bluuebunny/crossref_metadata_2025_split huggingface dataset:
STRIvE-01: Phase I study of EGFR806 CAR T-cell immunotherapy for recurrent/refractory solid tumors in children and young adults.
Authors: Albert Catherine Michelle , Pinto Navin R. , Taylor Mallory , Wilson Ashley , Rawlings-Rhea Stephanie , Mgebroff Stephanie , Brown Christopher , Lindgren Catherine , Huang Wenjun , Seidel Kristy , Narayanaswany Prabha , Wu Vicky , Rudzinski Erin R. , Vitanza Nicholas A. , Gust Juliane , Gardner Rebecca Alice , Jensen Michael C. , Park Julie R. 
Published: June 2022

2541 Background: The epidermal growth factor receptor (EGFR) is a cell surface tyrosine kinase receptor associated with cell proliferation and differentiation. EGFR expression and activating mutations are associated with aggressive neoplastic disease, chemotherapy resistance, and increased metastatic potential. Published data and EGFR immunohistochemistry (IHC) performed on tissue microarrays indicate that 15-40% of pediatric solid tumors (ST) express EGFR. The unique EGFR monoclonal antibody (mAb) 806 selectively binds to an epitope that is conformationally hidden when EGFR is tethered but revealed when tethering is perturbed as occurs with EGFR overexpression, truncation, or through extra-cellular domain missense mutations. Methods: Children and young adults (CYA) with EGFR-expressing recurrent/refractory (R/R) ST were enrolled on a Phase 1 trial to examine the safety and feasibility of administering autologous chimeric antigen receptor (CAR) T cells derived from autologous T cells genetically modified to express a second generation EGFR806-specific scFV-IgG4hinge-CD28tm/cyto-4-1-BB-zeta and EGFRt tracking/suicide contract. All subjects received lymphodepleting chemotherapy with fludarabine and cyclophosphamide prior to the administration of cryopreserved CAR T cells a the prescribed dose level. The biologically effective dose (BED) or maximum tolerated dose was determined based upon observed toxicity through day 28 from initial CAR-T infusion and using a 3+3 statistical design. Results: Eleven subjects (n=10 evaluable, age range 9-25, median 18) were enrolled and received either dose level (DL) 1 (0.5 x 106 CAR-T/kg, n=4) or DL2 (1 x 106 CAR-T cells/kg, n=7). CAR T were manufactured successfully in all subjects. Most common toxicities were fatigue, tumor-related pain and cytokine release syndrome (n=2, maximum CTCAE grade 1). Dose limiting toxicity of CTCAE grade 4 transaminase level and hyperbilirubinemia occurred at DL2 (n=1). Maximum circulating CAR-T expansion was 29.66 cells/uL (range 0.05-29.66 cells/uL) with median persistence of 28 days (range 0-90). Two subjects on DL1 and one subject on DL2 demonstrated mixed response on day 28 and tolerated additional CAR T infusion without dose limiting toxicity. Conclusions: EGFR806 directed CAR-T cells have an acceptable toxicity profile in CYA with R/RST and demonstrate anti-tumor activity in some patients. Additional analyses are ongoing to identify biomarkers of response and toxicity. Clinical trial information: NCT03618381.
Pharmacogenomic prediction of immune-related adverse events from immune checkpoint inhibitors among Asian patients.
Authors: Huang Yiqing , Aminkeng Folefac , Wong Alvin S.C. , Tay Sen Hee , Zhao Joseph J , Ang Yvonne , Soo Ross A. , Goh Boon Cher 
Published: June 2022

2547 Background: Immune checkpoint inhibitors (ICIs) have ushered in a unique entity known as immune-related adverse events (IrAEs) that can be debilitating and challenging for physicians. Given that genomic variation underlies both disease susceptibility and drug response, there is reasonable cause to believe that genomic markers are predictive of IrAEs. We perform a pioneering pharmacogenomic study to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: Since March 2018, we recruited cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital. IrAEs were clinical characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed using SVS/HelixTree. Genetic association was performed by logistic regression. Bonferroni corrected P < 7.1E-08 was considered statistically significant. Results: We conducted a pilot pharmacogenomic genome-wide association study (GWAS) on 307 patients of Asian Ancestry. Median age was 62. Majority were male (68.1%), Chinese (75.9%), ECOG PS 0-1 (91.6%), stage IV cancer at diagnosis (64.6%). Non-small cell lung cancer (36.2%), renal cell carcinoma (12.4%) and hepatocellular carcinoma (7.2%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, atezolizumab and durvalumab, respectively (44.6%, 26.1%, 10.1% and 10.1% respectively). Nine percent of patients received dual ICIs concurrently. Median duration of treatment was 152 days and median follow up was 212 days. IrAEs were seen in 50.5% of patients. Skin (21.8%), endocrine (6.8%) and hepatotoxicity (5.9%) were the most common IrAEs. Eight percent of patients had CTCAEv5 grade ≥3 toxicity, of which hepatotoxicity (2.6%), skin (1.6%) and pulmonary toxicities (1.3%) were the most common. A preliminary pharmacogenomic investigation revealed one potential novel genetic locus associated with IrAEs: LOC105373202 rs5915369; Unadjusted P= 6.6E-08, OR (95%CI) = 27.8 (3.7-206.5), minor allele = A, 10.7% in cases vs 0.4% in controls. We also identified an additional 3 independent SNPs (rs167609, rs2341687, DMDrs5928214) with nominal significance (7.1E-0-8≤ P< 5.0E-7). Conclusions: This pilot pharmacogenomics GWAS uncovered 4 potential novel genetic loci predictive of IrAEs from ICIs amongst Asian patients. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing to identify specific genomic biomarkers that predispose individual patients to IrAEs.
