bluuebunny/crossref_metadata_2025 huggingface dataset:
Consensus on the utility of breast cancer multigene signatures in routine clinical practice: Results of the PROCURE Project.
Authors: Curigliano Giuseppe , Cardoso Fatima , Gnant Michael , Harbeck Nadia , King Judy W. , Laenkholm Anne-Vibeke , Penault Llorca Frederique , Prat Aleix
Published: June 2022

e13639

Background: Several Breast Cancer Multigene Signatures (BCMS) are available to profile early breast cancer (eBC) that according to current evidence, can provide reliable information on the risk of recurrence but the knowledge regarding their real use in clinical practice is scarce. The PROCURE Project aims to establish recommendations on the use of BCMS in clinical practice. Methods: A Scientific Committee consisting of 8 European experts in BC, including oncologists, pathologists, and surgeons, developed a Delphi questionnaire that was administered twice to clinicians across different European centers. The questionnaire included 5 sections: 1) Panelists’ profile and experience with BCMS, 2) Current clinical practice in eBC and use of BCMS, 3) Panelists’ opinion on the utility of the BCMS in eBC according to patient profiles, 4) Agreement with a set of recommendations on the use of BCMS in clinical practice and 5) Identification of unmet needs and future applications of BCMS. 70% agreement was used to determine consensus on a topic. Results: 133 panelists from 11 European countries completed both rounds of the survey. Most of the panelists worked in a teaching hospital (86.5%) and 72.2% of them were medical oncologists. 93.6% of the panelists used BCMS routinely or in selected patients and 73.4% had more than 5 years of experience using BCMS. According to panelists, for being useful in clinical practice BCMS should consider clinical and pathological features of the disease (91%). Additionally, BCMS must provide both, prognostic and predictive information (82%), and information on the risk of late distant recurrence from 5 to 10 years (74%), all based on prospective randomized clinical trials (85%). BCMS must also provide accurate results to guide adjuvant chemotherapy decision (81%). Regarding recommendations for improving BCMS utility, 76% of the panelists agreed that hospitals policies on the use of BCMS must be based on clinical practice guidelines. Panelists also agreed that patients should have the right to access their BCMS results to take part in the treatment decision (86%) and more training is needed for patients (79%) as well as oncologists (84%) and pathologists (82%). Finally, panelists mostly disagree on the fact that BCMS must be performed in all patients when BC is suspected (76%). Conclusions: The high degree of importance that panelists attributed to the fact that a BCMS should provide both prognostic and predictive information, reflects a misconception on the utility of BCMS as they are primarily prognostic tools but not predictive about the effect of a therapeutic intervention. Also, consensus reached on the need of providing risk of late recurrence from 5 to 10 years shows that panelists evaluate the long-term treatment even in the early setting.
Iron surveillance and management in gastrointestinal oncology patients: A national survey of physician practice.
Authors: Brezden Christine , Remtulla Tharani Alliya , Hrycyshyn Adriyan , Abbruzzino Alexandria , Smith Janet , Kachura Jacob , Sholzberg Michelle , Mosko Jeff , Chadi Sami A. , Burkes Ronald L.
Published: June 2022

e13644

Background: In 2018, there were an estimated 4.8 million new cases of gastrointestinal (GI) cancers worldwide and 3.4 million related deaths. Iron deficiency (ID) is a frequent complication of GI malignancy that eventually manifests as iron deficiency anemia (IDA). Early recognition and treatment of ID/IDA in GI oncology patients is an important aspect of care. Traditional serum ferritin monitoring and oral iron supplementation hold limited diagnostic and therapeutic value in this population as it may be falsely elevated and confounded by poor absorption and blood loss, respectively. Therefore, we conducted a survey of Canadian physicians to assess disparities in IDA surveillance and management practices in GI cancer patients. Methods: From February 2020 to September 2021, a 20-question electronic survey was sent to Canadian medical oncologists (MO), surgical oncologists (SO), and gastroenterologists (GE). The survey collected information on four domains: demographics, screening practices, treatment practices, and knowledge of the latest guidelines of ID/IDA. Analysis was conducted using descriptive statistics. Results: A total of 108 (55 GE, 19 SO, and 34 MO) of the 872 (12.4%) invited physicians completed the survey. A greater proportion of GE (70.9% compared to 36.8% of SO, and 26.5% of MO) measured baseline iron parameters. Of these, a slight trend of iron parameters were being measured mainly at initial consult (61.5% of GE, 85.7% of SO, and 44.4% of MO), with little continuing surveillance throughout treatment course. Most physicians who measured iron parameters relied on ferritin mainly (82.1% of GE, 100% of SO), while MO were evenly distributed in their evaluation of ferritin (88.9%), serum iron (100%), total iron binding capacity (100%) and iron saturation (88.9%). The majority supplemented iron if ID/IDA was identified prior to systemic/surgical oncologic treatment (94.2% of GE, 85.7% SO, and 66.7% of MO). Of these, parenteral iron was the preferred modality for SO (85.7%), while oral iron was preferred among GE (82.8%) and MO (55.6%). The majority of physicians (81.3%) were not aware of the ASH/ASCO guidelines regarding the use of erythropoiesis stimulating agents in conjunction with parenteral iron supplementation for treatment anemia in this setting (92% of GE, 66.7% of SO, and 80.9% of MO). Conclusions: Results from this Canadian survey suggests a disparity in practice pattern for IDA management between different specialties caring for GI oncology patients. Moreover, there appears to be a gap in knowledge and thus a gap in care surrounding evidence-based IDA management principles which may be contributing to poor clinical outcomes. Focused knowledge translation and exchange efforts are required to improve treatment of ID/IDA in patients with GI cancer nationally.
Meta-analysis and systematic review of the role of preemptive oral antibiotics and topical vitamin K for acneiform rash induced by EGFR-targeted therapies.
Authors: Costa Lima Andre Bacellar , Sasse Andre Deeke
Published: June 2022

