bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of an explainable AI-based therapeutic recommendation-tool utilizing tumor gene expression profiles in advanced and refractory solid tumors.
Authors: Al Jarroudi Ouissam , Williams Coralie , Santos Rita , Dufresne Armelle , Attignon Valéry , Ferrari Anthony , Boyault Sandrine , Tonon Laurie , Tabone-Eglinger Séverine , Cassier Philippe Alexandre , Corradini Nadège , Vinceneux Armelle , Swalduz Aurélie , Viari Alain , Chabaud Sylvie , Pérol David , Afshar Mohammad , Blay Jean-Yves , Tredan Olivier , Saintigny Pierre
Published: June 2022

1554

Background: Precision oncology aims to guide patient (pts) treatment decisions by matching biological features with available drugs. Extensive genomic analysis allows to identify an actionable alteration in 40-60% of patients. In a recent study of 50 pts with advanced refractory diseases included in PROFILER (NCT01774409), whole exome and fusion transcripts had a limited value over a 90-tumor gene panel (TGP) to increase molecular-based treatment recommendations (MBTR). Herein, we evaluated the feasibility, in the same cohort of pts, of the AI-transcriptional-based therapeutic recommendation-tool OncoKEM to guide treatment recommendations. Methods: 77 fresh frozen (FF) and/or FFPE samples including paired specimens for 53 pts with available RNA-Seq gene expression profiles were included. For each pts, a tumor transcriptional profile (TTP) was generated by identifying differentially expressed genes between the pts tumor and a cohort of matched healthy tissue. A large database of drug transcriptional signatures (DTS) was queried in order to identify a “reversal relationship” between the TTP and a DTS. A total of 205 drugs were ranked, including a subset of 61 FDA and/or EMA approved targeted therapies (aTT). Results: Most common diagnoses were breast cancers (21% of which 63% were TNBC), followed by ovarian cancers (OC, 18%) and soft-tissue sarcomas (STS, 13%). The median number of previous treatment lines was 4 (range: 1 - 10). Among the 77 tumor samples analyzed, 54 (70%) specimens led to the generation of an OncoKEM report, with no differences between FF and FFPE samples (p = 0.85). The overlap between the top 10 proposed drugs between paired FF and FFPE samples was 56% on average. All patients had at least 2 propositions (range: 2-9) of aTT among the top 10 ranked drugs in the Onco KEM reports. Most frequently proposed drugs among the top 10 were palbociclib, talazoparib, infigratinib in TNBC; bosutinib, sapanisertib, SAR125844 in OC; ipilimumab, cabozantinib, sapanisertib in STS. Among the 30 pts (79%) without any MBTR based on TGP/WES/fusion transcript analysis, all had at least 2 proposed aTT in the Onco KEM report (median: 4, range: 2-9). Top ranked drugs were MET (18%), VEGFR (12%), Abl (12%), FGFR (11%), PI3K/AKT/mTOR (11%), PARP (10%) and CDK4/6 inhibitors (7%). Conclusions: AI-transcriptional-based therapeutic recommendation-tool OncoKEM is feasible and has the potential to expand personalized cancer treatment in pts with advanced & refractory diseases without tractable genomic alterations. The clinical relevance assessment is planned in an upcoming clinical trial.
Participation in cancer research in BNSSG, England: A Health Equity Audit 2021.
Authors: Hamilton Kathryn , Winter Helen , Benton Diana , Lewis-White Helen , Ainsley Owen , Eyles Emily
Published: June 2022

1565

Background: Cancer is a cause of health inequalities, and nationally, patients from deprived communities have lower participation rates in cancer research. Equitable access to research benefits patients, healthcare organisations and improves applicability of research. Methods: We undertook a health equity audit of participation in cancer research (trials and non-trials based) in Bristol, North Somerset and South Gloucestershire (BNSSG), England from 1.4.2019-30.3.2020 using data from the Acute Trust patient datasets. Comparison cohorts were extracted from a regional primary care dataset (the system wide dataset). Firstly, an incident cancer cohort: diagnosed from 1.11.2019-1.10.2020. Secondly a “living with cancer” cohort: cancer flag in the 5 years prior to 1.7.2021. Deprivation is measured by IMD of home postcode small area (LSOA). Results: Results are presented for the audit in the table below, with 95% confidence intervals where appropriate. Compared to people newly diagnosed with cancer, adults aged 70 or older were 56% less likely to take part in research (OR 0.44, 95% CI 0.39-0.51), and adults aged 80 or older were 77% less likely to take part in research (OR 0.23, 95% CI 0.18-0.29). Compared to people newly diagnosed with cancer, people from the most deprived 20% of the population were 27% less likely to take part in research (OR 0.73, 95% CI 0.88-0.92). The most deprived research participants were more likely to be younger, have one or more comorbidities and a recent emergency admission. Patients from outside BNSSG (18%) appear similar in profile to those from within BNSSG, including for deprivation. Better data are needed for other factors relevant to equity, including ethnicity and Inclusion Health. Conclusions: This health equity audit confirms and quantifies inequities in access to cancer research in our region. Under-representation of deprived and older patients appeared multifactorial in this audit, but further work to understand facilitators and barriers to recruitment is needed. These results are a call to action. [Table: see text]
A retrospective cohort analysis of return-to-work outcomes for cancer survivors using a digital coaching intervention.
Authors: Aung Yuri Yin-Moe , Smith Justin , Ballurkar Kieran , Fox Simonie , Tynan Kate , Lo Jonathon , Murali-Ganesh Raghav , Boyer Michael J.
Published: June 2022