Network analysis to determine association between immuno-related toxicities and immune soluble profile in patients treated with anti–PD-1.
Authors: Botticelli Andrea , Cirillo Alessio , Pomati Giulia , Cortesi Enrico , Rossi Ernesto , Schinzari Giovanni , Tortora Giampaolo , Tomao Silverio , Nuti Marianna , Fiscon Giulia , Farina Lorenzo , Pisegna Simona , Ciurluini Fabio , Chiavassa Antonella , Amirhassankhani Sasan , Di Filippo Alessandra , Zizzari Ilaria , Mezi Silvia , Marchetti Paolo 
Published: June 2022

2553 Background: Immune checkpoint inhibitors (ICIs) have peculiar, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies by ICI class, administered dose and treatment schedule. The aim of the study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods: A prospective, multicenter study evaluating the IP of 79 patients with advanced cancer, treated with anti-PD-1drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. IDO levels were evaluated through a modified liquid chromatography–tandem mass spectrometry. Data were first pre-processed by performing logarithmic transformation and Shapiro-Wilk-test. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (23%). A positive and statistically significant correlation between the cumulative toxicity and IP10 and IL8, sLAG3, sPDL-2 sHEVM, sCD137, sCD27 and sICAM1 was found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern characterized by disruption of most of the paired connections between cytokines (all the connections of the cytokine IL8, most of the connections between the pro-inflammatory chemokines, or all the connections of CD137, CD27, and CD28), while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients with toxicity. Conclusions: A peculiar pattern of immune dysregulation in patients who develop irAEs was defined. This immune serological profile could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.
Characterization of tumor antigen expression and myeloid immune profiles to inform the development of immune stimulating antibody conjugates (ISACs).
Authors: Blum Lisa K. , Ptacek Jason , LeBlanc Heidi , Mallet William G. , Hug Bruce A. , Alonso Michael N. , Perez Edith A. , Dornan David , Kowanetz Marcin 
Published: June 2022

2557 Background: Immuno-oncology (IO) has historically focused on T cell-driven effects, but a growing class of myeloid therapies are under investigation. This class includes immune-stimulating antibody conjugates (ISACs), which comprise a tumor-targeting antibody conjugated to an immune-stimulating payload. ISACs may require both tumor-associated antigens and tumor-resident myeloid cells for activity. As new IO strategies such as TLR-activating ISACs are developed, understanding the myeloid landscape is relevant for cancer biology and drug development. Methods: Tumor microarrays with formalin-fixed paraffin embedded sections of breast (BC), colorectal (CRC), gastric (GC), head and neck squamous cell (HNSCC), and non-small cell lung (NSCLC) cancers were analyzed by immunohistochemistry for tumor antigens (HER2, CEA, PD-L1), myeloid cell markers (CD68/CD163/CD11c/BDCA2), and CD8+ T cells. Results: Tumor infiltrating myeloid cells and CD8+ T cells varied across indications (Table). Low densities of intra-tumoral CD8+ T cells (<100/mm2) were observed in CRC, with higher CD8+ T cell counts observed in other cohorts. In contrast to T cells, substantial myeloid infiltrates were observed across tumor types. While MSI status was associated with higher CD8+ T cell infiltration in CRC, myeloid cells were abundant in both MSI and MSS samples. Monocyte-derived (mDC) and conventional DCs (cDC), which respond strongly to TLR activation, were present in all indications, with highest numbers observed in NSCLC. HER2+ BC samples had high infiltration of plasmacytoid DCs, a key TLR7-responsive population. PD-L1 expression on immune cells was associated with higher CD8+ T cell and myeloid cell numbers. In contrast to HER2 and PD-L1, CEA expression was independent of immune infiltration. Conclusions: Abundant myeloid infiltrates were observed across solid tumors, independent of T-cell infiltration. The presence of myeloid cells in multiple tumor types offers broadscale therapeutic targets for ISACs and other myeloid-directed therapies that can activate the innate immune system as a bridge to adaptive immunity.[Table: see text]
Exploiting GLAAD molecules to drive an antitumor immune response in a colorectal cancer mouse model.
