of telemedicine use before and after the declaration of COVID-19 PHE and conducted multivariable logistic regression to examine the association between state policies and telemedicine use while controlling for other confounders. Results: Of the 10,813 privately insured non-elderly patients, the adjusted rate of telemedicine use was 23.6%. The average age was 53.2 (SD = 9.24). Race/ethnicity distribution was 71.20% non-Hispanic White, 10.07% non-Hispanic Black, 8.56% Hispanics, 3.77% Asians, and 6.39% others. Lymphoma, female breast, colorectal, lung, and prostate cancer accounted for 10.55%, 46.55%, 13.27%, 7.56%, and 22.07% of patients. A sharp increase was observed early on (from 32.4% in March 2020 to 42.5% in April 2020), followed by a steady decline, down to < 15% by March 2021. Compared to patients residing in states with coverage and payment parity, those in states with only coverage parity and no parity were significantly less likely to use telemedicine (OR = 0.79, 95% CI: [0.71 – 0.88]; OR = 0.77, [0.68 – 0.87]). Patients residing in states with more restrictions/regulations on cross-state practice were significantly less likely to use telemedicine (OR = 0.84, [0.76 – 0.93]) than those in states that were less restrictive. Other factors predicting lower likelihood of telemedicine use included older age (OR = 0.69 [0.62-0.77] for age 50-64 vs. 20-49), non-Hispanic Black (OR = 0.84 [0.72 – 0.98] vs. non-Hispanic White), colorectal cancer (OR = 0.82 [0.70 – 0.96] vs. female breast), and more recent diagnosis. Conclusions: With the approaching end of COVID-19 PHE, states are deciding whether to permanently relax certain telemedicine policies or return to existing more restrictive policies. Our study suggests patients residing in states that move toward less generous parity and more restrictive cross-state practice rules may be less likely to benefit from telemedicine.
Immune profiling in patients with glioblastoma treated with VT1021 in a phase I/II expansion study.
Authors: Chen Jian Jennifer , Vincent Melanie , Peereboom David M. , Watnick Randolph , Fyfe Susanne , Li Wendy , Wang Suming , Mahoney James , Cieslewicz Michael , Watnick Jing
Published: June 2023

2021

Background: The cyclic peptide VT1021 is a first-in-class therapeutic agent that has been shown to inhibit tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprogramming the immune tumor microenvironment (TME) in preclinical models. Subsequently, VT1021 has been tested in a phase I/II clinical study in solid tumors (NCT03364400) and has advanced to a phase II/III clinical study in glioblastoma (NCT03970447). VT1021 has demonstrated promising single-agent clinical activity against recurrent glioblastoma (rGBM) in a phase I/II expansion study. Among 22 evaluable subjects with rGBM, 3 had complete response (CR), 1 had partial response (PR), and 6 had stable disease (SD) with an average study duration of over 120 days. One subject has been on VT1021 treatment for > 900 days with no measurable lesion left. The overall disease control rate (DCR) was 45%. Here, we sought to examine the peripheral immune cell profile(s) in response to VT1021 and explore the association between these profiles and clinical responses in rGBM subjects. Methods: In the phase I/II expansion study, 22 evaluable rGBM subjects received VT1021 at a dose of 11.8 mg/kg (twice per week intravenously) until disease progression. Peripheral blood samples were collected from all evaluable subjects; immune cell profiles were analyzed by flow cytometry. Results: The immune profiles following VT1021 treatment on day 1 did not vary significantly among rGBM subjects, regardless of response. Intriguingly, after long-term VT1021 treatment (day 53), our analysis of the immune profiles revealed beneficial and sustained changes in three cytotoxic T Cell (CTL) parameters and PD-L1+ MDSCs that correlated with response. Specifically, CR/PR subjects showed a 20% increase in total CTLs (Pre 33.79% vs. 6hr 40.42%), a 66% increase in proliferating CTLs (Pre 1.37% vs. 6hr 2.28%) and a 63% increase in CTL/Treg ratio (Pre 7.85 vs. 6hr 12.81) on day 53 of VT1021 treatment. In contrast, SD and PD subjects exhibited no change or decrease in these three CTL parameters, respectively. We also observed that CR/PR subjects experienced a sustained decrease in PD-L1+ MDSCs after VT1021 treatment (day 1 Pre 95.96% vs. day 53 Pre 92.66% and day 53 6hr 88.06%). Conversely, the sustained decrease of PD-L1+ MDSCs after VT1021 treatment was not observed in SD and PD subjects. Conclusions: Here we report that the durable responses of peripheral immune cells to VT1021 may be associated with better clinical outcomes in rGBM subjects. These findings are consistent with the MOA of TSP-1 to reprogram the TME by stimulating immune and inflammatory cell functions. While the interpretation of our data is limited by the lack of a control arm and the small sample size, the results provide a signal and warrant continued analysis of these parameters in the ongoing phase II/III trial.
Ombipepimut dosing emulsion (ODE) + bevacizumab (bev) vs bev alone in patients (pts) with recurrent or progressive glioblastoma (rGBM).
Authors: Goldlust Samuel Aaron , Chang Jong Hee , Narita Yoshitaka , Welch Mary Roberta , Green Richard M. , Drappatz Jan , Piccioni David Eric , Kim Yu Jung , Melear Jason M. , Tanaka Shota , Wei Kuo-Chen , Fink Karen L. , Pitz Marshall W. , Cloughesy Timothy Francis , de Groot John Frederick , McClellan Nanci , Hitron Matthew , Xu Bo , Jin Bo , Lebedinsky Claudia
Published: June 2023

