tbuckley/cabot-search huggingface dataset:
OS06.2A Local immunotherapy of glioblastoma via AAV-mediated gene transfer of checkpoint inhibitors in combination with CAR-NK cells
Authors: M I Strecker, K Wlotzka, F Strassheimer, J Reul, P N Harter, T Tonn, J P Steinbach, W S Wels, C J Buchholz, M C Burger
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GB) is the most common primary brain tumor which is characterized by low immunogenicity of tumor cells and prevalent immunosuppression in the tumor microenvironment (TME). Since expression of PD-L1 on GB cells has been described, immunotherapy with checkpoint inhibitors (CIs) may be a promising approach for GB treatment. However, systemic administration of CIs bears the risk of autoimmune-like side effects, while the intratumoral drug concentration reached may not be sufficient. METHODS We studied delivery of CIs through targeted Adeno-associated viral vectors (AAVs) encoding an anti PD-1 immunoadhesin (aPD-1) as a novel approach towards local immunotherapy in the syngeneic GL261-HER2 glioma model. Tumor cell-specific delivery was achieved by targeting HER2 via a specific designed ankyrin repeat protein (DARPin). We investigated the effects of this strategy alone and in combination with local injection of HER2-specific CAR-NK cells (NK-92/5.28.z), which have already shown efficacy in preclinical GB models and are currently under investigation in the CAR2BRAIN phase I clinical trial. Furthermore, aPD-1 functionality and cellular response to viral transduction as well as compatibility of both therapy approaches has been evaluated in various in vitro models. RESULTS HER2-AAV transduction efficacy of GB cells correlated with HER2 expression level, while target cells did not show anti-viral responses upon transduction. After transduction with aPD-1 HER2-AAVs, aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T-cells due to PD-1 blockade. AAV-transduction did not interfere with CAR-NK cell mediated tumor cell lysis. Biodistribution studies in mice revealed the presence of aPD-1 up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 tumors, local treatment with HER2-AAVaPD-1 or HER2-AAVIgG-Fc+ NK-92/5.28.z therapy had no significant effect, whereas combination therapy profoundly delayed tumor growth. CONCLUSIONS Local therapy with aPD-1 encoding HER2-AAVs in combination with NK-92/5.28.z cells is a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce side effects.
OS05.8.A A Phase 0/1 ‘Trigger’ Trial of Ribociclib Plus Everolimus in Recurrent High-Grade Glioma
Authors: N Sanai, A Tien, J Jiang, Y Chang, C Pennington-Krygier, A DeSantis, Y Fujita, S Kim, J Li, S Mehta
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients. MATERIAL AND METHODS Eligible patients had recurrent HGG with (1) intact RB expression, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of presurgical ribociclib (400mg QD) plus everolimus (2.5mg QD) and then underwent tumor resection at 2, 8 or 24 hours following the last dose. Five subsequent dose-escalation cohorts each enrolled three additional patients, reaching a maximum dose-level of ribociclib (600mg QD) plus everolimus (60mg QW). Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects, including RB and S6 phosphorylation, were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration &amp;gt; 5-fold biochemical IC50) and a PD ‘trigger’ (&amp;gt;30% decrease in both pRB and pS6) were set for each drug. Gd-nonenhancing tissue exhibiting both PK and PD effects in excess of these thresholds qualified patients for postoperative combination therapy. RESULTS 21 patients with WHO Grade III (n=2) and WHO Grade IV (n=19) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM (i.e., &amp;gt; 5-fold biochemical IC50 for CDK4/6 inhibition), whereas the unbound everolimus tumor concentrations in all patients were below the lower limit of quantitation (i.e., &amp;lt; 0.2 nM). The median total concentrations of everolimus in tumors at dose-levels 0 to 5 were 2.9, 8.8, 10.3, 5.0, 15.7, and 13.7 nM, respectively. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor, consistent with the observed tumor PD effects. Everolimus exhibits very limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.
Racial disparities in comprehensive biomarker testing and clinical trial enrollment among patients with metastatic colorectal cancer (mCRC).