Authors: Adesokan Yemi , Spalinger Marianne Rebecca , Wyss Romain , Miao Yong , Scharl Michael 
Published: June 2022

2565 Background: Only a minority of colorectal cancer (CRC) patients benefit from immune checkpoint inhibitors (ICI), with less than half of eligible patients responding to the treatment. Abnormal glycosylation of tumor cells is a signature of cancer development. Here, we described novel immunomodulatory molecules, named GLAAD (glycopeptides with adjuvant and tumor-associated antigen delivery). We hypothesized that GLAAD, by sharing similarities with aberrant glycans expressed in many cancers, may be a safe and effective treatment strategy to promote response and overcome resistance to ICI, thus addressing an urgent clinical need. Using a CRC mouse model, we tested whether two GLAAD candidates reduce tumor burden when orally administered alone or in combination with ICI. Methods: C57/BL6J mice were supplemented with 3% GNU-201 or 3% GNU-101 in the drinking water starting 14 days prior to tumor cell injection (d-14), while control mice received normal drinking water. On day 0, all mice were injected subcutaneously with MC38 CRC cells in each flank. On days 6, 9, 12, and 15, mice in each group received anti-PD1 antibody (aPD1) or an isotype control. Tumor size was measured every 3rd day. On day 18, the mice were sacrificed. Results: The aPD1 therapy alone showed a limited anti-tumor efficacy overall. Groups treated with GNU-201, GNU-101, GNU-201+aPD1 or GNU-101+aPD1 exhibited reduced growth, resulting in a significantly reduced tumor volume vs control on day 18. In contrast, GLAAD candidates alone significantly reduced tumor volume compared with control and led to a numerically larger decrease than aPD1 treatment alone, suggesting a higher efficacy. When analyzing tumor infiltrating myeloid cells on day 18, no differences were seen for neutrophils or dendritic cells but the proportion of macrophages was decreased in mice receiving GNU-201 or GNU-101. GNU-101 resulted in reduced serum levels of IL-10, a molecule participating in the suppression of antitumor immune responses. The tested GLAAD candidates stimulated robust anti-tumor T cell responses. GNU-201 and GNU-101 supplementation alone or in combination with aPD1 increased the proportion of T cells and among those CD8+ T cells, IFNγ producing CD4+ T cells, IFNγ+ and perforin+ CD8+ T cells. GNU-101 and GNU-201 elicited memory T cell responses after priming of the mice, measured as the ex vivo recall response (CD69 expression) of CD8+ T cells isolated from the tumor. Conclusions: GNU-201 and GNU-101 as standalone treatment induce a strong anti-tumor response that is as good as or even better than aPD1 alone. The therapeutic efficacy is associated with increased tumor infiltration and activation of T cells, in particular CD8+ T cells, highlighting the role of these GLAAD candidates as potent adjuvants in supporting specific tumor-associated antigen recognition by the immune system.
Safety results of Q-1802, a Claudin18.2/PD-L1 bsABs, in patients with relapsed or refractory solid tumors in a phase 1 study.