2022

Background: ODE is an investigational cancer vaccine derived from Wilms tumor 1. WIZARD was a randomized, adaptive, phase 3 study to test ODE + bev vs bev in rGBM pts (NCT03149003). Patients were stratified prior to randomization based upon KPS [60 or 70] vs [80 to 100] and extent of resection at initial diagnosis. Patients with low KPS (e.g., 60) are generally underrepresented in clinical trials. Methods: Pts ≥18 years with GBM at first recurrence were enrolled. Overall survival (OS) was the primary endpoint; the key secondary endpoint was the 12-month OS rate. The primary and the key secondary endpoints were tested using 1-sided test with an overall significance level 2.5%. The Lan-DeMets error spending function based upon O’Brien-Fleming stopping boundaries was used to adjust the significance level for the interim and final analyses. Results: From April 2018 to Aug 2021, 217 pts were randomized 1:1; 109 to ODE + bev and 108 to bev. OS was analyzed after 185 events with a median follow-up of 31.8 months (mo). Pts at baseline had a median age of 60 years, 45.2% reported corticosteroid use, 29% had KPS 60 or 70, 7.8% had tumors that harbored IDH1 or 2 mutations, and the median tumor volume was 10,532 mm3. Baseline characteristics between treatment arms were balanced in the ITT and KPS subgroups. Pts with KPS 60 or 70 had more corticosteroid use, worse NANO scores, and larger tumor burden than those with KPS 80-100. The study did not meet its primary endpoint of OS by ITT (ODE + bev: 10.2 mo vs bev: 9.4 mo, 1-sided p-value: 0.2159). Pts with KPS 60 or 70 had longer OS when treated with ODE + bev (8.2 vs 6.3 mo, 45% death risk reduction, 1-side p value: 0.0119). Grade 1 or 2 injection site reaction was the most common TEAE in the ODE + bev arm. No clinically significant difference in safety was noted between KPS subgroups. Conclusions: The data in pts with KPS 60 or 70 suggested benefit with ODE + bev that was consistent across different endpoints and that warrants further validation. Clinical trial information: NCT03149003 . [Table: see text]
An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.
Authors: Shang Xiaoyun
Published: June 2023

2043

Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×107 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of >50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .
Lisavanbulin in patients with recurrent glioblastoma: Phase 2a results and a consolidated analysis of response-predictive biomarkers.
Authors: Lopez Juanita Suzanne , Haefliger Simon , Plummer Ruth , Clement Paul M. , Laubli Heinz Philipp , Roth Patrick , Evans T.R. Jeffry , Brazil Lucy , Tabatabai Ghazaleh , Wick Antje , Yau Wing Hing Hing , Wunderlich Benjamin , Beebe Kirk , Eisner Joel Robert , Engelhardt Marc , Kaindl Thomas , Lane Heidi A , Hau Peter , Hundsberger Thomas , Steinbach Joachim
Published: June 2023

2044

Background: Lisavanbulin (BAL101553, prodrug of BAL27862) destabilizes microtubules and promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic small molecule shown in rodents to penetrate the brain, with antitumor activity in orthotopic glioblastoma (GBM) models. In the Phase 1 part of this study1 (NCT02490800), 2 of 5 patients with recurrent IDH-mutated G4 astrocytoma treated at active dose levels (15–30 mg/day) showed long-lasting objective responses and strong end-binding protein 1 (EB1) expression in GBM tissue by IHC. EB1 is a regulator protein on microtubules. Methods: The objective of the Phase 2 study was to investigate prospectively the response-predictive value of EB1, and to identify RNA-based response signatures in patients with recurrent GBM. A Simon’s two-stage design was used with an objective response rate (ORR) ≥ 2/9 required in Stage 1 to enable a final ORR ≥ 6/19. A prescreening program identified patients with EB1-positive archival GBM tissue. All patients received 25 mg oral lisavanbulin once daily. RNA-seq was performed on archival GBM tissues. Results: GBM tissue samples from 64 of 629 patients (10.2%) obtained from 13 sites in four countries were EB1-positive, and 18 of these patients received lisavanbulin. Of 9 patients with measurable disease evaluable for response in Stage 1, one patient had a partial response, and another had a 44% target lesion area reduction. Despite sustained activity in these patients, formal stage transition criteria were not met, and the study was closed. IHC testing for EB1 did not show sufficient enrichment for response, but it is thought that IDH status may play a role. In addition, RNA-seq analyses identified a five-gene signature that is distinct from expression patterns observed with EB1-IHC positivity, and predicts current responses irrespective of IDH status. This signature is characterized by homeobox gene downregulation, which may be implicated in the control of microtubule dynamics. Conclusions: This Phase 2a study supports previous study results that lisavanbulin is associated with durable responses and clinical benefit in a subset of patients with GBM. RNA-seq analyses of GBM samples suggest further evaluation of the lisavanbulin predictive response signature. 1Lopez et al, JCO 2019;37,15 suppl, 2025. Clinical trial information: NCT02490800 . [Table: see text]
A single-arm, phase 2 clinical trial of abemaciclib in adult patients with recurrent grade 3 oligodendroglioma.
Authors: Bagley Stephen Joseph , Mohan Suyash , Nabavizadeh Seyed Ali , Patel Thara , Prior Timothy , Mansour Maikel , Mccoy Emily , Angeloni Natalie , O'Neill Meghan , Albright Karen , Frangos Suzanne , Blessing Caroline , Coghlan Leah , Maloney Eileen , Desai Arati Suvas
Published: June 2023