Authors: Lisa M. Hess, Debora S. Bruno, Xiaohong Li, Eric Wen Su, Monaliben Patel
Journal: Journal of Clinical Oncology (2021)

125 Background: Racial disparities may exist at many levels in the health care system; in oncology, yet little is known about racial disparities in biomarker testing and clinical trial enrollment among patients with mCRC. This study was designed to explore racial differences in comprehensive biomarker testing and clinical trial enrollment in the US using a large real-world database. Methods: This retrospective observational study utilized the Flatiron Health electronic health records database, which includes longitudinal data from patients diagnosed with mCRC. Patients with mCRC were eligible for this study if they had evidence of systemic therapy from 1/1/2017 through 10/30/2020 and were alive for at least 120 days after metastatic diagnosis. Unadjusted analyses summarized differences in biomarker testing and clinical trial enrollment between White and Black race, adjusted regression analyses were conducted using all baseline variables as covariates. These data are de-identified and are not considered human subjects research in accordance with the US Code of Federal Regulations (45 CFR Part 46). Results: A total of 7,879 patients were eligible: 4,803 (61.0%) were White and 838 (10.6%) were Black. Comprehensive testing by next-generation sequencing (NGS) was received by 51.6% and 41.8% of patients who were White and Black, respectively (p &lt; 0.0001). There was no significant difference in clinical trial participation across all lines of therapy (2.9%, White and 2.9% Black). There was a statistically significant relationship between NGS-based testing and clinical trial enrollment (p &lt; 0.0001), however, race was not identified a moderating factor in this relationship in adjusted regression analyses. The receipt of molecularly-targeted therapy was comparable between both races (11.9% and 9.7% for White and Black, respectively; p = 0.06). Patients received FOLFOX+bevacizumab most commonly in the first line (34.3% White; 40.5% Black), all other regimens were within 2 percentage points between racial groups. Targeted agents were each used by less than 7.4% of the study population. Conclusions: The use of NGS-based testing is significantly different by race in this database. The significant relationship between NGS testing and clinical trial enrollment at any time in the database did not appear to be moderated by race; however, descriptive analyses suggest that the ongoing analyses by line of therapy and considering timing of testing may better quantify these relationships. These data may not be generalizable to the entire US population as they are obtained from a single database that is limited to practices using this EHR system.
The Safety of Bridging Radiation with Anti-BCMA CAR T-Cell Therapy for Multiple Myeloma
Authors: Shwetha H. Manjunath, Adam D. Cohen, Simon F. Lacey, Megan M. Davis, Alfred L. Garfall, J. Joseph Melenhorst, Russell Maxwell, W. Tristram Arscott, Amit Maity, Joshua A. Jones, John P. Plastaras, Edward A. Stadtmauer, Bruce L. Levine, Carl H. June, Michael C. Milone, Ima Paydar
Journal: Clinical Cancer Research (2021)

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells (CART-BCMA) are a promising treatment for relapsed/refractory multiple myeloma (r/rMM). We evaluated the safety and feasibility of bridging radiation (RT) in subjects treated on a phase I trial of CART-BCMA.Twenty-five r/rMM subjects were treated in three cohorts with two doses of CART-BCMA cells ± cyclophosphamide. We retrospectively analyzed toxicity, response, and CART manufacturing data based on RT receipt.Thirteen subjects received no RT <1 year before CART infusion (Group A). Eight subjects received RT <1 year before CART infusion (Group B) with median time from RT to apheresis of 114 days (range 40-301). Four subjects received bridging-RT (Group C) with a median dose of 22 Gy and time from RT to infusion of 25 days (range 18-35). Group C had qualitatively lower rates of grade 4 (G4) hematologic toxicities (25%) versus A (61.5%) and B (62.5%). G3-4 neurotoxicity occurred in 7.7%, 25%, and 25% in Group A, B, and C, respectively. G3-4 cytokine release syndrome was observed in 38.5%, 25%, and 25% in Group A, B, and C, respectively. Partial response or better was observed in 54%, 38%, and 50% of Group A, B, and C, respectively. RT administered <1 year (P = 0.002) and <100 days (P = 0.069) before apheresis was associated with lower in vitro proliferation during manufacturing; however, in vivo CART-BCMA expansion appeared similar across groups.Bridging-RT appeared safe and feasible with CART-BCMA therapy in our r/rMM patients, though larger future studies are needed to draw definitive conclusions.