e13646

Background: Acneiform rash (AR) is the most frequent adverse event associated with epidermal growth factor receptor (EGFR) inhibitors, which are widely used to fight solid tumors. Multiple trials studied prophylactic measures to help prevent the incidence and severity of this skin toxicity. The aim of this systematic review and meta-analysis (MA) was to analyze the clinical efficacy of the two most studied prevention strategies to mitigate the severity of skin rash induced by EGFR inhibitors. We sought to understand the current role of oral antibiotics and topical vitamin K in this scenario. Methods: A wide search through electronic databases and congress abstracts was performed. Studies with control groups reporting the pre-emptive role of both oral antibiotics and topical vitamin K were selected for two separate MA. Overall incidence and severity of AR were the analyzed dichotomous outcomes. Results: Fourteen studies (n=1085) were included in the antibiotics MA. Antibiotics prevented both moderate to severe (OR 0.38; CI 95% 0.24-0.60) and all-grade AR (OR 0.55; CI 95% 0.39-0.78). Four studies (n=507) were selected for the vitamin K MA. No benefit in the prevention of grade ≥ 2 AR was observed for this topic agent in the prophylactic setting (OR 1.21; CI 95% 0.79-1.85). Conclusions: There is still need to seek more efficacious ways to manage skin toxicities associated with EGFR inhibitors since this can impair quality of life and cancer treatment adherence. The use of oral antibiotics should be more encouraged as a prophylactic measure in the current guidelines.
A rare subtype of the glial tumor with H3F3B p.K28I in Chinese adult diffuse midline gliomas.
Authors: Ding Feng , Luo Ningning , Han Tiantian , Guo Didi , Lu Guanghua , Bu Fanfeng
Published: June 2022

e14012

Background: Diffuse midline gliomas (DMGs) with H3 K27 altered are extremely aggressive WHO grade IV tumors, with no significant therapeutic progress made in the past. DMGs with H3 K27 altered have been classified as a rare subtype of glial tumor according to 2021 WHO Classification of CNS Tumors. K27M mutation always occurs in the H3F3A gene or HISTIH3B/C gene, and the majority of DMGs harbor H3 K27M-mutation. Studies have been reported that systematic in vitro modification of the lysine 27 predicts K27I as the only substitution other than K27M to result in a repressive effect on H3K27me3. Herein, we reported two adult patients with DMGs harboring somatic H3-K27I mutation. It is important to identify H3 K27-mutation accurately for accurate diagnosis, prognostication, and also for treatment selection. Methods: Next-generation sequencing (NGS) 539-gene panel (Simceredx) profiling was performed using postoperative tissue. The molecular characteristics, K3 K27 mutation types, and other co-mutations were also evaluated. Results: Patient one was a 36-year-old female. Magnetic resonance images (MRI) of the brain were performed and showed the pons tumor in the brainstem. Postoperative pathology showed astrocytoma (WHO Grade II) with diffuse slightly dense cells. NGS results showed that the patient was carried H3F3B exon2 p.K27I (allele frequency, AF 57.64%), TP53 exon7 p.M237I (AF 80.27%). Patient two was a 44-year-old male and was diagnosed with spinal cord glioma, WHO grade III. NGS panel profiling was performed and H3F3B exon2 p.K27I (AF 30.46%), ATRX exon9 p.S1173* (AF 75.23%), KRAS exon2 p.G12A(AF 38.11%) and NF1 intron42 c.6580-1G > A(AF 36.44%) were identified. Conclusions: In our study, we identified the H3F3B K27I mutation in two adult DMG patients by NGS, which expanded the detection gene spectrum of DMG patients. The type of histone H3 mutated could also predict the outcome and accurate diagnosis and glioma grading of DMG patients, which was more efficient than clinical and radiological characteristics of the tumors. Accurate genetic testing should be given more attention to those patients.
FGL2 expression and relation with survival and prognosis in patients treated with concurrent temozolamide and radiotherapy in high-grade glioma.
Authors: Elnaggar Maha , Mohamed Mohamed Alaa , Makboul Rania , El Hakeem Ahmed A.S. , Abd El-Ghani Wael M.A. , Essam Sohaila Mohammed , Eid Samir-Shehata M.
Published: June 2022