2045

Background: Oligodendroglioma is a malignant glial neoplasm arising primarily in young adults. Although radiotherapy (RT) and chemotherapy result in durable disease control, tumor recurrence is inevitable and life-limiting. The cyclin D1-CDK4 axis is frequently dysregulated in recurrent oligodendroglioma. Abemaciclib is a selective CDK4/6 inhibitor that has been shown to achieve pharmacologically-relevant concentrations in brain tumor tissue. Methods: We conducted a single-center, single-arm, phase 2 trial evaluating the efficacy of abemaciclib in patients with recurrent oligodendroglioma, IDH-mutant and 1p/19q-codeleted, WHO Grade 3, following prior RT and ≥ 1 line of alkylating chemotherapy. Patients received abemaciclib 200mg twice daily. Primary endpoint was progression-free survival status at 6 months (PFS-6). Ten patients were needed for 80% power to detect the difference between the null (PFS-6 = 50%) and alternative (PFS-6 = 85%) hypotheses; one-sided α = 0.05. Modified RANO criteria were used for patients with enhancing tumors and RANO low-grade glioma criteria for patients with nonenhancing tumors. Results: Between November 2019 - August 2022, 10 patients were enrolled (Baseline Characteristics). Most common treatment-related adverse event (trAE) was grade 1-2 diarrhea, occurring in all 10 patients. Grade 3-4 trAEs included grade 4 thrombocytopenia (n=2), grade 3 neutropenia (n=1), grade 3 fatigue (n=2), and grade 3 ALT increase (n=1). In patients with enhancing tumor (n=9), best response was partial response in 2 patients (ORR=22.2%; DOR 13.1 and 7.7 months, respectively), stable disease (SD) in 3 patients (33.3%; duration of SD 17.0, 6.7, and 2.5 months, respectively), progressive disease in 3 patients (33.3%), and not evaluable in 1 patient (11.1%). In the patient with nonenhancing tumor, best response was SD (duration 10.2 months). Median PFS was 7.7 months (95% CI, 1.7 – 13.1 months); median overall survival was not reached (median follow-up 17 months). The study’s primary endpoint was not met; 5/10 patients (50%) were alive and progression-free at 6 months, below the minimum required (8/10) to consider abemaciclib worthy of further investigation. Conclusions: Despite objective responses and durable disease control in a small subset of patients, the efficacy of abemaciclib in recurrent grade 3 oligodendroglioma was not adequate to warrant further clinical evaluation of abemaciclib monotherapy in unselected patients. Correlative studies are ongoing to identify which patients with oligodendroglioma may benefit from abemaciclib. Clinical trial information: NCT03969706 . [Table: see text]
Safety and efficacy of tumor treating fields (TTFields) prior and concomitant to radiotherapy in patients with newly diagnosed glioblastoma: Results from PriCoTTF.
Authors: Kebir Seid , Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Proescholdt Martin , Hau Peter , Grosu Anca L. , Krex Dietmar , Sure Ulrich , Scheffler Björn , Kleinschnitz Christoph , Pöttgen Christoph , Stuschke Martin , Glas Martin
Published: June 2023

2050

Background: Tumor Treating Fields (TTFields) therapy is a locoregional, antimitotic cancer modality that utilizes electric fields delivered noninvasively to the tumor region using arrays. Preclinical findings have demonstrated that TTFields have an enhanced inhibitory effect on glioblastoma (GBM) cell proliferation when used concomitantly with radiotherapy (RT). These results provided the rationale for the phase 1/2 PriCoTTF study that investigated the safety and efficacy of TTFields therapy initiated prior and concomitant to radio-chemotherapy in adult patients with newly diagnosed (nd)GBM. Methods: TTFields therapy was initiated following surgery and continued concomitant with radio-chemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was permitted upon GBM recurrence. RT was conducted with arrays placed on the patients’ scalp. The primary endpoint was safety and tolerability gauged by a series of pre-selected treatment-limiting toxicities (TLTs). Results: The baseline characteristics of 33 patients enrolled to date were typical for GBM, except for a small proportion of patients with gross total resection (22.5%). The frequency of adverse events (AEs) grade ≥ 3 was comparable to other studies in GBM. Of note, grade ≥ 3 skin AEs only occurred in 2 patients (6%) and no patients developed a TLT. The median duration of TTFields therapy was 8.4 months. Median overall survival (OS) was not reached (48% of events had occurred), which precluded conclusions regarding efficacy. However, notably, multivariable Cox regression found that OS was independently associated with the number of days patients achieved > 23 h TTFields therapy (HR 0.96, 95% CI 0.93–0.99, P = 0.008). Conclusions: The PriCoTTF study met its primary endpoint by finding that TTFields therapy concomitant with RT was well tolerated in patients with ndGBM. This included that high-grade skin toxicities were rare. Longer follow up is needed to estimate the efficacy of TTFields therapy in this setting, and will need to consider the relatively low overall duration of TTFields therapy and proportion of patients who received GTR.
Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial.
Authors: Le Rhun Emilie , Gorlia Thierry , Furtner Julia , Felsberg Joerg , Jongen Joost , Maurage Claude-Alain , Ducray Francois , Roth Patrick , Hau Peter , Chinot Olivier L. , Preusser Matthias , Cartalat Stephanie , Van Den Bent Martin J. , Collienne Maike , Reifenberger Guido , Weller Michael
Published: June 2023