1566

Background: Return-to-work (RTW) is a key unmet need for working age cancer survivors, with up to 40% failing to RTW 1 to 2 years post-diagnosis. This study sought to evaluate RTW outcomes of a multidisciplinary digital coaching intervention provided as routine employee support. Methods: A retrospective cohort analysis was conducted from October 2018 to February 2020 where cancer patients with more than 3 months absent from work were provided by their insurance carriers with a multidisciplinary intervention comprising digital resources and telephone calls with a health coach. A logit regression model was used to calculate a propensity score using covariates of age, gender, insurance benefit type, cancer diagnosis date and time from diagnosis. Participants were then matched on a 1:1 basis using the nearest-neighbour method without replacement to create a matched control group out of 1,856 participants who did not receive the intervention. Primary outcomes, derived from insurance-claims data as standard business practice, included rate and time to RTW, along with death and other reasons for claim closure. Results: 220 participants enrolled in the intervention, of which 125 met the criteria for analysis (median age 53, IQR 45-58, 91% female). These participants were matched with 125 controls (median age 53, IQR 47-59, 94% female). Median follow-up from cancer diagnosis was 79 weeks (IQR 60-106). Of the matched controls, 22 returned to work (17.6%) compared with 38 (30.4%) in the intervention group (P =.02). 19 matched controls died prior to claim closure (15.2%) compared with 13 in the intervention group (10.4%; P =.26). Finally, Kaplan-Meier method estimated median time for the first 15% of participants to RTW was 87.1 weeks for controls (CI 60.0-109.1 weeks) compared with 70.6 weeks for the intervention group (CI 52.6-79.6 weeks; P =.08). Conclusions: This study evaluated the impact of a digitally delivered coaching program in a real-world setting for cancer patients, demonstrating a 12.8% increase in RTW rate over 18 months compared to matched controls. These findings corroborate and add to the literature on cancer as a chronic and manageable disease in the workplace.
Evaluating an AI-based nutrition expert platform delivered via SMS-text to support patients with cancer.
Authors: Buchan Marissa Lubin , Tang Hao , Bratton Susan , Padmanabhan Sridevi , Raben David
Published: June 2022

1569

Background: Interventions incorporating nutritional strategies can prevent and manage nutrition-related symptoms, however, due to a shortage of oncology dietitians (RD CSO) combined with healthcare access disparities, many patients do not receive the support they need, resulting in poor outcomes and quality of life (QoL). High rates of cell phone utilization among all demographics offers a unique opportunity to provide interventions using mobile technology. Methods: Launched to select groups in 2019, Ina (trademarked by Savor Health LLC) is a virtual nutrition assistant powered by an artificial intelligence (AI)-enabled expert platform, to facilitate self-management of cancer treatment side effects. The platform combines evidence, expertise, and unique patient data to deliver the personalized guidance patients would receive from an RD CSO, “on-demand” via text. This study applied the RE-AIM framework to evaluate the intervention from five dimensions. Results: Reach: The program reached 1,706 users as of 2021. Based on self-report among 1209 users, 78% are patients, 18% are caregivers, and 5% are healthcare professionals with 66% female and 34% male. Ina supports all cancer types, and top diagnoses among users are genitourinary (28%), lung (20%), gynecologic (16%), gastrointestinal (15%), and breast (11%). Disease burden is high, with 62% of users reporting they are experiencing nutrition-addressable symptoms at any given time. Effectiveness: Based on weekly patient reported outcome (PRO) surveys, 87% of respondents report Ina helps them manage symptoms, and 80% report that using Ina has improved their QoL. The cumulative likelihood to recommend is 4.1 on a 5-point scale. Adoption: Users are from over 18 cancer organizations, proving the feasibility and accessibility of this intervention. Implementation: Ina is accessible 24/7 via text, and is offered to patients in a B2B2C model. Users typically receive responses to nutrition-related questions within seconds from the AI platform (or 1-3 minutes with live RD oversight). Each active user (one that engages at least once in a given month) asks an average of 2.8 questions per month. Maintenance: The median time users remain on the platform is 156 days (range 0-884) and 57% of evaluable users stayed on the platform 6 months or longer. The platform’s database, which includes over 54,000 referenced interventions, grows daily via supervised machine learning supported by RD CSOs. When surveyed on future feature development, respondents are most interested in tele-nutrition (57%), mental health (65%), and stress management (62%). Conclusions: Initial data suggests this is a feasible and accessible tool to support cancer patients’ unique nutrition and symptom-management needs. Clinical trials are needed to validate feasibility and assess impact on clinical and QoL outcomes. Product development to integrate language and cultural preferences is ongoing.
Exploring country priorities and contextual considerations for implementing national cancer control plans (NCCP) among participants of International Cancer Control Partnership (ICCP) ECHO.
Authors: Kizub Darya Aleksandrovna , Eldridge Linsey , Tittenbrun Zuzanna , Cira Mishka K. , Duncan Kalina , Hohman Karin , Given Leslie , Foxhall Lewis E. , Adsul Prajakta
Published: June 2022