Improving Prediction of Risk for the Development of Type 1 Diabetes—Insights From Populations at High Risk
Authors: Diane K. Wherrett
Journal: Diabetes Care (2021)

Prevention of type 1 diabetes has been brought closer to reality through the ability to identify populations at increased risk and through therapies that can modify the disease course (1). Identification of those who are at risk is based on the detection of diabetes-related autoantibodies (Ab) that can be found many years before clinical diagnosis. Those identified as being at increased risk due to having a family member who lives with type 1 diabetes or who have an increased genetic risk based on high-risk HLA have been followed in a number of longitudinal cohort studies (2–8) The preclinical phase of type 1 diabetes is described as progression from genetic susceptibility and immune activation to the development of single and then multiple Ab, to early abnormalities of glucose tolerance, and finally to clinical diabetes (9). Those who are found to have multiple Ab almost inevitably progress to diabetes (10). However, the time from detection of multiple Ab to diagnosis varies widely. To move the goal of the prevention of type 1 diabetes from research to clinical reality, refinements of strategies to predict progression to diabetes are needed. Anand et al. (11) and Bonifacio et al. (12), in two articles in this issue of Diabetes Care , help to define characteristics of Ab development and diabetes progression in >24,000 children at risk.

The work by Anand et al. brings together data from five cohorts with a focus on the risk associated with the age at autoantibody (Ab) development, the number of Ab, and the HLA-DR-DQ genotype. The >16,000 children in these cohorts came from Germany, Sweden, Finland, Washington state, and Colorado and were tested for Ab before the age of 2.5 years and then followed …
Adoption of telemedicine (Telemed) by medical oncologists/hematologists (mO/H) during the COVID-19 pandemic.
Authors: Yolaine Jeune-Smith, Gorica Malisanovic, Bruce A. Feinberg, Ajeet Gajra
Journal: Journal of Clinical Oncology (2021)

285 Background: The COVID-19 pandemic has dramatically impacted access to and delivery of healthcare in the U.S. At the height of the pandemic, many practices began initiating or increasing telemed visits to meet care demands in a quarantined environment. The objective of this descriptive study was to assess mO/H perceptions of benefits and barriers to current and post-pandemic use of telemed in oncology. Methods: Web-based surveys were fielded to mO/H before virtual meetings held between September and November 2020. Participants submitted their demographic information and responses to questions about pandemic impacts on their practice and patients. Responses were aggregated and analyzed using descriptive statistics. Results: A total of 259 mO/H across the U.S. completed the survey; 73% practice in a community setting; 44% identify as hospital employees. The participants spend a median of 90% of their working time in direct patient care, have a median of 18 years of clinical experience, and see a median of 20 patients per day on clinic days. Before the pandemic, 92% of the participants’ practices had telemed capabilities but of those, 77% were not utilizing telemed for any visits. During the pandemic, almost all the participants’ practices were offering telemed, with 97% reporting some patient visits being conducted via telemed. Most (78%) anticipate continuing to offer or conduct some patient visits via telemed. Two-thirds stated that up to 25% of their patient visits could be converted to telemed outside of a pandemic environment. The types of visits that most believe are suitable for telemed include reviewing test/lab results, routine surveillance of chronic conditions, and survivorship care visits. Most (60%) stated that their patients view telemed favorably. About half reported a positive overall experience with telemed, with 47% reporting a better-than-expected experience. Most (79%) estimated that pivoting to telemed equates to a revenue loss of up to 50% for that visit; 53% feel that telemed has had an overall negative financial impact on their practice. Two-thirds have experienced challenges getting reimbursed for telemed claims. The most common challenges with telemed reported were reluctance or inability of patients to participate in telemed (39%) and technology challenges (37%). The most common benefit of telemed reported was safety, i.e., less potential exposure to COVID-19 for providers and staff (65%). Conclusions: Telemed use was infrequent before the pandemic, but utilization has dramatically increased during the pandemic. Despite favorable experiences with telemed, mO/H expect telemed use to decline significantly post-pandemic. This prediction may be driven by the perceived loss of revenue when an in-person visit is converted to telemed visit. Further research is needed in identifying factors that may allow for the long-term adoption of telemed for appropriate patients.