2054

Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor, including CDK-9, that inhibits tumor growth down-stream via depletion of survival proteins such as MCL-1 and MYC. MCL-1 and MYC are frequently overexpressed in glioblastoma. Methods: The EORTC 1608 (NCT03224104) (STEAM) phase 1b trial had a three parallel group (A,B,C) open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of zotiraciclib in elderly patients (more than 65 years) with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of zotiraciclib in IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months. Secondary objectives included efficacy, quality of life, and safety. Results: The MTD was 150 mg in combination with radiotherapy alone (group A, n=12) or temozolomide alone (group B, n=9) in elderly patients. Two dose-limiting toxicities were observed at 150 mg, one in group A (grade 3 seizure) and one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastro-intestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C (n=50) was 6.7%. Conclusions: Zotiraciclib exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials may be required to explore activity in combination with radiotherapy or temozolomide. Clinical trial information: NCT03224104 .
Prospective phase I study of checkpoint blockade for the treatment of patients with newly diagnosed high-grade glioma prior to radiochemotherapy: Results of nivolumab plus ipilimumab treatment arm.
Authors: Kesari Santosh , Wojcinski Alexandre , Gill Jaya M. , Carrillo Jose Arganda , Wagle Naveed , Nguyen Minhdan , Truong Judy Dang , Juarez Tiffany M.
Published: June 2023

2057

Background: The limited success of checkpoint inhibitors (CPI) targeting the programmed death-1 (PD-1) axis in the adjuvant setting for glioblastoma has prompted a deeper understanding of the brain tumor and immune microenvironment and evaluating how the sequence of immunotherapy administration impacts antitumor response. We initiated a feasibility study (NCT03425292) of postoperative nivolumab (anti-PD-1) monotherapy and combination therapy in adults with newly diagnosed high-grade gliomas (HGG) prior to radiotherapy. Methods: Within six weeks from surgical resection of newly diagnosed HGG, patients in study Arm 3 received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. The primary endpoint was the rate of dose-limiting toxicities (DLT). Secondary objectives included adverse events, antitumor activity and pharmacodynamic effects of study treatment. Next-generation sequencing (NGS) was performed on archival tumor specimens before treatment and at the time of subsequent surgery. Results: Fifteen patients were treated with nivolumab plus ipilimumab. 27% (4/15) of patients were receiving dexamethasone at treatment initiation. MGMT promoter was methylated in 5 tumors, unmethylated in 9, and equivocal in one. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and Grade 4 cerebral edema occurred in 1 patient. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months. Paired tumor specimens obtained before and after treatment were analyzed in six patients and revealed molecular changes in response to treatment as well as differences between patients with shrinking tumors versus progressing tumors. Conclusions: We show that nivolumab plus ipilimumab can be safely administered prior to radiation. To our knowledge, this is the first study in which checkpoint blockade therapy was administered for newly diagnosed glioblastoma prior to standard radiotherapy. Despite the short mPFS, mOS was suggestive of a potential long-term benefit from early CPI exposure, and three patients deferred chemoradiation greater than seven months. Analysis of other study arms is ongoing. Clinical trial information: NCT03425292 .
Intra-operative desorption-electrospray ionization mass-spectrometry for real-time diagnosis, margin assessment, and maximization of brain cancer resection.
Authors: Garcia Diogo , Brown Hannah , Jentoft Mark , Middlebrooks Erik , Chaichana Kaisorn , Cooks Graham , Quinones-Hinojosa Alfredo
Published: June 2023