1581

Background: Promoting NCCP implementation by low- and middle-income countries (LMICs) is key to addressing inequities in cancer outcomes and the global burden of cancer. We explored contextual factors that may influence implementation of NCCP priorities in LMICs. Methods: Seven countries participated in the 2021 International Cancer Control Partnership ECHO (R) geared toward creating a community of practice to inform NCCP implementation. Using qualitative methods, we conducted focus group discussions (FGDs) with country teams who were asked to identify NCCP priorities and provide contextual considerations around implementing these in the 12-months program. FGDs were audio-recorded, transcribed, double-coded, and underwent thematic analysis. Results: Thirty-three participants from 6 Sub-Saharan African countries and 1 country in Asia took part in 7 FGDs, including 14 physicians, 9 non-governmental organizations, 6 Ministry of Health/NCCP and 4 cancer registry representatives. All seven country teams (100%) prioritized cancer early detection, especially for cervical (71%) and breast (57%) cancer, including by educating primary care clinicians (57%) and general population (43%) about cancer signs and symptoms. Related contextual factors included late-stage diagnosis of cancer (43%) and low knowledge about cancer among primary care clinicians and the general population (29% each), respectively. Finding resources for implementation of NCCP priorities was important given lack of funding (57% each). Harmonizing programs and building partnerships for implementation (57%) was prioritized given perceived fragmentation of efforts and benefit of leveraging limited resources (29% each). Improving access to treatment (43%) was a priority given a lack of oncology specialists (29%) and unaffordable treatment (14%). Improving access to palliative care (43%), including by writing guidelines (29%), was prioritized due to late-stage diagnosis and insufficient access to palliative care (14% each). Improving cancer registry data was essential for NCCP program planning (43% each), while cancer research (43%) was key to answering specific questions related to cancer registry data (14%) and program impact (29%). Additional contextual considerations for making progress on these priorities dicussed by country teams included leveraging existing programs (100%) and learning from other countries and ICCP technical experts (57% each). Conclusions: There were similarities in country NCCP priorities and contextual factors affecting implementation. These results allow for future exploration of how LMIC country teams implement NCCPs and examine the value of communities of practice promoted by ICCP and facilitated by ECHO, towards improving cancer outcomes.
Financial payments from the pharmaceutical industry to U.S. cancer centers, 2014-2019.
Authors: Mitchell Aaron Philip , Brown Meredith , Trivedi Niti U. , Bach Peter Brian
Published: June 2022

1582

Background: Payments from the pharmaceutical industry to US health care providers were made public through Open Payments in 2013. Since then, industry payments to individual physicians have been studied extensively, but payments to hospitals remain uncharacterized. The goal of this study was to examine trends in industry payments to US cancer centers. Methods: We identified all US cancer centers that were National Comprehensive Cancer Network (NCCN) members or were National Cancer Institute (NCI) comprehensive cancer center as of 2019. Each institution was manually mapped to Open Payments, which contains industry payment data. Where applicable, subsidiary hospitals were included with the parent center. Among the NCCN centers, we used National Plan and Provider Enumeration System data to identify medical oncologists practicing there. Oncologists were linked to Open Payments by name and address. We analyzed “research payments” (RP), which include payments related to preclinical and clinical research, and “general payments” (GP), which include non-research-related payments in categories such as speaker fees, consulting fees, meals, grants, charitable contributions, and licensing fees. We ascertained public research support from NIH data, and included all research project grants. We used correlation analysis and linear regression models to assess the association between industry payments to a cancer center and to oncologists practicing at that center. All dollar values were inflation-adjusted to 2019 dollars using the Consumer Price Index for medical care from the US Bureau of Labor Statistics. Results: Overall industry RP to US cancer centers increased from $527 million in 2014 to $653 million in 2019, while GP increased from $346 million to $786 million. NCI research funding increased from $1,397 million in 2014 to $1,583 million in 2019 (13.3% increase) while overall industry payments (RP+GP) increased from $873 million to $1,439 million (64.8% increase). Industry payments were highest as a portion of total income (industry + NCI) at MD Anderson (64.2%) and lowest at St. Jude (0.1%). Among NCCN institutions, industry payments to cancer centers and the oncologists practicing at those centers were correlated (coefficient = 0.382). A $1,000 increase in GP to a cancer center from a given pharmaceutical company was associated with a $1.00 ($0.61 - $1.30) increase in GP from that company to oncologists at that cancer center. Conclusions: From 2014-2019, cancer center funding from industry sources grew quickly, driven by an increase in non-research payments, and now approaches the amount of public research funding cancer centers receive. Cancer center acceptance of industry payments is associated with increased industry payments to its employed physicians, which are known to sway prescribing practices. These trends raise concerns regarding the ability of these institutions to fulfill their public missions.
Patient efficacy in telehealth is moderated by distress among patients with cancer: A cross-sectional survey study.
Authors: McCollom Joseph William , Drouin Michelle , Flanagan Mindy , Pfafman Rachel
Published: June 2022