Immune status in hematological cancer patients after covid19
Authors: I. Kamaeva, I. Lysenko, N. Nikolaeva, A. Sagakyants, E. Bondarenko, O. Shulgina, E. Kapuza, T. Pushkareva, O. Kit, A. Velichko, Y. Gaysultanova
Journal: HemaSphere (2021)

Background: Patients with immunosuppression, including those with hematologic cancers, are at greater risk of developing SARS-CoV infection. The virus is capable of infecting monocytes, macrophages and dendritic cells in order to promote the secretion of cytokines, and IL-6 can contribute to the excessive activation of the effects of the acquired immune system (usually lymphocytes) and innate immunity (neutrophils, monocytes, NK cells, etc.). Aims: The purpose of the study was an assessment of the immune status of patients with hematological cancers after multi-course chemotherapy, therapy with anti-CD20+ antibodies and PCR-confirmed COVID19. Methods: The study included12 adult patients with lymphoproliferative diseases with a history of PCR-confirmed COVID-19. All patients underwent 4 to 6 chemotherapy cycles. The BD FACSCanto II flow cytometer with Becton Dickinson reagents were used to assess the immune status of patients. The research group consisted of patients with non-Hodgkin's large B-cell lymphomas. The blood plasma taken into a vacuum system with K2EDTA as an anticoagulant was used. The relative and absolute numbers of the main populations of T- and B-lymphocytes, the immunoregulatory index, and subpopulations of T-lymphocytes were assessed. Results: Most patients showed a decrease in the relative number of lymphocytes, on average by 73%. The absolute and relative numbers of monocytes in half of the cases exceeded the norm or were similar to it. The immunoregulatory index in most cases (N=7) was decreased on average by 42%, compared to the norm. The absolute number of T-lymphocytes (CD3+) in 6 patients decreased on average by 42%±0.6. The population of T-helpers (CD3+CD4+) in 5 patients was reduced by an average of 44%±0.8. The number of double-positive (CD3+CD4+CD8+) T-lymphocytes in most cases (N=10) was reduced by 80%±0.8. At the same time, the number of double-negative (CD3+CD4-CD8-) T-lymphocytes increased by177% in 7 patients. All patients showed a decrease in the B-cell immunity component. The relative number of B-lymphocytes (CD19+) was decreased on average by 78%, absolute number by 61%. The increase in all types of memory cells, both helper-inducer and cytotoxic populations, was registered. Summary/Conclusion: Conclusions. Elevated numbers of various memory cells, together with a decrease in T-lymphocytes, could indicate the activation of the cellular adaptive immunity. A decrease in B-lymphocytes could indicate a decrease in the activity of the humoral component of adaptive immunity. The latter could also be a result of multi-course chemotherapy with anti-CD20+ monoclonal antibodies.
Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy – results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial
Authors: S. Peters, J.-L. Pujol, U. Dafni, M. Dómine, S. Popat, M. Reck, J. Andrade, A. Becker, D. Moro-Sibilot, A. Curioni-Fontecedro, O. Molinier, K. Nackaerts, A. Insa Mollá, R. Gervais, G. López Vivanco, J. Madelaine, J. Mazieres, M. Faehling, F. Griesinger, M. Majem, J.L. González Larriba, M. Provencio Pulla, K. Vervita, H. Roschitzki-Voser, B. Ruepp, P. Mitchell, R.A. Stahel, C. Le Pechoux, D. De Ruysscher, R. Stahel, A. Hiltbrunner, M. Pardo-Contreras, A. Gasca-Ruchti, N. Giacomelli, R. Kammler, N. Marti, R. Pfister, A.C. Piguet, S. Roux, S. Troesch, M. Schneider, R. Schweri, I. Zigomo, Z. Tsourti, P. Zygoura, S. Tsouprou, M. Kassapian, K. Vervita, G. Dimopoulou, C. Andriakopoulou, F. Morin, E. Amour, G. Mariaule, N. Archirel, M. Fernandez, E. Pereira, L. Benito, K. Lopez, A. Hernández, S. Chinchen, H. Jurkovic, A. Livingstone, J. Mitchell, M. Walker, P. Mitchell, S. Ng, C. Steer, K. Briscoe, A. Saqib, E. Abdi, B. Houghton, K. O’Byrne, B.R. Chittajallu, B.G. Hughes, A. Black, K. Nackaerts, H. Werner, R. Gervais, G. Zalcman, F. Vaylet, P. Merle, I. Monnet, D. Moro-Sibilot, O. Molinier, N. Girard, P.-J. Souquet, F. Barlesi, D. Debieuvre, H. Senellart, M. Poudenx, A. Dixmier, D. Pouessel, J. Cadranel, H. Lena, E. Quoix, S. Friard, C. Audigier-Valette, J. Mazieres, E. Pichon, M. Faehling, K. Kokowski, H. Kirchen, F. Griesinger, A. Tufman, C. De-Colle, J. de Langen, J.L. González Larriba, A. Insa, M. Majem, B. Massutí, M.P. Pulla, S.P. Aix, N. Villanueva, G.L. Vivanco, J. Andrade, A. Curioni-Fontecedro, K. Franks, R. Califano
Journal: Annals of Oncology (2021)
Implementation of ePROs in the care of long-term cancer survivors.