2071

Background: Despite advances in our understanding of brain cancer, the ability to discern between infiltrated and non-infiltrated tissue with current adjuncts, remains elusive. Isocitrate dehydrogenase (IDH) mutation is unique to IDH-mut glioma cells and can be used as a surrogate for tumor infiltration. Further, emerging evidence has shown unique signatures in brain cancer lipidomic profiling, with lipid metabolism playing a key role in brain cancer biology. Here, we aimed to evaluate the impact of desorption electrospray ionization-mass spectrometry (DESI-MS) as a near real-time method to determine infiltration status and the use of DESI-MS to perform intra-operative histological diagnosis. Methods: This is a prospective multi-institution cohort study using intra-operative DESI-MS on freshly obtained tumor samples to evaluate 2-hydroxyglutarate (2HG), with post-hoc validation by review by a board-certified neuropathologist. For tumor cell estimation and tissue diagnosis, high-throughput DESI-MS was used for rapid analysis of high-density arrays using lipidomic profiling. Analysis of the data was performed using a pre-written algorithm employing a combination of Python- and MATLAB-based custom software allowing results in less than a second per sample. Results: A total of 496 tumor biopsies from 72 patients have been analyzed. Earlier iterations focused on absolute quantitation of 2HG in 247 biopsies from 49 patients to determine IDH genotype yielding sensitivity, specificity, and accuracy values of 89, 100, and 94% for core biopsies (71). Improvement in accuracy was obtained with relative measurement of 2HG in comparison to glutamate allowing for detection of IDH-mut infiltration at the margin, resulting in 93% sensitivity, 100% specificity, and 98% accuracy with turnover times averaging 3 minutes in 183 biopsies from 23 patients. Margin assessment beyond the limits of neuro-navigation and surgeon assessment showed tumor infiltration in 88% of margin biopsies from IDH mutant tumors (30 of 34 biopsies) with 100% accuracy. Intra-operative tissue diagnosis was pursued in 66 unique tumor samples using DESI-MS lipidomic profiling, including samples of normal brain parenchyma, gliomas, meningiomas and pituitary adenomas, split into two microarray sets (36 and 40 samples). Using estimated principal components as input features, high accuracy ( > 90%; ROC AUCs ≥ 0.89) was obtained for supervised tissue classification using simple machine learning algorithms. Conclusions: We present a novel system for intra-operative evaluation of tumor infiltration at the margin in gliomas and for intra-operative tissue diagnosis of brain cancer. Our method identified tumor infiltration beyond the surgical margins and serves as a foundation for future uses employing DESI-MS to allow for molecularly guided surgery in IDH-mut gliomas.
FOXC1 expression in meningiomas.
Authors: Wedemeyer Michelle , Xiu Joanne , Walker Phillip , Kaur Jasmeet , Davidson Christian , Ahluwalia Manmeet Singh , Sumrall Ashley Love , Zada Gabriel
Published: June 2023

2074

Background: Meningiomas account for nearly 1/3 of brain tumors and are characterized by a low mutational burden and dysregulation of DNA methylation. The promoter of FOXC1 is hypomethylated relative to dura in meningiomas of all grades and knockdown of FOXC1 in murine models causes craniofacial hypoplasia and absent frontal dura, suggesting a role as a meningeal identity gene. Here we perform a multi-omic analysis of FOXC1 expression in a large cohort of meningiomas. Methods: A total of 555 meningiomas (148 grade I, 255 grade II and 87 grade III) were analyzed with next-generation DNA sequencing (592 gene NextSeq panel; n=150 or Agilent WES whole exome sequencing, n=405) and whole mRNA (WTS, NovaSeq, 555) at Caris Life Sciences (Phoenix, AZ). Top quartile transcripts per million (TPM) for FOXC1 expression were considered high (FOXC1-H) and bottom quartile low (FOXC1-L). Immune cell infiltration was estimated using RNA deconvolution by QuantiSeq to calculate median cell fractions (MCF) or positive percentages (PP). Data were analyzed using X2/Fisher’s-exact/Mann-Whitney U tests. A p-value<0.05 after BH correction was considered significant. Results: Median FOXC1 expression was 33 TPM. Expression of FOXC1 transcript was higher in lower grade tumors (I: 34, II: 29, III: 27, q<0.05). NF2 mutations were significantly more common in FOXC1-L than FOXC1-H tumors (45% vs. 68%, q<0.05). Although a higher percentage of FOXC1-H meningiomas harbored TERT promoter mutations (2% vs. 9%, p<0.05) and a higher percentage of FOXC1-L meningiomas harbored a TRAF7 mutation (19%. Vs. 5.5%, p<0.05), these differences were not significant after correction for multiple comparisons. Programmed cell death ligand1 (PD-L1/CD274, 2.27 vs. 492) and MHC-I (HLA-A: 58 vs. 109, HLA-B: 59 vs. 74, and HLA-C: 61 vs. 101) transcripts were more highly expressed in FOXC1-H than FOXC1-L tumors. FOXC1-L tumors exhibited significantly more B cells (MCF: 5% vs. 4%), M1 Macrophages (MCF: 2% vs. 1%), CD8+ T cells (PP: 27% vs. 7%), and a higher interferon gamma transcript signature than FOXC1-H. Infiltrates of NK cells (MCF: 3.5% vs. 4.3%) and dendritic cells (MCF: 6% vs. 8%) were higher in FOXC1-H (all q<0.05). Conclusions: The craniofacial patterning transcription factor FOXC1 was found to be widely expressed in a large cohort of meningiomas and its expression is inversely correlated with WHO tumor grade. Multi-omic analysis reveals a significant relationship between FOXC1 transcript levels and key markers of the immune environment including PD-L1 transcript expression. These data suggest that FOXC1 is a marker of meningiomas in addition to its role as a meningeal identity marker during development. Functional studies are warranted to determine whether FOXC1 is necessary for meningioma growth, whether FOXC1 plays a direct immunomodulatory role in meningiomas, and whether the lower FOXC1 expression levels in high grade tumors represent a more embryonic phenotype.
CLDN6 CAR-T cell therapy of relapsed/refractory solid tumors ± a CLDN6-encoding mRNA vaccine: Dose escalation data from the BNT211-01 phase 1 trial using an automated product.
Authors: Mackensen Andreas , Haanen John B. A. G. , Koenecke Christian , Alsdorf Winfried , Wagner-Drouet Eva Maria , Heudobler Daniel , Borchmann Peter , Bokemeyer Carsten , Klobuch Sebastian , Kutsch Nadine , Müller Fabian , Desuki Alexander , Lüke Florian , Wiegert Erol , Flemmig Carina , Schulz-Eying Catrine , Rengstl Benjamin , Preußner Liane , Türeci Özlem , Şahin Uğur
Published: June 2023