1590

Background: The COVID-19 pandemic increased the use of telehealth to reduce exposure, which was critical for patients with cancer. The extent to which patients with cancer view telehealth visits as meeting their medical needs was investigated using a cross-sectional survey. Methods: Patients currently receiving cancer treatment at a single cancer institute who had had at least one telehealth visit were emailed an online survey. Response rate was 5% (94/1944). The survey measured patients’: 1) Emotional Thermometer (i.e. distress, anger, depression, anxiety, and need for help on a 0-10 scale); 2) Telehealth usability questionnaire (TUQ; 21-items with various subscales, like interaction quality; α=0.98).); and 3) Perceived Efficacy in Patient-Physician Interactions (PEPPI-5) scale (five items, e.g., “How confident are you in your ability to make the most of your visits with your doctors?”). Respondents completed the PEPPI-5 for in-person visits and for telehealth visits. Descriptive statistics were calculated for all measures. A generalized linear model was estimated predicting PEPPI-5 for telehealth visits from emotional thermometer and TUQ scores. The interaction between emotional thermometer and TUQ scores was estimated to test the hypothesis that emotional distress moderated the relationship between TUQ and efficacy in patient-provider interactions during telehealth visits. Results: Across all five thermometers, 30.8% (28/91) reported a high score on at least one metric. The most frequently reported high score was for anxiety, 23.3% (21/90) and least frequently reported high score was for anger, 12.2% (11/90). The mean TUQ score was 5.5 (SD=1.5) and mean PEPPI-5 score for telehealth visits was 8.1 (SD=2.4). As shown in Table, emotional thermometer scores did moderate the relation between TUQ and patient self-efficacy during telehealth visits. For high emotional thermometer scores, self-efficacy decreased as TUQ scores decreased. Conclusions: For patients experiencing high emotional distress, low comfort and ability with telehealth usability resulted in low patient self-efficacy in communicating with providers and getting medical needs met. Telehealth is a convenient and effective modality; however, in times of emotional distress for patients who are not familiar with telehealth, in-person clinic visits may result in greater patient self-efficacy.[Table: see text]
Reproducibility of outcomes in sequential trials using CMV-targeted dendritic cell vaccination for glioblastoma.
Authors: Sampson John H. , Batich Kristen A , Mitchell Duane Anthony , Herndon James Emmett , Broadwater Gloria , Healy Patrick , Sanchez-Perez Luis , Nair Smita , Congdon Kendra , Norberg Pamela , Weinhold Kent J. , Archer Gerald E. , Reap Elizabeth A. , Xie Weihua , McLendon Roger E. , Reardon David A. , Vredenburgh James J. , Friedman Henry S. , Bigner Darell , Friedman Allan H.
Published: June 2022

2005

Background: Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. Methods: To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with newly diagnosed GBM eligible to receive standard of care resection and adjuvant radiation therapy and temozolomide chemotherapy. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. Results: Our initial study was the phase II ATTAC study (NCT00639639; total n = 12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning ( P = 0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR = 0.820, P = 0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n = 24, unpulsed DC n = 19; 24h, P = 0.031 and 48h, P = 0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td ( P = 0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%). Conclusions: We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM. Clinical trial information: NCT00639639, NCT02366728.
CSF proteomics for differentiation of brain malignancies.
Authors: Mikolajewicz Nicholas , Trifoi Mara , Khan Shahbaz , Glantz Michael J. , Moffat Jason , Zadeh Gelareh , Kislinger Thomas , Mansouri Alireza
Published: June 2022

2021

Background: Accurate diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk. Although the cerebrospinal fluid (CSF) is the ideal liquid biopsy source, the traditionally high volumes required for impactful analyses have deterred progress. The objective of this study was to identify diagnostic and prognostic CSF proteomic signatures in glioblastoma (GBM), brain metastases (BM), and central nervous system lymphoma (CNSL). Methods: CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics with ultra-low sample volumes. Proteomic signatures were identified using machine learning classifiers and survival analyses. Results: Using 30µL CSF volumes, we recovered 800 unique peptides across 73 samples [20 normal pressure hydrocephalus (NPH, non-tumor control), 22 GBM, 17 BM, and 14 CNSL]. Externally-validated proteomic-based classifiers identified malignancy with AUROC of 0.94 and distinguished individual tumor entities from others with AUROC ≥0.96. More clinically relevant triplex classifiers, comprised of just 3 peptides, distinguished individual tumor entities with AUROC ≥0.90. Novel biomarkers were identified among the top classifiers, including TFF3 and CACNA2D2, and characterized using single-cell RNA sequencing data. Survival analyses validated previously implicated prognostic signatures, including blood brain barrier disruption. Conclusions: Reliable classification of intra-axial malignancies using ultra-low CSF volumes is feasible, which has ramifications for longitudinal tumor surveillance. Novel biomarkers identified here necessitate future validation. Based on emerging evidence, upfront implantation of CSF reservoirs in brain tumor patients warrants consideration.
Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.
Authors: Le Rhun Emilie , Devos Patrick , Winklhofer Sebastian , Lmalem Hafida , Brandsma Dieta , Kumthekar Priya , Smits Marion , Tonn Joerg , Jaeckle Kurt A. , Preusser Matthias , Glantz Michael J. , Wen Patrick Y. , Bendszus Martin , Weller Michael ,   EORTC RANO LM scorecard task force, including 38 colleagues
Published: June 2022