e14019

Background: FGL2 is a member of the fibrinogen-related protein, Literature suggests that FGL2 contributes to the progression of glioblastoma multiforme (GBM) through inducing multiple immunosuppression mechanisms. The present study aimed at evaluation of the expression and the prognostic value of FGL2 in high grade glioma. Methods: In our study, we analysed sixty specimens retrieved at diagnosis of high grade glioma patients. They received concurrent Temozolamide and radiotherapy, as a standard of care, during the period from October 2019 to December 2020 and and were followed up for 12 months . Evaluation of FGL2 expression done by using FGL2 Immunohistochemistry .ClinicalTrials.gov Identifier: NCT04113278. Results: Mean age of studied patients was (48.88± 12.45) . Majority (75%) of patients were males. Mean FGL2 expression was 61 ± 31.80 (%) with range between 3% and 95%. It was found that 7 (11.7%) patients had negative FGL2. Over the period of follow up, incidence of disease progression was significantly higher among the patients with higher percentage of FGL2 in comparison to those with lower FGL2 percentages (76.54 ± 18.52 vs. 56.17 ± 33.41(%); P= 0.04). number of deaths was also significantly higher among the high FGL2 percentage group (64.86 ± 31.58 vs. 54.16 ± 31.71(%); P= 0.03). Intensity of FGL2 was mild 16 (26.7%), moderate 20 (33.3%) and strong 17 (28.3%) . Intensity of FGL2 was more among patients with disease progression. All patients with progression had either moderate intensity (46.2%) or strong intensity (53.8%). Seven (14.9%) patients without disease progression had negative FGL2 expression with ( P= 0.01). Disease free progression (DFP) was significantly negatively correlated with increasing in the intensity of FGL2. Patients with strong intensity had the lowest DFP (14 month) while patients with negative FGL2 and mild intensity had the highest DFP (25 month) with ( P <0.001). Overall survival was significantly worse with increasing in the intensity of FGL2 where patients with strong intensity had the lowest overall survival (19 month), while patients with negative FGL2 and mild intensity had the highest overall survival (27and 26 month, respectively) with ( P <0.001). For prediction of progression among patients with high grade glioma, FGL2 at cut off point > 60% has 92.3% sensitivity and 28% specificity with ( P= 0.04). For prediction of mortality among patients with high grade glioma, FGL2 at cut off point > 70% has 67% sensitivity and 61% specificity with ( P= 0.03). Conclusions: FGL2 expression in high grade glioma patients can be used as a prognostic factor but additional studies are required to clarify the prognostic value.
Comprehensive analysis of non-transplant central nervous system lymphoproliferative disease associated with immunosuppressant use.
Authors: Tadipatri Ramya , Ekhator Chukwuyem , Narayan Ram , Azadi Amir , Yuen Kevin C.J. , Grewal Jai , Fonkem Ekokobe
Published: June 2022

e14043

Background: Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens, with additional survival benefit gained by CD-20 targeting with rituximab. With increasing prevalence of autoimmune disease and a corresponding rapid rate of development and approval of new immunosuppressant medications, a new type of lymphoproliferative disorder (LPD) has been described, known as iatrogenic immunodeficiency associated LPD. These disorders are typically EBV positive and have distinct histologic and genetic features. Furthermore, many of them arise in the setting of prior methotrexate use, raising the question of whether standard HD-MTX based regimens would still be effective. Our objective was to further characterize this disorder, with a focus on cases with central nervous system involvement, and to determine the optimal management strategy. Methods: We describe a case of a 76-year-old female with iatrogenic immunodeficiency associated PCNSL following 10 years of mercaptopurine, which was successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency associated LPD involving the central nervous system (CNS). We used a linear probability statistical model to determine correlations with outcome. Results: While the majority of immunosuppressants were associated with EBV positive tumors, natalizumab was associated with EBV negative tumors (95% CI -0.951, -0.076), and EBV positive tumors were associated with improved outcomes (95% CI 0.074, 0.687). Surgical resection (95% CI 0.028, 0.574) was associated with improved outcomes, although limited by potential confounding effect. Although they did not reach statistical significance, antiviral treatment (95% CI -0.039, 0.459) and rituximab (95% CI -0.073, 0.524) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusions: Based on this data, we propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency associated LPD of the CNS. However, further study through randomized clinical trials is warranted.
Early safety and efficacy from a phase I open-label clinical study of LVGN7409 (CD40 agonist antibody) in patients with advanced or metastatic malignancies.
Authors: Fu Siqing , Vandross Andrae Lavon , Hsu Yi Hsin , Shi Naiyi , Jiang Lynn , Su Fusheng , Wang Jieyi , Chan C. Hubert
Published: June 2022

e14501

Background: LVGN7409 is a recombinant monoclonal antibody against CD40. The modified Fc fragment binds FcγRIIB selectively. LVGN7409 activates CD40 in Fc-FcγRIIB cross-link dependent manner and thus optimally in CD40 and FcγRIIB enriched tumor microenvironment. LVGN7409 demonstrated more robust antitumor efficacy and superior safety profile than published CD40 agonist antibodies in preclinical models. An open-label, first in human phase 1 study of LVGN7409 as a single agent, combined with LVGN3616 (anti-PD-1 antibody), and combined with LVGN3616 and LVGN6051 (CD137 agonist antibody) is ongoing. Methods: LVGN7409 was given intravenously every 3 weeks. For single agent dose-finding, LVGN7409 accelerated doses from 0.01 to 0.1mg/kg, and then conventional “3 + 3” design from 0.3 mg/kg. The objectives evaluate LVGN7409 safety, RP2D in a single agent and combination therapy, PK, immunogenicity, preliminary antitumor activity, and exploratory PD biomarkers. Results: As date on January 24, 2022, 12 patients (5 males, 7 females; median age 56, range 29-76; all ECOG 1 at screening; median 6 lines of prior therapies, range 2-14) have been treated with LVGN7409 monotherapy into 6 cohorts (0.01-0.03mg/kg n=1, 0.1-0.3mg/kg n=3, 1mg/kg n=6, 2mg/kg n=2). They received a median of 3 (range 1-10) treatment cycles. No DLT event was observed up to 2mg/kg of LVGN7409. Treatment-related adverse events (TRAEs) of any grade occurred in 10 out of 12 patients (n=10) including infusion related reaction (n=7), amylase increased (n=5), lipase increased (n=5), ALT increased (n=5), AST increased (n=5), bilirubin increased (n=1), WBC or neutrophil decreased (n=1), nausea (n=1), and cytokine release syndrome (n=1). Two patients experienced grade 3 TRSAEs: amylase/lipase increased (n=1) and ALT/AST increased (n=1). Most TRAEs were transient, asymptomatic, self-limited, and occurred in the initial cycle without recurrence upon rechallenge. Four of nine evaluable patients (44%) hadstabledisease by RECIST1.1 and iRECIST, with one active patient being treated for more than 8 months. CD40 receptor occupancy was achieved at the dose of 0.3 mg/kg and above; preliminary pharmacodynamic marker changes were observed. Conclusions: Preliminary evidence showed LVGN7409 monotherapy was well tolerated up to 2mg/kg. Approximately 44% of stable diseases were observed in these heavily treated patients. The favorable safety profile and preliminary antitumor activity warrant further evaluation of LVGN7409 as a single agent and in combination with other cancer therapeutics in patients with advanced malignancies. Clinical trial information: NCT04635995.
SNS-101, a highly selective monoclonal antibody against the active form of VISTA, demonstrates significantly reduced cytokine release.
Authors: van der Horst Edward , Jiang Zhi-Gang , Malhotra Kanam , Mukherjee Arnab , Biesova Zuzana , Cifuentes Anokhi , Thisted Thomas , Pierce Robert Hamilton , Martin Gaëlle , Thiam Kader
Published: June 2022