2518

Background: We are developing a chimeric antigen receptor (CAR)-T cell therapy targeting claudin 6 (CLDN6), an oncofetal antigen that is undetectable in healthy somatic tissue and highly expressed in various solid cancers. Autologous CLDN6 CAR-T cells are being tested alone and in combination with CLDN6-encoding CAR-T cell Amplifying RNA Vaccine (CARVac), a nanoparticulate RNA vaccine designed to stimulate and expand CLDN6 CAR-T cells. Methods: The ongoing first-in-human trial BNT211-01 evaluates the safety and feasibility of CLDN6 CAR-T cell transfer ± CARVac in lymphodepleted patients with relapsed/refractory solid tumors. Patients are pre-screened for CLDN6 expression with a cut-off of 50% positivity of intermediate or strong intensity by immunohistochemistry staining. Key endpoints are safety, tolerability, and anti-tumor activity. Pharmacokinetics of adoptively transferred CAR-T cells in peripheral blood is monitored by quantitative PCR. Dose escalation proceeds according to a classical 3+3 design, testing CLDN6 CAR-T cells at each dose level as both as monotherapy and in combination with CARVac. We previously reported results from 22 patients from 4 dose escalation cohorts with a manual CAR-T production process ± CARVac (ESMO-IO LBA38) which followed the same methodology. We observed durable responses along with a manageable safety profile, in line with commercial CAR-T products used to treat B-cell malignancies. No on-target/off-tumor toxicity and only a single case of (grade 1) neurotoxicity was observed. Given the encouraging efficacy, we have implemented an automated process to scale-up manufacturing. Accordingly, we are repeating the dose escalation with an automated CAR-T cell product, and with a modified CARVac regimen. As of 1st February 2023, 7 patients with epithelial ovarian carcinoma (EOC), 4 with testicular germ cell tumors (GCT), and a further 5 patients with tumors of various indications have been infused with CAR-T cells up to DL2. We intend to submit efficacy, safety and CAR T-cell pharmacokinetics data from 5 cohorts treated with 1x106, 1x107 or 1x108 CLDN6 CAR-T cells ± CARVac with a data cut-off of March 14th, 2023 from ≥17 treated patients as a late-breaking abstract. Clinical trial information: NCT04503278 .
The immune microenvironment in hormone positive, HER2 negative breast cancer: A focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures.
Authors: Lucas Mairi , Kinsella Zak , Gonzalez Claudia Aura , Hurley Camille , O'Grady Anthony , Fay Joanna , Murphy Verena , Jahangir Chowdhury Arif , Rahman Arman , Gallagher William M. , Kelly Catherine Margaret , O'Connor Darran
Published: June 2023

2522

Background: Hormone positive, HER 2 negative breast cancer (ER+/HER2-) has traditionally been considered an immune cold tumour subtype. Research to date indicates that TILs in ER+/HER2- breast cancer may be a negative prognostic marker. However, there is a paucity of data in this area regarding immune subpopulations and spatial phenotypes. Tertiary lymphoid structures (TLS) have been associated with improved prognosis and response to immunotherapy in other solid organ malignancies. We aim to explore the immune microenvironment in early stage ER+/HER2- breast cancer with a focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures (TLS). Methods: Full face sections of archival tissue samples from patients with early stage ER+/HER2- breast cancer were stained with CD45 antibody (DAKA clone M0701) via the automated Leica Bond III system. Open source digital pathology analysis software, Qupath, was utilised to identify positive cells and calculate the percentage of positive CD45 staining cells (CD45%) within the tumour area. Spatial analysis was done to divide tumour area into three spatial phenotypes; Immune cold -lacking immune infiltrate;Immune excluded- immune cells restricted to the tumour periphery and immune hot - immune cells infiltrating the tumour core. A tissue micro array (TMA) was created and stained manually with a multiplex chromogenic immunohistochemistry panel for CD20/CD3/DCLamp to identify immune subpopulations associated with tertiary lymphoid structures. Results: A total of 409 patient samples were included in the analysis. 89% (n=367) of samples had a CD45% of 0-10%. CD45% stratification by 21-gene-recurrence score(RS) into Low, Intermediate and High showed a statistically higher CD45% in those with a High RS compared to Low RS (p value= 0.0015). We identified a trend towards worse disease free survival (DFS) in the CD45%high group which did not reach statistical significance. The immune hot spatial phenotype was associated with a worse DFS (p value = 0.034) with no statistically significant difference in DFS between immune cold and immune excluded phenotypes. The majority of samples had minimal immune infiltrate. Staining with a TLS panel revealed that samples with a significant infiltrate could broadly be divided into T cell only infiltrate or those with the presence of TLS, the significance of this is unclear. Conclusions: The majority of ER+/HER2- breast cancer samples had low numbers of TILs, however there is clear heterogeneity within this subgroup. Spatial elements and immune cell subpopulations may further guide the value of TILs in prognosis in this breast cancer subtype.
AMPLIFY-201, a first-in-human safety and efficacy trial of adjuvant ELI-002 2P immunotherapy for patients with high-relapse risk with KRAS G12D- or G12R-mutated pancreatic and colorectal cancer.
Authors: O'Reilly Eileen Mary , Wainberg Zev A. , Weekes Colin D. , Furqan Muhammad , Kasi Pashtoon Murtaza , Devoe Craig E. , Leal Alexis Diane , Chung Vincent , Perry James , Seenappa Lochana , McNeil Lisa , Welkowsky Esther , DeMuth Peter , Haqq Christopher M. , Pant Shubham
Published: June 2023