2026

Background: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. Methods: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the inter-observer pairwise agreement. Results: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. Conclusions: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with “blocking options” may be required to enforce completeness and quality of scoring.
Final data from the phase 2a single-arm trial of SurVaxM for newly diagnosed glioblastoma.
Authors: Ciesielski Michael J , Ahluwalia Manmeet Singh , Reardon David A. , Abad Ajay P. , Curry William T. , Wong Eric T. , Peereboom David M. , Figel Sheila A. , Hutson Alan , Groman Adrienne , Withers Henry G. , Liu Song , Belal Ahmed , Qiu Jing-Xin , Mogensen Kathleen , Schilero Cathy , Casucci Danielle M. , Mechtler Laszlo , Fenstermaker Robert Alan
Published: June 2022

2037

Background: Newly diagnosed glioblastoma (nGBM) routinely treated with surgery, radiation, and temozolomide (TMZ), still result in early progression and near-universal lethality within 5 years. Tumor associated “survivin” is expressed in >95% of nGBM and targetable by SurVaxM immunotherapy. Results from the recently completed multi-center phase 2a trial of SurVaxM in nGBM are presented. Methods: nGBM patients (pts) were enrolled at 5 trial sites. Eligibility criteria included: age ≥ 18, Karnofsky performance status ≥70, IHC confirmation of survivin expression, expression of HLA-A*02, A*03, A*11 or A*24 MHC-I alleles and residual contrast enhancement of ≤1 cm3 by MRI within 72h post-resection. Pts received standard TMZ chemoradiation followed by initiation of 4 priming doses of SurVaxM (500 mcg in emulsion with Montanide ISA 51, every 2 weeks) with 100 mcg sargramostim. Maintenance doses of SurVaxM-Montanide plus sargramostim were thereafter administered every 12 weeks. Adjuvant TMZ was administered for at least 6 cycles, after at least the first dose of SurVaxM and beginning no sooner than 28 days after completion of chemoradiation. Pts were monitored by MRI every 8 weeks, and progression was assessed using modified RANO criteria. The primary endpoint was 70% progression free survival (PFS) at 6 mos. Primary analyses of median PFS (mPFS) and median overall survival (OS) were measured from first immunization. Safety, tolerability, and immune responsiveness were also determined. Results: 63 pts with nGBM were enrolled, comprised of 38 males and 25 females with a median age of 60 years. The cohort was consistent with the 4 commonly observed primary molecular GBM subtypes (classical, mesenchymal, neural and proneural). SurVaxM was well tolerated, with no serious adverse events. A strong positive correlation, accounting for censoring, was observed between PFS and OS of all pts (r = 0.79; 95% CI (0.66,0.87)). SurVaxM was immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers in both methylated and unmethylated MGMT pts and both groups showed clinical benefit. Conclusions: SurVaxM appeared to be safe and well-tolerated in pts with nGBM. SurVaxM was effective at stimulating survivin-specific immune responses and the primary endpoint was met. SurVaxM represents a promising therapy for nGBM, including for those pts with unmethylated MGMT genes. For pts treated with SurVaxM, PFS may be an acceptable surrogate for OS. Clinical trial information: NCT02455557. [Table: see text]
Phase I study of drug-resistant immunotherapy (DRI) with gene-modified autologous γδ T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).
Authors: Nabors Louis B. , Lobbous Mina , Lamb Lawrence S. , Rochlin Kate , Pillay Thriumaine , Youngblood Samantha , ter Haak Mariska , Goswami Trishna
Published: June 2022