e14504

Background: Active cancer immunotherapeutics frequently give rise to immune-mediated adverse events (AEs), including cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). On-target, off-tumor activation of myeloid lineage cells (e.g. monocytes) has been implicated as a factor in the generation of these immune-mediated AEs. VISTA (V-domain Ig suppressor of T-cell activation) is an immune checkpoint, which is highly expressed on myeloid cells, and binds PSGL-1 on T-cells, but only when ‘activated’ by protonation at low pH (̃pH 6). Inhibition of the VISTA:PSGL-1 interaction in the acidic tumor microenvironment has been shown to be efficacious in multiple syngeneic murine tumor models. However, antibodies binding to VISTA at physiological pH 7.4 have significant potential to induce dose-limiting toxicities such as CRS and/or ICANS and be prematurely eliminated from circulation through targeted-mediated drug disposition (TMDD), reducing the likelihood of reaching efficacious drug occupancy levels. Among several non-pH-selective antibodies in clinical development, JNJ-61610588 (now CI-8993) induced dose-limiting on-target CRS at subtherapeutic dose levels and exhibited TMDD. To mitigate potential CRS and prevent TMDD, we developed SNS-101, a highly selective monoclonal IgG1 antibody for “active” VISTA, which inhibits the critical interaction with PSGL-1. Methods: Using flow cytometry at physiological pH, we compared SNS-101 with clinical stage non-pH-selective anti-VISTA antibodies and examined binding to VISTA-positive cell populations in human PBMCs as well as in human CD34+ cord blood cells reconstituted BRGSF-HIS mice (humanized BRGSF-HIS mice), which develop both human lymphoid and myeloid compartments. Furthermore, we performed in vitro and in vivo CRS studies in a HUVEC/PBMC co-culture system and humanized BRGSF-HIS mice, respectively. Results: Under physiological pH, non-pH-selective antibodies bound to monocytes, neutrophils and NK cells whereas SNS-101 did not exhibit any significant interactions. CRS assays indicate that the magnitude of induced cytokine levels was significantly higher with non-pH-selective antibodies compared to SNS-101. Conclusions: We assessed the binding profile of SNS-101 vs. non-pH-selective VISTA antibodies. Our results demonstrate that SNS-101 does not bind to VISTA-positive cells in circulating blood. In addition, in vitro and in vivo CRS studies suggest that SNS-101 has a lower risk of inducing CRS compared to non-pH selective anti-VISTA antibodies, alleviating liabilities previously associated with anti-VISTA antibodies. IND-enabling studies, including pharmacokinetic and toxicology studies, are ongoing.
Characteristics of CRC01, an investigational CD19 CAR-T product with PD-1 and TIGIT genes silenced by shRNAs.
Authors: Park YoungSam , Jeon Dong-Hyuk , Yi Hyunhwan , Lee Sang-Hoon , Kim Hyung Cheol
Published: June 2022