Authors: Guadalupe R. Palos, Katherine Ramsey Gilmore, Patricia Hansberry Chapman, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2021)

334 Background: Standard methods for implementation of electronic patient reported outcomes (ePROs) in the routine care of cancer survivors remain unclear. To address this gap, we assessed the technical and operational feasibility of implementing ePROs into the clinical workflow of four survivorship clinics, Genitourinary (GU), Head &amp; Neck (HN), Thyroid (THY), and Stem Cell Transplant (SCT). Methods: This quality improvement study was conducted from 9/1/2019 to 4/30/2021. Benchmarks of ≥ 50% were established for two outcomes including: (1) Delivery Rate - percentage of patients who received the ePRO prior to their clinic visit and (2) Adherence Rate - percentage of patients who completed one ePRO. Data were collected at T0 (Baseline) (09/01/2019 to 12/31/2020) and T1 (1/1/2021 to 4/30/2021). Patients completed the survey 3-7 days prior to a clinic visit. The timing to capture ePROs’ data was tailored to the specific cancer site. Operational steps were: 1) questionnaire was ordered for scheduled survivorship appointment; 2) electronic medical record system (EMRS) pushed the questionnaire to the patient portal app with a message asking the patient to complete and submit the ePROs survey, 3) data was pushed back to the provider by the EMRS; and 4) results stored in the medical record were accessed by the provider prior to or on the day of the patient’s visit. Data were collected and stored using the EPIC Data Universes and reported through Microsoft Power BI. This institutional Quality Improvement Assessment Board approved this study. Results: The Table shows the improvement in the benchmark for sent and adherence rates between T0 and T1. A few clinics showed room for improvement. Patient engagement facilitators included being scheduled for a virtual visit and having staff sent prompts prior to visits. Challenges were: (1) variation in the time ePROs were available in the medical records, 2) inconsistent linking of scheduled visits and prompt to send the survey, and 3) patients’ not opening, completing, or submitting the survey even when prompted to do so. Opportunities included (1) developing a patient education flyer describing ePROs’ role in patient care, (2) providing instruction on the completion and completion of how to complete the ePRO, and (3) conducting staff education sessions on how to link scheduled visits with ePROs’ patient prompts. Conclusions: Our preliminary results indicate that integration ePROs can be considered an acceptable approach to improve follow-up care of cancer survivors but with room for improvement in some clinics. Future evaluation will further explore patients’ ePROs’ impact on clinical outcomes and patient engagement.[Table: see text]
Reply to Laurence Klotz’s Letter to the Editor re: Jeremy Yuen-Chun Teoh, Daniele Castellani, Claudia Mercader, et al. A Quantitative Analysis Investigating the Prevalence of “Manels” in Major Urology Meetings. Eur Urol 2021;80:442–9
Authors: Jeremy Yuen-Chun Teoh, Declan G. Murphy, Inge M. van Oort, Stacy Loeb, Maria J. Ribal
Journal: European Urology (2021)