2044

Background: γδ T cells, MHC unrestricted immune cells, target NKG2D ligands differentially expressed on tumor cells. DeltEx drug resistant immunotherapy (DRI), a novel ex vivo expanded, activated γδ T cell expresses MGMT, conveying TMZ resistance. NCT04165941 , a phase 1 trial assessing the safety of single and multiple infusions of autologous DeltEx DRI cells presents updated safety and efficacy data. Methods: Adult newly diagnosed GBM patients with adequate organ function and KPS≥70% are enrolled. Cells engineered from apheresis after tumor resection were infused through a Rickham catheter placed during surgery. Cohort (C) 1, 2 and 3 receive 1, 3 and 6 doses of cells respectively on day (D) 1 of each 28-day maintenance cycle. Patients receive 1 x 107 γδ T cells intratumorally on D1 with 150 mg/m2 of TMZ intravenously with the Stupp regimen. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade 3 cardiopulmonary or hepatic toxicity, grade 4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 12 patients (58% male; median age 66.5 (range: 21-76); 66.7% IDH-WT, 66.7% MGMT unmethylated) were enrolled with 6 dosed (3 in C1, 3 in C2). No patients had DLTs, cytokine release syndrome (CRS), or neurotoxicity. The most common adverse events (AEs) were Grade 1/2 events including fever, leukopenia, nausea, and vomiting attributable to TMZ or radiotherapy. One subject had Grade 3 treatment related AEs of UTI, dehydration, and thrombocytopenia. Three evaluable C1 patients have PFS of 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. In C2, three patients have been dosed, with one patient with stable disease at 8.2 months after receiving all three doses and no DLTs. Patient recruitment continues with anticipated completion in 2022. Conclusions: Data demonstrates that single, repeat doses of DRI T cells have manageable toxicity with encouraging trend in PFS.
Predicting CNS penetration of precision medicine therapies in oncology: A comparison of the CNS TAP tool and the BOILED-Egg computational model.
Authors: Walker Gianni , Franson Andrea Flynn , Pai Manjunath , Ravi Karthik , Roberts Holly , Schepers Allison , Koschmann Carl Johannes , Marini Bernard L.
Published: June 2022

2062

Background: The number of available targeted therapies has vastly expanded in recent years; however, only a selection of such therapies achieve adequate central nervous system (CNS) penetration. The CNS Targeted Agent Prediction (CNS TAP) Tool was developed to aid in the selection of precision medicine therapies based on preclinical data, clinical data, patient-specific genomic data, and importantly, optimal blood brain barrier penetration. Using a standardized murine pharmacokinetic (PK) model, we sought to determine the concordance of CNS penetration prediction by the CNS TAP Tool compared to the SwissADME BOILED-Egg computational model. Methods: Eleven drugs were chosen based on the most commonly altered and targeted pathways by our CNS tumor board. Mice were injected individually with the compounds of interest and sacrificed at four different time points to quantify drug concentration via LC-MS in brain tissue and blood samples for PK analyses (1,2,4,7 hours). The percent brain penetration (AUCbrain/plasma) was compared to published human phase I PK data and pathway IC-50 to determine if agents were adequately CNS penetrant. These results were compared against the CNS TAP Tool and BOILED-Egg prediction of CNS penetrance. Results: All 11 drugs chosen (Table) demonstrated adequate CNS penetration, suggesting likely CNS efficacy. The CNS TAP Tool correctly predicted 10/11 agents (91% concordance), the lone exception being panobinostat. In contrast, the BOILED-Egg model only successfully predicted 3/11 agents (27%). When restricting the analysis to drugs with >50% CNS penetration (ponatinib, panobinostat, and ONC-201), the BOILED-Egg model successfully predicted CNS penetration of all agents. Conclusions: The clinician-curated CNS TAP Tool more accurately predicted CNS penetration of precision medicine therapies than the BOILED-Egg computational model, which performed best for drugs that achieve extremely high CNS penetration. The resulting PK and CNS penetration data for all agents was utilized to update and refine the CNS TAP tool for future patient use. [Table: see text]
Risk factors for cranial irradiation-related late neurocognitive toxicity: A prospective cohort study.
Authors: Bhanja Debarati , Tuohy Kyle J. , Wilding Hannah E. , Aregawi Dawit , Glantz Michael J.
Published: June 2022

2066

Background: Neurocognitive dysfunction is a common complication of cranial irradiation, occurring in up to 50% of irradiated brain tumor patients. Symptoms often severely compromise quality of life long before patients succumb to their tumor; however, risk factors are poorly understood, and consequently, prognostication and prevention have not been possible. The objective of this study was to evaluate the prognostic value of vascular risk factors for the development of irradiation-related brain injury. Methods: This single-institution prospective cohort study included patients with malignant primary brain tumors who received cranial irradiation as part of their initial tumor-directed therapy. Three putative vascular risk factors – homocysteine, total cholesterol, apoprotein E genotype (ApOE) – were measured and dichotomized (above vs. below the laboratory normal). Univariate analyses compared each risk factor with four measures of neurocognitive dysfunction: mini-mental status exam (MMSE), MRI white matter changes at 6 months (MRI), physician (Phys) assessment, and patient (Pat) assessment. Decision analysis was used to construct a prediction algorithm. Results: 80 patients were included in this analysis. Elevated homocysteine was the most powerful and consistent predictor of neurocognitive toxicity, followed by elevated triglycerides and the ApOE genotype (Table). Logistic regression revealed a highly significant (p<0.01) association between homocysteine level and each of the four outcome variables. Decision tree analysis using homocysteine level (high vs. low) and ApoE genotype (yes vs. no) provided the most efficient predictive algorithm. Conclusions: Two putative vascular risk factors (homocysteine level > 14 and ApOE genotype) provide moderate ability to predict post-radiation neurocognitive dysfunction using a variety of simple but clinically meaningful definitions of dysfunction. This predictive algorithm should be validated in prospective trials. If these findings are corroborated, studies examining additional risk factors as well as studies looking at risk factor mitigation will be appropriate. [Table: see text]
Changes in circulating tumor DNA (ctDNA) and outcomes in solid tumors treated with immune checkpoint inhibitors (ICIs).
Authors: Al-Showbaki Laith , Iafolla Marco , Tamimi Faris , Molto Consolacion , Mittal Abhenil , Cescon David W. , Amir Eitan
Published: June 2022