e14514

Background: Currently, CAR-T therapy has been successful in the treatment of certain types of hematological malignancy. However, not all patients benefit from this novel therapy due to various resistance mechanisms, such as suppression of immune cell function by inhibitory immune checkpoint signaling. To overcome this, we have developed a novel two-in-one lentiviral vector system that can efficiently induce shRNA-based silencing of PD-1 and TIGIT genes in CAR-T cells while maintaining robust CAR expression. This PD-1 and TIGIT-silenced CD19 CAR-T, CRC01, showed an enhanced anti-tumor activity in vitro and in vivo, compared to conventional CD19 CAR-T. For the development of CRC01 as an investigational new drug, IND-enabling non-clinical studies have been conducted and CRC01 is currently being evaluated in a clinical trial for r/r LBCL patients (NCT04836507). Methods: T cells were enriched from leukapheresis products of r/r LBCL patients and transduced with the two-in-one lentiviral vector. Transduced T cells were expanded within a semi-closed culture system and formulated for cryopreservation. For phase I clinical trial of CRC01, ten batches of CRC01 were manufactured and characterized in quality. Results: In the manufacturing of ten batches of CRC01, manufacturing time was in the range of 8-14 days and total cells expanded 32-53 folds. In the final product of CRC01, T cell percentage (Live CD3+) and viability were not less than 98% and 85%, respectively. The range of transduction efficiency was 11.3%-28.6% and the range of vector copy number was 1.0-3.5 copies/CAR-T. Generally, CRC01(CAR-positive T cells) showed higher CD4/CD8 ratio than leukapheresis product and CAR-negative T cells, and central memory and effector memory T cell subsets were the main populations of CRC01. All batches of CRC01 released IFN-γ in response to CD19-expressing target cells, but the level of IFN-γ production was quite different from batch to batch. When PD-1 and TIGIT expression levels of CRC01 were analyzed after CD3/CD28 stimulation, CAR-positive T cells were found to express PD-1 and TIGIT much lower than CAR-negative T cells, demonstrating an efficient silencing of PD-1 and TIGIT genes in CRC01. Conclusions: Ten batches of CRC01 were manufactured in GMP facility for CRC01 phase I clinical trial. All batches met acceptance criteria for release, showing that CRC01 manufacturing process is a robust one and that silencing of PD-1 and TIGIT genes via shRNAs, a unique feature of CRC01, was successfully implemented in the investigational products.
Extracorporeal microchannel device to capture and eliminate circulating tumor cells from cancer patient’s blood.
Authors: Khandare Jayant , D'Souza Alain , Arora Smriti , Singh Balram , Aland Gourishankar , Kale Narendra , Gore Isha , Deshmukh Arnav , Kamble Rick , Jadhav Vikas , Chaturvedi Pankaj ,   Actorius Innovations and Research
Published: June 2022

e14522

Background: Metastatic progression accounts for nearly 90% of cancer-related deaths and has been directly correlated with the presence of circulating tumor cells (CTCs) in numerous carcinomas including breast, lung, ovarian, colorectal, and head and neck cancers. The removal of CTCs from cancer patient’s blood is directly implicated with reduction of extravasation and disease invasiveness to secondary organs. Methods: We designed and printed 3 Dimensional (3D) microchannel devices using biocompatible polymer and packed it with anti-EpCAM (EpCAM) mediated glass-based (G) compositions (G-EpCAM). The computational fluid dynamic (CFD) analysis simulation was explored to optimize the hemodynamic effect of the G-EpCAM device for measuring the pressure and velocity difference for blood along the spiral flow microchannels. Red blood cell (RBC) hemolysis was estimated using G-EpCAM compositions packed in a device to determine optimal biocompatibility. We assessed cancer cell lines (breast cancer MCF7, lung cancer A549) interactions and capture with varying incubation time points, effect of anti-EpCAM concentrations, number of G-EpCAMs, and series of devices. We evaluated G-EpCAM-on-device’s CTC capture capability and biocompatibility using head and neck, colorectal, lung, and ductal breast cancer patient’s blood samples. All G-EpCAM captured CTCs were immuno-stained for cytokeratin 18 (CK18) expression and the optimal fluorescence acquisition intensity was quantified. Results: Extracorporeal G-EpCAM microchannel device was 3D printed and consisted of interlocking top lid and bottom base with inlet and outlet channels. The path length of the spiral device consisted of 20 microchannels with 6.0-feet length. Device accommodated 28 gm of non-hemolytic G-EpCAM compositions. CFD analysis showed 3.8 mm as the ideal channel diameter and 2mm as the superlative G-EpCAM diameter for maximal cells and CTC capture with minimal blood hemolysis (less than 1%) as compared to control. Series 1 and 2 device indicated 90% and 85% cell capture efficiency, respectively using G-EpCAM devices indicating highest interactions and efficiency with cells. Conversely, the first device in series captured the highest cells. In addition, the efficiency improved as the number of G-EpCAM compositions was increased. We accounted device to capture CTCs with specificity having G-EpCAM composition and observed no hemolysis and non-specific interactions with other blood cells like RBCs or leukocytes. Conclusions: Continuous CTC removal from cancer patient’s blood circulation using such device offers promising therapeutic utility in stemming aggressive metastatic invasion and progression for improving the overall survival of epithelial origin cancer patients. Clinical trial information: CTRI U1111/1192-3951.
Immune response during regional chemotherapy.
Authors: Aigner Kornelia , Drothler Stephan , Aigner Karl R. , Aigner Karl R.
Published: June 2022