Authors: Gong Jifang , Shen Lin , Hou Jie , Chen Xiaohua , Yu Qin , Zheng Ying , Wang Yakun , Zhang Jian , Qu Xiangdong , Lu Qiying , Du Yejie , Pan Qin , Xu Wencheng 
Published: June 2022

2568 Background: Q-1802 is a humanized bispecific antibody that targets both the tumor -specific antigen CLDN18.2 and the immune checkpoint PD-L1. Methods: This is a first-in-human, phase 1a/1b, multicenter, dose escalation and dose expansion study of Q-1802 administered intravenously to adult pts with resistant/refractory advanced or metastatic solid tumors who had failed standard therapies. Monotherapy of Q-1802 was conducted in 20-30 enrolled subjects. In the dose escalation phase (phase 1a), an accelerated titration followed by a 3+3 design was used to assess the safety and tolerability of Q-1802 monotherapy (dose range 0.1 mg/kg to 20 mg/kg); and determine the maximum tolerated dose (MTD). Q-1802 was administered Q3w on a 21-day treatment cycle and dose limiting toxicity (DLT) observation period. Tumor assessments per RECIST v1.1 were performed once every 6 weeks (2 cycles). Q-1802 PK and PD analyses were performed. Results: As of Jan 20, 2022, a total of 9 patients (median age 57y; most patients received ≥3 prior regimens) were enrolled in phase 1a with DLT evaluation of the 20 mg/kg cohort currently in progress. The most common tumor types were GI cancers. There were no DLTs up to 10 mg/kg of Q-1802, inclusive. Phase 1a with DLT evaluation of the 20 mg/kg cohort currently in progress. The most common treatment related adverse events (TRAEs) were Gastrointestinal AE (66.7%, 6/9), including nausea 6/9 (66.7%), vomiting 5/9 (55.6%), abdominal pain 2/9 (22.2%) and diarrhea 2/9 (22.2%). The second common TRAEs were IRR (infusion related reaction) (33.3%, 3/9), including Fatigue 3/9 (33.3%), Fever 2/9 (22.2%), Chill 2/9 (22.2%), face pain 1/9 (11.1%). There was G1/2 except for one patient experienced a G3 skin rash, and one patient reported with a G3 Gastrointestinal AE. Two SAEs (G2 fever and G3 Gastrointestinal AE) were reported, both were considered as possibly related to study drug, but recovered shortly. No death reported due to study related treatment. Safety evaluation of the 20 mg/kg dose level is in progress. One Gastric cancer patient (moderate CLDN18.2 expression at baseline) with prior heavily treatment observed clinical benefit and response with Non-CR/Non-PD at first tumor assessment at dose of 10mg/kg and continues the therapy. Q-1802 drug exposure increased with increasing dose. The elimination of Q-1802 appears to follow first-order elimination kinetics. Conclusions: Q-1802 bsABs has presented safe and well-tolerated profile up to doses of 10 mg/kg. The dose escalation is still in progress. Clinical trial information: NCT04856150.
Safety and tolerability of T-SIGn vectors when administered using “flat” versus “low-high-high” (LHH) dosing regimens.
Authors: Lillie Thomas , Rosen Lee S. , Krige David , Patel Minesh , Prieto González-Albo Isabel , Carter Jo , Ravanfar Behnaz , Evilevitch Vladimir , Naing Aung 
Published: June 2022

2572 Background: Tumor-selective viruses, particularly those dosed systemically to deliver transgenes, are potentially powerful cancer therapies. However, acute cytokine reactions to viral particle (vp) infusion may affect vector tolerability [Small 2006], thereby limiting the maximum tolerated dose (MTD) and subsequent transgene delivery. T-SIGn vectors (e.g. NG-641 and NG-350A) are transgene-armed variants of the epithelial tumor-selective adenovirus enadenotucirev (EnAd). Acute serum cytokine increases post-dosing have been seen at the MTD of EnAd (“flat” dosing of 3 x 1012 vp on Days [D] 1, 3 and 5) [Machiels 2019]. Following supportive preclinical data [McElwaine-Johnn 2019], we explored if a LHH dosing regimen, in which a lower dose is given on D1 prior to two higher doses on D3 and 5, may improve vector safety/tolerability thereby allowing higher cumulative doses to be given. Methods: Data were pooled from three Phase 1 dose-escalation studies in advanced/metastatic epithelial cancer: SPICE (EnAd + pembrolizumab/nivolumab; NCT02636036), FORTITUDE (NG-350A ± pembrolizumab; NCT03852511) and STAR (NG-641; NCT04053283). Serum cytokines were measured using a 17-analyte Luminex assay. IL-6/MCP-1 data for D1, 3 and 5 (pre- and 6-10 hrs post-dose) were analyzed to examine acute cytokine changes. TNFα/IFNγ were examined due to their association with cytokine release syndrome (CRS). Samples analyzed from SPICE/FORTITUDE were taken before PD-1 inhibitor administration. Results: 84 patients (SPICE n=51; FORTITUDE n=18; STAR n=15) were included in these analyses; 79 had cytokine data. AEs and Gr≥3 AEs within 1 wk of first dose, and DLTs at any time, were less frequent with a LHH vs flat dosing regimen (Tbl). Importantly, a LHH dose of 1-6-6 (1 x 1012 vp on D1; 6 x 1012 vp on D3 and 5; greater than the previous flat MTD) was tolerated. Acute increases in TNFα/IFNγ were limited and no severe CRS was seen. Increases in IL-6/MCP-1 with 1 x 1011 or 1 x 1012 vp flat dosing were negligible, whereas acute increases in IL-6/MCP-1 were seen after the first dose of 3 x 1012 vp when given as a flat dose (negligible increases on D3/5). Notably, cytokine responses with 1-3-3 dosing (1 x 1012 vp on D1; 3 x 1012 vp on D3 and 5), including after the first 3 x 1012 vp dose on D3, were negligible. Cytokine responses after the first dose of 6 x 1012 vp in the 1-6-6 regimen were similar to those seen with the first dose of the flat 3 x 1012 vp regimen. Conclusions: LHH dosing appears to induce a desensitization mechanism allowing higher cumulative doses of T-SIGn vectors to be given without the associated acute reactions to viral infusions. This finding may have implications for optimizing safety-efficacy profiles of viral vectors in cancer. Clinical trial information: NCT02636036, NCT03852511 and NCT04053283. [Table: see text]
The effects of AVM0703 mobilization of endogenous gamma delta/invariant TCR+ bispecific natural killer T-like cells against solid tumors and blood cancers.