2544

Background: Quantification of ctDNA levels can be a reliable prognostic tool in several malignancies. More recently, detection of genomic alterations in ctDNA have been validated as a predictive biomarker to guide treatment planning. Dynamic changes in ctDNA levels over time and in response to treatment may also provide prognostic information. However, less is known about the value of changes to ctDNA levels in response to immune checkpoint inhibitors (ICIs). Methods: We searched MEDLINE (host:PubMed) and reviewed trials exploring outcomes of patients with advanced solid tumors receiving ICIs in which outcomes were reported based on changes to ctDNA levels. ctDNA clearance was defined as reported in individual trials. Typically, this was defined as either >50% reduction or a reduction to undetectable levels. We extracted progression free survival (PFS) and/or overall survival (OS) values, related 95% Confidence intervals (CI) and/or p-values. Data were then included in a meta-analysis utilizing the generic inverse variance and random effects model. Variation in effect size was examined using random effects meta-regression analysis. Results: A total of 17 trials were included in the meta-analysis; ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. Method of detection included next generation sequencing and/or droplet digital polymerase chain reaction assays. Overall, low to undetectable ctDNA levels, measured 6-16 weeks after starting treatment was associated with significantly better PFS, (HR 0.20 95% CI, 0.14-0.28; p<0.001). Similarly, OS was superior in patients with substantially reduced or undetectable ctDNA levels after receiving ICIs, (HR 0.18, 95% CI, 0.12-0.26; p<0.001. The results were consistent across all disease sites, lines of treatment, level of change (undetectable vs. >50% reduction) and whether treatment exposure comprised single or multiple ICIs (see Table). Conclusions: In unselected advanced solid tumors, a substantial fall in ctDNA levels in response to ICIs is associated with substantial improvements in both PFS and OS. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs, or support treatment de-escalation strategies. Further research is needed to quantify variations in sensitivity between the available NGS assays, as well as differences discovery range between assay platforms. [Table: see text]
Baseline peripheral T-cell composition in relation to radiographic phenotypes of immune-related pneumonitis.
Authors: Henick Brian S. , Bukhari Shoiab , Winchester Robert , Lin Ziyan , Khodadad-Jamayran Alireza , Tsirigos Aristotelis , Lerrer Shalom S. , Adam Kieran , Salvatore Mary M. , Lagos Galina , Pabani Aliyah , Maniar Rohan , Reiner Steven L. , Dallos Matthew , Mathew Matthen , Rizvi Naiyer A. , Mor Adam
Published: June 2022

2545

Background: Pneumonitis is one of the most morbid complications from immune checkpoint inhibitor (ICI) treatment, but pathogenic mechanisms are unclear and no biomarkers permit pre-treatment risk assessment. We sought to characterize peripheral T cell subsets of pneumonitis patients on the single cell level. Methods: Blood was collected before and during ICI treatment in 24 patients. Cells were processed for single cell RNA sequencing (scRNAseq) employing CITEseq methodology using multiplexed cell surface markers labelled with a cocktail of oligonucleotide-tagged Total-Seq anti-human antibodies against CD4, CD8, CD45RA and CD27 followed by Chromium 10X sequencing. Principal Component Analysis was performed with iCellR, K-nearest-neighbor-based Network graph drawing Layout, and PhenoGraph clustering to assign cell types. CT scans were performed per standard of care and were reviewed by an experienced thoracic radiologist. Results: Seven of 24 patients developed pneumonitis; 9 did not experience an immune-related adverse event, and the remainder experienced arthritis (4), thyroiditis (3), or neurotoxicity (1). Pneumonitis patients had expanded proportions of TH2 TCF7+ T cells at baseline as compared to the other patients. Radiographically, two patients’ pneumonitis manifested as Chronic Hypersensitivity Pneumonitis (CHP), and four had Organized Pneumonia (OP). At baseline, CHP patients had significantly lower levels of CD8+ TCM cells (CXCR3+), double-positive T cells, gamma-delta T cells, and higher levels of naïve-like CD4+ TN TCF7+LEF1+ and CD4+ TH1/2 CXCR3+GATA3+ cells compared to OP. Gene expression levels also distinguished between these radiographic phenotypes. Conclusions: The peripheral T cell composition of patients who developed pneumonitis was distinct from those who did not in our cohort and unique by radiographic manifestation, suggesting potential pathogenic mechanisms and a prelude to circulating predictive markers of ICI toxicity.
LAG3 transcriptomic expression correlates with high levels of PD-1, PD-L1, PD-L2, and CTLA-4 checkpoints and with high tumor mutational burden across cancers.
Authors: Adashek Jacob J. , Kato Shumei , Pabla Sarabjot , Nesline Mary , Conroy Jeffrey M. , Subbiah Vivek , DePietro Paul , Kurzrock Razelle
Published: June 2022