e14537

Background: Regional chemotherapy is known to yield high drug concentrations in the treated tumor area while keeping systemic drug concentrations low. Regional Chemotherapy can be performed as an intra arterial infusion or isolated perfusion. Known perfusion techniques are isolated limb perfusion, hypoxic pelvic perfusion, hypoxic abdominal perfusion, upper abdominal perfusion, and isolated thoracic perfusion, Only little is known on the effect of chemotherapy on immune cells, especially not if chemotherapy is applied regionally. Since more and more immuno oncologic treatment possibilities arise, that often are combined with chemotherapy, knowledge on the effects on immune cells is crucial. Since systemic chemotherapy often decreases the number of immune cells in general, the more targeted approach of regional chemotherapy is investigated in this study. Methods: In this work, we investigate subpopulations of T-lymphocytes, Natural Killer cells and B-lymphocytes during regional chemotherapy and report on their changes after cycles of intra-arterial chemotherapy infusion followed by chemofiltration. Surface phenotyping of cells from EDTA blood was performed with combinations of monoclonal antibodies (anti- CD3,CD16, CD56, CD45, CD4, CD19, CD8, CD28, HLA-DR, CD39, CD25, CD127, CD45RA, CD45RO) for FACS analysis. 58 Patients with advanced breast cancer, ovarian cancer, head and neck cancer, lung cancer, or bladder cancer received regional chemotherapy as an intra arterial infusion therapy or an isolated perfusion therapy. Results: Contrary to the mild immune cell depletion during the first two cycles a more activated immune status is seen after treatment cycle three. Non-significant increase or stable numbers are observed for T-Lymphocytes and its subsets of CD4+ T-helper cells, CD8+ cytotoxic T-cells, and terminal memory T-cells (CD8+/CD28-/CD57+). Significant increase of cell numbers is observed for B-lymphocytes, regulative CD8+ T-cells (CD8+/CD28-/CD57-), activated HLA-DR+ T cells, and Natural Killer cells while regulative CD4+ T cells are significantly decreased. Conclusions: The data show that regional chemotherapy has controversial effects on the immune cell subpopulations. As every chemotherapy, it does affect immune cells, however to a limited extend, but importantly has an activating potential. Immune activation prevalently takes place after the third cycle of therapy which might be a hint for auto-vaccination caused by phases of repeated tumor necrosis after locally high drug concentrations. Finding the optimal dosage of chemotherapeutics may be crucial to balance direct tumor response, immune toxicity and immune activation.
Analysis of phase I clinical trials (Ph1-CT) new enrollment patterns in the immuno-oncology era.
Authors: Erasun Lecuona Carlos , Soto Juan José , Llop Serna Sandra , Mulet Margalef Nuria , Stradella Agostina , Villanueva Rafael , Calvo Campos Mariona , Jove Casulleras Maria , Cuadra Amor Carmen , Salazar Soler Ramon , Gil-Martin Marta , Oliva Marc , Martin-Liberal Juan
Published: June 2022

e14549

Background: Immuno-Oncology (IO) has revolutionized anticancer therapeutics and changed the early drug development paradigm. Positive results and limited access to IO drugs in some countries have led to increased enrollment in IO Ph1-CT at an earlier timepoint in patients (pts) disease journey. We evaluated the impact of IO era on enrollment patterns in Ph1-CT. Methods: We retrospectively reviewed pts with recurrent/metastatic solid tumors enrolled in Ph1-CT from January 2018 to June 2021 at the Phase 1 Unit of Catalan Institute of Oncology (ICO), Barcelona, Spain. The primary goal was to assess Ph1-CT enrollment patterns, including use of molecular pre-screening/personalized drug matching, and the availability of alternative standard of care (SOC). Overall response rate (ORR) was assessed according to RECIST 1.1. Clinical benefit rate (CBR) was defined as complete/partial response+stable disease for ≥6 months. Median progression-free survival (mPFS) and overall survival (mOS) using Kaplan-Meier method were provided. Results: A total of 175 pts were enrolled in Ph1-CT. Median age was 54 years (range 43-75), Male:Female = 99:76, 99% had ECOG 0-1. The most prevalent tumors were: 32 (18%) breast, 31 (18%) colorectal, 25 (14%) urogenital and 23 (13%) glioblastoma multiforme. One hundred forty-six (83%) pts were enrolled in Ph1-CT with IO (alone or in combination) and 29 (17%) pts with targeted therapy (TT). Molecular pre-screening tests were required in 24 (14%) pts (22 pts IO vs 2 pts TT trial). Eleven (42%) pts were pre-screening failures. Screening failure (SF) rate was 19%, the main reason being clinical worsening for 7 (4%) pts. Thirty-three (19%) pts had an alternative SOC treatment available at time of enrollment. One hundred two (58%) pts had received ≤1 prior lines and 26 (89%) were IO-naïve. Finally, 129 (74%) out of 175 pts enrolled were treated within Ph1-CT. Out of 129 treated pts, ORR was achieved in 18 (14%) pts (3% complete response) and 44 (34%) had stable disease. CBR was observed in 36 (28%) pts. mPFS was 2.8 months and mOS was 10.9 months. Toxicity grade 3-4 occurred in 25 (19%) of pts and 6 (5%) pts had to interrupt treatment. Seventy-one (55%) pts received subsequent therapies: 22 (17%) in Ph1-CT; 49 (38%) SOC. Eleven (9%) pts received IO as subsequent therapy. Decline in ECOG status (baseline vs end of treatment) occurred in 65 (50%) pts. Conclusions: In our cohort of Ph1CT pts, there has been an increasing number of pts enrolled in IO trials compared to TT. Most pts received treatment within Ph1-CT at an earlier timepoint in the course of their disease (1st or 2nd lines). Our results suggest a clear impact of the IO era on the trends of Ph1-CT availability and enrollment patterns.
A phase 1 study of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, in patients with advanced solid tumors.
Authors: Ho Ching-Liang , Chao Tsu-Yi , Chang Chia lun , Lin Hsuan-Yu , Yang Futang , Wang Qingyu , Zhu Jun
Published: June 2022