2528

Background: RAS mutations occur in 25% of solid tumors with G12D being the most frequent variant. ELI-002 2P is a vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D and G12R mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Preclinical amphiphile data (relative to non-amphiphile controls) showed increased immunogenicity, tumor clearance and survival in mouse models. Methods: This first-in-human multicenter phase I trial assessed safety, immunogenicity and antitumor activity using a novel adjuvant trial design in patients (pts) with minimal residual disease (MRD) following standard locoregional treatment. Eligibility: elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker elevation (CA19-9/CEA), and KRAS/NRAS mutation. In a 3+3 dose escalation, n=22 received a subcutaneous course of 6 prime and 4 booster injections of fixed dose Amph-peptides (1.4 mg), admixed with escalating Amph-CpG-7909 (Table). Dose escalation based on observed safety in first 28 days. Safety, antitumor activity including biomarker reduction/clearance and relapse free survival using immune Response Evaluation Criteria in Solid Tumors (iRECIST) were assessed. Immunogenicity assessed by direct ex vivo Fluorospot and intracellular cytokine staining of peripheral blood mononuclear cells (T-cell responders = ≥ 2-fold increase over baseline) and by tumor CD3 immunohistochemistry in subset who underwent a biopsy. Results: No dose-limiting toxicities, treatment related SAEs or cytokine release syndrome were observed, and no maximum tolerated dose was identified. Safety: all grade 1, fatigue (19%), headache (19%), and injection site reaction (9.5%). Biomarker reduction was observed in 15/19 (79%) and in 5/5 at highest doses; clearance of MRD was observed in 4/19 (21% - n=2 pancreas, n=2 colorectal). Polyfunctional mKRAS-specific T cell responses observed in 80% of pts (n=12/15), with both CD8+ and CD4+ T cell responses for most, and CD3+ T cells observed on biopsies. The recommended phase 2 dose (RP2D) is 10.0 mg Amph-CpG-7909. Conclusions: ELI-002 2P, evaluated in a novel MRD+ trial, was safe with ctDNA and serum tumor biomarker reduction and clearance and notable immune responses. The RP2D is the start dose for a phase 1/randomized phase 2 study evaluating a new seven peptide formulation for G12 D, R, V, S, A, C, and G13D mutated solid tumors (NCT05726864). Clinical trial information: NCT04853017 . [Table: see text]
Phase Ib/IIa safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced solid tumors.
Authors: Guo Ye , Guo Jun , Cheng Ying , Wang Zhen , Li Yongsheng , Lv Dongqing , Yin Yongmei , Li Guiling , Wu Lingying , Huang Yi , Wei Shuqing , Shen Lin , Duan Huaxin , Cui Jiuwei , Luo Hong , Li Xiumin , Nan Kejun , Wang Chunyan , Luo Su-xia , Liu Ruonan
Published: June 2023

2536

Background: PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. We had completed dose escalation from 1mg/kg to 45mg/kg and had not found DLT/MTD. In a Phase Ib dose expansion and Phase IIa studies we are evaluating the safety and preliminary anti-tumor activity of PM8002 as a monotherapy. Here, we provide an update of PM8002 Phase Ib/IIa results. Methods: During Phase Ib dose-expansion and Phase IIa studies, the majority of patients received PM8002 at 20mg/kg Q2W or 30mg/kg Q3W as a monotherapy (recommended phase II doses). The primary endpoint was ORR with secondary endpoints/objectives including safety. Results: As of Feb 3, 2023, 263 patients of advanced solid tumor with prior 0 to 4 line systematic treatment had been enrolled (1mg/kg Q2W [n=1], 10mg/kg Q2W [n =1], 20mg/kg Q2W [n=190], 20mg/kg Q3W [n=4], 30mg/kg Q2W [n=4], 30mg/kg Q3W [n=52], and 45mg/kg Q3W [n=11]). The median duration of exposure was 10.6 weeks (range, 0.1—51.0). Of the 263 enrolled patients, 211 had completed their first evaluation for efficacy. The overall ORR, regardless of tumor type, was 15.2% (32/211) with 32 PRs (20 confirmed PRs), and the DCR was 75.4% (159/211) per RECIST 1.1. Twenty-five patients with cervical cancer had an ORR of 28% (7/25). Twenty-six patients with renal cell carcinoma had an ORR of 26.9% (7/26). Twenty-six patients with platinum-resistant ovarian cancer had an ORR of 15.4% (4/26), and 27 patients with NSCLC (with EGFR mutations) had an ORR of 18.5% (5/27). Any-grade TRAEs occurred in 68.8% patients (181/263), with 18.3% Grade ≥3 (48/263). The most common TRAEs were proteinuria (17.5%), hypertriglyceridemia (11.4%), Aspartate aminotransferase (9.9%), Alanine aminotransferase increased (9.5%), Hypoalbuminemia (8.7%), and increased gamma-glutamyl transferase levels (6.8%). Thirty-six patients (13.7%) discontinued PM8002 due to TRAEs. No death-related cases occurred, and most patients remain on treatment. Conclusions: PM8002 showed encouraging antitumor activity and good safety in patients with advanced solid tumors. Phase 1b/IIa of PM8002 as a monotherapy and Phase II combination trials of PM8002 with chemotherapy are ongoing for multiple indications. Clinical trial information: ChiCTR2000040552.
A pilot study of lymphodepletion intensity for PBMC-derived, neoantigen-specific CD8+ T cells (Neo-Ts) therapy in patients with advanced solid tumors.
Authors: Li Dandan , Chen Chao , Li Jingjing , Yue Jianhui , Ding Ya , Wang Hailun , Liang Zhaoduan , Zhang Le , Qiu Si , Liu Geng , Gao Yan , Huang Ying , Li Dongli , Liu Wei , Wen Xizhi , Li Bo , Zhang Xiaoshi , Zhang Xi , Xu Rui-Hua
Published: June 2023