2561

Background: Lymphocyte Activation Gene 3 (LAG3) or CD223 is an immune checkpoint that can be found on various T cells: CD4+, CD8+, regulatory T cells (Tregs), natural killer T cells, natural killer cells, and plasmacytoid dendritic cells. The expression of LAG3 molecule acts to increase T-cell exhaustion, leading to decreased tumor killing as well as an increase in immune suppressive cytokine release. Many clinical trials of LAG3 inhibitors have had modest effects, but recent data suggests that the LAG3 antibody relatlimab together with nivolumab (anti-PD1) provided greater benefit than nivolumab alone in patients with melanoma. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, OmniSeq (https://www.omniseq.com/). Following removal of germline variants, synonymous variants, indels and SNVs with < 5% VAF, TMB is reported as mutations/megabase. Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high LAG3 expression was calculated and Bonferroni corrected for multiple genes and cancer histologies with > 40 samples. Results: A total of 116 (22.6%) tumors had high LAG3 (≥75) across 32 different histologies. Cancers with the highest proportion of LAG3 were neuroendocrine (47%), uterine (43%), sarcoma (33%), breast (31%), ovarian (30%), pancreatic (24%), lung (20%), stomach (16%), and colorectal (15%). There was significant association for high LAG3 with high PD-L1 (adj P < 0.001), high PD-1 (adj P < 0.0014), high PD-L2 (adj P < 0.0014), high CTLA-4 (adj P < 0.0014), TMB ≥10 mt/mb (adj P = 0.0504). There was no significant association between histologies colorectal (adj P = 0.1834), breast (adj P = NS), ovarian (adj P = NS), pancreatic (adj P = NS), or gender (adj P = 0.272). Conclusions: High LAG3 was found in almost a quarter of tumor samples and significantly associated with other immune checkpoints with FDA-approved drugs. Ongoing studies combining LAG3 inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit if individualized immunomic transcript interrogation is undertaken, rather than population-based approaches without employment of rationally combined agents matched to each patient’s cancer.
A phase II study to evaluate the safety and efficacy of radiotherapy combined with irinotecan liposome followed by camrelizumab and apatinib for advanced solid tumors that failed standard treatments.
Authors: Shen Jie , Li Rutian , Yan Jing , Du Juan , Wei Jia , Zhu Sihui , Liu Ying , Li Huajun , Liu Baorui
Published: June 2022

2567

Background: Liposomes deliver the drug to tumors based on enhanced permeability and retention (EPR) effects. Radiotherapy further prompts the distribution of liposomal drugs to tumor sites receiving radiotherapy by altering the tumor microenvironment. In addition, radiotherapy might enhance systemic antitumoral responses to immunotherapy. Herein, we aimed to explore safety and efficacy of radiotherapy in combination with irinotecan liposome, immunotherapy, and antiangiogenic therapy in advanced solid tumors patients (pts) that failed standard treatments. Methods: Anopen single-arm, multi-center, phase II study was conducted to enroll solid tumors pts who have failed standard treatments. Eligible pts would receive radiotherapy combined with irinotecan liposome followed by camrelizumab and apatinib. Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Irinotecan liposome (80mg/m2 i.v.) was administered once within 48 hours after radiotherapy and followed by camrelizumab (200mg i.v. q3w) and apatinib (250mg po qd) until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) of the irradiated lesions evaluated by the investigators as per RECIST V1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse event (TRAE). Results: As of Dec 2021, 55 pts were enrolled includin 9 with biliary tract cancer, 8 with pancreatic cancer, 8 with sarcoma, 5 with lung cancer, 2 with liver cancer, 2 with cervical cancer, 2 with gastric cancer, and 22 with other cancer types. 26 (47.3%) pts failed at least 3 lines of therapy before enrollment. The median follow-up was 41 weeks and 42 pts can be evaluated. 15 partial response, 26 stable disease, and 1 progressive disease were achieved. The ORR and DCR of irradiated target lesions were 35.7% and 97.6%, respectively. The ORR and DCR of every cancer type are listed in table. TRAEs (all grades) occurred in 87.3% (48/55) pts. The most common grade 3-4 related TRAEs were lymphocyte count decreased (29.1%), white blood cell count decreased (10.9%), and anaemia (10.9%). Conclusions: The combination of radiotherapy, irinotecan liposome, camrelizumab, and apatinib demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors that failed standard treatments. Clinical trial information: NCT04569916. [Table: see text]