e14560

Background: Serplulimab, a novel humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T cells and showed anti-tumor activity in several xenograft models. This phase 1 study was designed to assess the safety and tolerability of serplulimab in patients with metastatic or recurrent solid tumors. Methods: This prospective, open-label, two-cohort (dose-finding cohort [up to 30 patients]; dose expansion cohort [up to 27 patients]) phase 1 study was conducted in patients with metastatic or recurrent solid tumors who had failed standard therapy. In the dose-finding cohort, Bayesian optimal interval (BOIN) design was adopted to explore the MTD of serplulimab. Patients were administered serplulimab (Q2W) at doses of 0.3, 1, 3, or 10 mg/kg via intravenous infusion until disease progression, the maximum of 1 year, withdrawal from the study, or death, whichever occurred first. In the dose expansion cohort, nine eligible patients were enrolled in each dose group to receive fixed doses of serplulimab at 200 (Q2W), 300 (Q3W) or 400 mg (Q4W). The primary objective of this study was to identify the safety profile and the MTD of serplulimab. The PK profile and the preliminary efficacy were also examined as secondary objectives. Results: Here we only report the results from the dose-finding cohort. As of July 27, 2020, 29 patients were enrolled and treated with at least one dose of serplulimab (0.3 mg/kg group, n = 3; 1 mg/kg group, n = 4; 3 mg/kg group, n = 6; 10 mg/kg group, n = 16). At baseline, the mean age of enrolled patients was 60.0 years, with a mean BMI of 24.7 kg/m2, a mean BSA of 1.7 m2, and a mean LVEF of 67.1%. All patients presented with stage IV tumors at baseline, among whom 79.3% were diagnosed with metastatic disease. Only one patient in the 3 mg/kg dose group experienced DLTs, which was reported during the first cycle. The MTD was not determined yet. Overall, 28 (96.6%) patients experienced at least one TEAE during the study, mostly of grade 1 or 2. No notable differences were observed among the dose groups with regard to the incidence of TEAEs. The most frequently reported TEAEs was decreased appetite (41.4%), fatigue (31.0%), nausea (27.6%), pyrexia (27.6%), and pleural effusion (27.6%). Minimal accumulation of serplulimab was observed following multiple dose administrations. The preliminary anti-tumor efficacy of serplulimab was demonstrated by a DCR of 60.0%, an ORR of 8.0%, and a median PFS of 107.0 days. Conclusions: In summary, serplulimab up to 10 mg/kg was well tolerated and showed promising anti-tumor activity in patients with metastatic or recurrent solid tumors. Serplulimab is currently being investigated in phase 3 studies among patients with NSCLC, SCLC, esophageal cancer, mCRC, etc. Clinical trial information: NCT03468751.
Solid tumor patients with G12V and G13D KRAS aberrations have poor survival following ICI treatment.
Authors: Jung Jaeyun , Park Sehhoon , Lee Jeeyun , Kim Seung
Published: June 2022

e14567

Background: KRAS gene has been well known as a dominant oncogene which activates downstream signaling for tumor growth. The new therapeutic drug targeting specific KRAS mutation (G12C) has been developed and several clinical trials are testing KRAS inhibitors in solid tumor patients. In line with this, we have surveyed the prevalence and clinical features of solid tumor patients with KRAS aberration in 1,744 oncology patients who received next generation sequencing (NGS) in a clinical practice. Methods: Between 2019 amd 2021, 1,744 oncology patients have received NGS (TruSight Oncology 500 panel; 523 genes) at Samsung Medical Center. . Matched clinical and histology outcomes including programmed cell death-ligand 1 (PD-L1) 22C3 expression (n = 798) and immunotherapy treatment outcomes (n = 409) were analyzed based on genomic alteration. Results: Among the thirty-three different cancer types, the most common cancer types were colorectal cancer (CRC) (N = 547, 31.4%), followed by gastric cancer (GC) (N = 381, 21.8%), and sarcoma (N = 155, 8.9%). Of 1,744 patients, any KRAS aberrations (CNVs, SNVs) were detected in 487 (27.9%) patients (CNV: Copy Number Variation, SNV: Small Nucleotide Variation). Of the 51 (2.9%) patients with KRAS amplification, 18 (35.3%) patients were CRC followed by GC (N = 9, 17.6%). Each 4 cases were found in Cholangiocarcinoma (CCC), sarcoma, melanoma and pancreatic cancer (8%, respectively). Copy number of KRAS were distributed from 4 to over 50, while bladder cancer had the highest median value of copy number(median: 148), followed by CCC(median: 16.2). Of 454 SNV cases, the most frequent cancer type was CRC (N = 259, 57.0%) and pancreatic cancer (N = 89, 19.6%). Except 4 cases, all SNV mutation type was missense mutation. G12D amino acid change was the most frequent(N = 182), followed by G12V(N = 100), G13D(N = 48), and G12C(N = 20). However, only the patients with G12V and G13D mutation had significantly shorter OS and PFS in ICI treatment. Conclusions: Based on our comprehensive survey of next generation sequencing focused on KRAS aberration, we identified approximately 2.9% KRAS amplification and 26.0% KRAS SNV in patients with metastatic solid tumors. It was demonstrated that G12V, G13D were important mutations which were related to the response to ICI treatment in real-world data.[Table: see text]
Slit mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Bao Aihua , Zhao Lele , Chen Dong-sheng , Li Si , Yu Yangyang , Xiao Mingzhe , Qi Chuang
Published: June 2022