2545

Background: Adoptive T cell therapy (ACT) using neoantigen-specific CD8+ T cells (Neo-Ts) derived from patient PBMC was recently developed aiming to target individual patient’s unique tumor mutations and increase treatment efficacy. But the optimal lymphodepletion intensity for Neo-T therapy has yet to be determined. Methods: In this phase I clinical trial (NCT02959905), we generated Neo-Ts from patients with locally advanced or metastatic melanoma or colon cancers that were refractory to standard therapies, and evaluated the effects of lymphodepletion at various dosages (high: 2x500 mg/m2 cyclophosphamide and 2x25 mg/ m2 fludarabine; low: 1x500 mg/m2 cyclophosphamide and 2x25 mg/ m2 fludarabine; and no lymphodepletion) during Neo-T therapy. The primary end point was safety and the secondary end point was objective response rate (ORR). Results: We showed that Neo-T therapy was safe with lymphodepletion at dosages from no lymphodepletion to high intensity. The median PFS was 7.1 months (95% CI:3.7-9.8), and median overall survival (OS) was 16.8 months (95% CI: 11.9-31.7). The ORR was 33.3% (3/9) among all groups. Three patients achieved PR, two of them were in the group without lymphodepletion. One of the PR patients refractory to prior anti-PD-1 therapy also responded to Neo-T therapy. Neoantigen specific TCRs were examined in two responding patients and showed expansion and persistence after treatment. Conclusions: Neo-T therapy with low intensity lymphodepletion or no lymphodepletion could be a safe and promising regimen for advanced solid tumors. Clinical trial information: NCT02959905 .
A phase 1 dose escalation trial of ex-vivo expanded allogeneic cord blood–derived natural killer cell immunotherapy for pediatric solid tumor malignancies.
Authors: Khazal Sajad , Gill Jonathan Benjamin , Foglesong Jessica , Yedururi Sireesha , Morani Ajaykumar , Sui Dawen , Bassett Roland L. , Gettys Suzanne , Tewari Priti , Mahadeo Kris , Gorlick Richard Greg , Shpall Elizabeth J. , Rezvani Katy , Daw Najat C.
Published: June 2023

2546

Background: Despite aggressive multimodality therapy, survival outcomes of most patients with recurrent/refractory solid tumors remain dismal. Preclinical data have shown that natural killer (NK) cells play a significant role in controlling cancer progression, metastasis, and survival. In this phase I dose escalation trial, we evaluated the safety and phase 2 recommended dose of cord blood derived NK cells in children and young adults with recurrent/refractory pediatric solid tumors. Methods: Eligible patients were 1-40 years old. Cord blood donors were 4, 5, or 6/6 HLA matched. Ex-vivo, antigen presenting cell-mediated expansion of human cord blood derived NK cells was performed over 14 days. All patients received lymphodepleting regimen with cyclophosphamide (500 mg/m2/day) and etoposide (100 mg/m2/day) for 5 days (days -7 to -3) followed by 2 days rest and a single infusion of NK cells on Day 0. The study evaluated two dose levels using a standard 3+3 phase I trial design with an expansion cohort at the maximum tolerated dose. Results: Twelve patients (median age 16 years) received NK cells infusions. Tumor types included osteosarcoma (n = 7), Ewing sarcoma (n = 4), and synovial sarcoma (n = 1). Three patients received NK cells at dose level 1 (5 X 107/Kg), and nine patients at dose level 2 (1 X108/Kg), which was determined to be the recommended Phase 2 dose. No dose-limiting toxicities were observed. Most adverse events were grade 1 and 2 (fatigue, dizziness, nausea and vomiting). Most frequently observed grade 3 and 4 adverse events were leukopenia, neutropenia, lymphopenia, and thrombocytopenia. No cytokine release syndrome or neurotoxicity was observed. Allogeneic NK cells were detected in recipients’ peripheral blood as high as 100% of all NK cell populations and as late as 9 days post infusion. Of the 9 patients evaluable for tumor response, 3 patients (with osteosarcoma) had stable disease and 6 had progressive disease. Conclusions: Allogeneic ex-vivo expanded NK cells immunotherapy demonstrated favorable safety profile in patients with advanced pediatric solid tumors. Strategies to improve efficacy are warranted including using adjuvant therapy to increase persistence, more stringent selection strategies and gene editing approaches to increase alloreactivity against recipient tumor cells. Clinical trial information: NCT03420963 .