Authors: Deisher Theresa , Rea Janet R. , Jarzyna Peter , Poulin Kendra , Zahid Yumna , Parthasarathy Vaishnavi , Sawas Spencer , Pathak Manisha , Lee-Diaz Stephanie , Suwito Kathleen , Rylatt Colleen 
Published: June 2022

2579 Background: Glucocorticoids (GC) are a common component of blood cancer regimens, typically at doses 40 mg or lower due to concerns of pancreatitis and hepatotoxicity (Walasik-Szemplińska et al. Thyroid Research. 2019;12:13; Ataallah et al. Cureus. 2020;12[7]) and neuropsychiatric effects. AVM Biotechnology has developed a high concentration, high volume, preservative-free, patent pending formulation of dexamethasone (AVM0703), that allows administration of up to 21 mg/kg (1470 mg for 70 kg) over a one-hour IV infusion. Prophylactic use of circadian physiologic hydrocortisone reduces the risk of GC neuropsychiatric side-effects (Warris LT, et al. J. Clin. Oncol. 2016;34:2287; Meijer & de Kloet Endocrinology. 2017;158:448). Acute supra-pharmacologic doses (>6 mg/kg) AVM0703 mobilizes endogenous bispecific gamma delta invariant TCR+ bi-specific Natural Killer T-like cells (AVM-NKT) (PCT/US21/19773), via a non-GC receptor, that rapidly home to diseased organs in preclinical models and are directly related to tumor killing, including Non-Hodgkin’s Lymphoma, Melanoma, and Multiple Myeloma. Methods: Cancer cell lines and (mouse host) were i) immune-resistant mouse A20 B lymphoma (Balb/c), ii) xenografted human T-ALL CCRF-CEM (NCRnu), iii) mouse B16F10 melanoma (B62DF1), and iv) mouse MOPC315 (Balb/c). Cancer cell lines were inoculated into the flank either as single cell suspensions or encased in Matrigel. When tumor volume reached between 100-500mm3 well-established tumors, mice were orally gavaged with a human equivalent dose (HED) of 15-18 mg/kg AVM0703 as monotherapy, or as a preconditioning prior to adoptive cell transfer (ACT), or in combination with chemotherapy. Responses were determined by tumor volume measurements, tumor immunohistochemistry or flow cytometry detection of residual cancer cells. Results: Immunohistochemistry analysis of tumors from AVM0703 treated mice demonstrated pseudoprogression similar to checkpoint inhibitors: i.e. tumors were measurable however in some cases all cancer cells had been eradicated. Therefore, subsequent tumor monitoring at end point was done by flow cytometry to quantify the total number of live cancer cells more accurately than tumor measurements by calipers or immunohistochemistry, due to pseudoprogression and limitations of examining only a few sections from each tumor. Conclusions: AVM0703 led to: i) complete response (CR) in 27% of immune-resistant mouse A20 tumors as monotherapy and CR in 60% when combined with 2 doses of cyclophosphamide/fludarabine (CyFlu); ii) tumor eradication and long-term memory against xenografted human T-ALL; iii) enhancement of ACT equivalent to CyFlu preconditioning in mouse melanoma; and iv) preliminary 95% CR against mouse multiple myeloma.