e14572

Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlyingpredictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Slits (Slit1, 2 and 3) are highly conserved secreted glycoproteins that play important roles in tumorigenesis, including cancer cell proliferation, motility and angiogenesis. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between SLIT and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between SLIT gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with SLIT mutation were significantly associated with better PFS (HR = 0.27; 95% CI, 0.14-0.52; P < 0.001), objective response rate (ORR, 63.3% vs 25.2%; P < 0.001) and durable clinical benefit (DCB, 86.7% vs 63.0%; P = 0.048) after ICIs therapy, compared with those with wide-type SLIT. SLIT mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between SLIT mutation and PFS remained significant (HR = 0.38; 95% CI, 0.19-0.77; P = 0.007). In contrast, no association between SLIT mutation and OS (LUAD: P = 0.57 ; LUSC: P= 0.1) or PFS (LUAD: P = 0.71; LUSC: P = 0.55) was observed in TCGA datasets, suggesting that SLIT mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, SLIT mutation was significantly associated with higher naive B cell, plasma B cell, activated memory CD4+ T cell, CD8+ T cell, as well as lower M2 macrophage and Treg cell. Moreover, SLIT mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. In addition, GSEA analysis revealed that SLIT mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway and activation of NF-κB in B-cell. Conclusions: Our results demonstrated that SLIT mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of SLIT in immunotherapy is needed to be further studied.
The utilization of artificial intelligence to produce clinically relevant scores on PD-L1 immunostained non-small cell lung cancer biopsies.
Authors: Mehra Navi , Patel Bhavika , Allen Stephanie , Talwalkar Sameer S. , Thagaard Jeppe , Ramsing Thomas W. , Overgaard Agnete , Caldara Jeni
Published: June 2022

e14576

Background: Immunotherapies targeting complex programmed death-ligand 1 (PD-L1) interactions have been groundbreaking in the treatment of non-small cell lung cancer (NSCLC), offering new strategies for patients who are likely to respond. PD-L1 binds to the checkpoint PD-1 to regulate T cells, which has an important role in boosting the immune response. Identifying patients who may benefit from PD-L1 focused care is dependent on the interpretation of the drug’s associated companion diagnostic (CDx) immunohistochemistry (IHC) assay. PD-L1 IHC assays stratify NSCLC patients using a Tumor Proportion Score (TPS), a manual scoring paradigm which must be applied by a clinical pathologist. Application of the score is complex as it requires the reader to visually exclude stromal and tumor-infiltrating immune cells across a full sample, retaining PD-L1 expression information for true tumor cells only. Methods: In this study, we utilized the PD-L1 [28-8] immunohistochemistry (IHC) assay to stain 10 NCSLC specimens. Stained slides were then imaged using the AT2 scanner (Leica Biosystems, Buffalo Grove, IL) scanner and analyzed using the Visiopharm Image Analysis platform. Results: The intricacy of TPS application is time consuming for the pathologist and introduces opportunity for inter- and intra-reader variability. Our novel image analysis approach utilizes artificial intelligence (AI) to automatically denote tumor nests and exclude tumor-infiltrating immune cells. The remaining true tumor cells may then be quantified for PD-L1 expression across the full biopsy, producing a TPS for each sample. Conclusions: This method allows for great accuracy and time-efficiency in providing a TPS than traditional methods, which may result in improved patient care.
Comprehensive characterization and functional implications of mesenchymal stem cell-related genes in pancancer: A new horizon for immunotherapy.
Authors: Tang Chaozhi , Ma Jiakang , Wang Xueting , Lei Fang , Lu Kaining , Zhang Wentao , Zhu Yuyan , Yao Xudong , Yang Bin
Published: June 2022

e14577

Background: Accumulated evidence demonstrates that mesenchymal stem cells (MSCs) contribute to tissue regeneration, tumor progression, chemotherapy resistance, and mediate tumor immune escape by modulating the stroma and immunity of the tumor microenvironment. However, little is known about the role of MSCs in cancer patients receiving immunotherapy. Therefore, we investigated the comprehensive characterization of MSC-related genes and their functional implications in pan-cancer immunotherapy. Methods: We performed a pan-cancer analysis of 59 MSC-related genes, which was used to calculate an MSC score with single sample gene set enrichment analysis. Multivariate Cox regression analysis was performed to identify a potential independent prognostic marker for cancer. TIDE algorithm and neural network were utilized to assess the predictive accuracy of MSC-related genes for immunotherapy. Results: MSC-related gene expression showed significant differences inconsistently between normal and tumor samples across the 33 cancer types (p < 0.05). Cox regression analysis suggested that the MSC score is an independent prognostic marker for papillary renal cell carcinoma (TCGA; OS, RFS and DSS, all p < 0.05), mesothelioma (TCGA and GSE29354, OS, all p < 0.05), glioma (TCGA and GSE107850, OS, all p < 0.05), and stomach adenocarcinoma (TCGA, GSE84437, GSE15459, GSE13861 and GSE62254, OS; GSE13861 and GSE62254, RFS; all p < 0.05). The abundance of fibroblasts was also more representative of the MSC score compared to the stromal score. Samples with a high MSC score were predicted to have low responsiveness to immunotherapy, which was validated across seven immune checkpoint therapy datasets (IMvigor210, 27.52% (low) vs 18.12% (high); GSE78220, 64.28% (low) vs 42.86% (high); GSE135222, 30.77% (low) vs 28.57% (high); GSE165252, 36.11% (low) vs 28.57% (high); GSE79671; 38.89% (low) vs 33.33% (high); PRJEB25780, 45.45% (low) vs 8.70% (high); GSE176307, 22.22% (low) vs 13.64% (high)). TIDE algorithm and Neural network demonstrated a good predictive accuracy of MSC-related genes for immunotherapy (CESC, COAD, DLBC, GBM, KIRC, LAML, LIHC, LUAD, LUSC, MESO, OV, PCPG, PRAD, SARC, SKCM, THCA, UCEC, and UCS; all ROC ≥0.9). Conclusions: We characterized the MSC-related genes across multiple cancer types and highlighted their potential as a predictive biomarker for immunotherapy response and prognosis. A prospective clinical trial is warranted to confirm these findings.