bluuebunny/crossref_metadata_2025 huggingface dataset:
A multicenter, randomized, double-blind, phase III trial comparing denosumab biosimilar QL1206 and denosumab in patients with bone metastases from solid tumors.
Authors: Li Huiping , Huang Yan , Zhang Li , Chen Zhendong , Zeng Aiping , Zhang Helong , Yu Yan , Wei Shihong , Li Qingshan , Wang Xiaojia , Wang Xiangcai , Wang Xiuwen , Yang Runxiang , Dai Xiumei , Bi Minghong , Sun Tao , Zhang Qingyuan , Han Cuicui , Liu Qianqian , Li Yujie
Published: June 2022

2526

Background: This phase III study compared clinical efficacy, safety of the first biosimilar QL1206 with denosumab in solid tumor patients with bone metastases. Methods: Patients aged 18-80 years, with bone metastatic solid tumors and ECOG performance status of 0-2 were randomly assigned 1:1 to receive subcutaneous QL1206 or denosumab (120 mg Q4W, both) based on stratification factors (tumor types, previous skeletal-related event [SRE], and current systemic anti-tumor therapy). The primary efficacy endpoint was the percentage changes from baseline to week 13 in urinary N-telopeptide/creatinine ratio (uNTX/uCr); Clinical equivalence would be confirmed if the two-sided 90% confidence intervals (CI) of the least-squares mean (LSM) difference of natural log-transformed ratio of week 13 uNTX/uCr to baseline calculated by analysis of covariance were within the margins of ±0.135. The secondary endpoints included the percentage changes from baseline to week 25 and 53 in uNTX/uCr, the percentage changes from baseline to week 13, 25 and 53 in serum bone-specific alkaline phosphatase (s-BALP) and the time to on-study SRE. Adverse events (AE), immunogenicity (IG) and pharmacokinetics (PK) were also assessed. Population PK was analyzed using nonlinear mixed effects model. Results: 717 patients were randomized to the QL1206 (n = 357) and denosumab (n = 360) groups, respectively. The median percentage changes at week 13 in uNTX/uCr were -75.2% for QL1206 and -75.8% for denosumab. LSM of natural log-transformed ratio of week 13 uNTX/uCr to baseline were -1.429 (standard error 0.130) and -1.441 (0.130) in the two groups. The LSM difference between the two groups was 0.012 (90% CI -0.078 to 0.103; P = 0.8208), within the equivalence margins. Analyses for subgroups of sex, age, and randomization strata showed almost no significant differences. The secondary endpoints were also similar between the two groups (median percentage changes in s-BALP from baseline to week 13: -38.0% vs -37.1%; hazard ratio of time to SRE: 1.264 [95% CI 0.670 to 2.383]; both P > 0.05). In the safety set, treatment-emergent AE occurred in 332 of 356 patients (93.3%) in the QL1206 group and 348 of 361 (96.4%) in the denosumab group. The proportions of positive anti-drug antibody (14/345 [4.1%] vs 16/352 [4.5%]), neutralizing antibody (three [0.9%], each), and PK characteristics were similar between the two groups. Conclusions: The results suggest that QL1206, the first biosimilar denosumab, is similar to denosumab with respect to clinical efficacy, acceptable safety, IG, and PK characteristics. The totality of evidence supports clinical equivalence of QL1206 and denosumab. Clinical trial information: NCT04550949.
Novel platform for identifying multiple cancer-specific antigens.
Authors: Mor Danielle , Farooqui Shakeel , Manavalan John , Davis Joseph , Davis Elliot
Published: June 2022

2530

Background: Virtually all cancer treatments that kill cancer cells also adversely affect normal cells and often have debilitating side effects. A key challenge has been to identify antigens that are suitable for antibody-based targeted therapeutics. We have developed a novel platform to detect and identify multiple cell surface antigens that are unique to human cancers. Methods: Breast Cancer cells (Hs578T) or Melanoma cells (Hs895.T) were injected into rabbits to generate polyclonal xeno-antibodies. The resulting serum against each cancer was then incubated with normal cells of the same tissue type derived from the same patients; Breast Epithelium (matched-pair Hs578Bst) or Skin Fibroblasts (matched-pair Hs895.Sk) in order to absorb antibodies that cross-react with antigens on normal tissue (U.S. Patent Application No. 16/243,161). Flow cytometry was used for measuring the binding capacity of the unfiltered serum and filtered serum (lacking cross-reacting antibodies) on both the cancer cells and normal cells. Cytotoxicity assays were performed using a secondary ADC (anti-rabbit IgG specific antibody conjugated to MMAF), to determine the cytotoxicity of the unfiltered antibodies and filtered antibodies on normal and cancer cells. Results: Flow cytometry revealed, for antibodies against breast cancer, there was 90.3% and 88.6% binding to breast cancer cells and normal breast epithelial cells, respectively, pre-filtration; and 78.9% and 23% binding, respectively, post-filtration. For antibodies against melanoma, there was 89.2% and 86.6% binding to melanoma cells and normal skin fibroblasts, respectively, pre-filtration; and 55.1% and 0% binding, respectively, post-filtration. The Table summarizes the cytotoxicity of unfiltered and filtered antibodies on cancer cells and normal cells. Remarkably, there was preferential killing of all the cancer cells tested by both unfiltered and filtered antibodies, while there was no cytotoxicity in the normal cells using filtered antibodies. Cytotoxicity was also observed when antibodies generated against one type of cancer were incubated with other cancer types. Conclusions: This data suggests that our xeno-antibody based method can detect cancer-specific sites, not found on normal cells, and diverse cancer types may share a common antigenic signature. These findings are significant for identifying unique antigens on cancer cells and designing targeted therapies against cancer. [Table: see text]
Multicenter phase Ib trial in the U.S. of salvage CT041 CLDN18.2-specific chimeric antigen receptor T-cell therapy for patients with advanced gastric and pancreatic adenocarcinoma.
Authors: Botta Gregory P. , Becerra Carlos Roberto , Jin Zhaohui , Kim Dae Won , Zhao Dan , Lenz Heinz-Josef , Ma Hong , Ween Audrey , Acha Petra , Li Zonghai , Yoon Harry H.
Published: June 2022

2538

Background: Claudin 18.2 (CLDN18.2) is a highly selective cell lineage marker with limited expression in normal gastric tissues and significantly higher expression in primary gastric, pancreatic tumors and their metastases. Anti-CLDN18.2-targeted CAR T cells, termed CT041, were developed to evaluate tumor response and patient-reported outcomes in the gastric and pancreatic cancer. Preliminary results of the trial (NCT03874897) showed an objective response rate (ORR) of about 60% in gastric cancer from a non-Western population. Here we report the results of CT041 for metastatic gastric cancer after ≥ 2 prior lines of systemic therapy or pancreatic cancer ≥ 1 prior line from six centers in the United States. Methods: This single-arm, open-label, phase Ib study (NCT04404595) investigated autologous CT041 CAR T cells in patients with CLDN18.2 positive advanced gastric (including diffuse, signet-ring) or pancreatic adenocarcinoma. All patients completed a conditioning regimen consisting of fludarabine, cyclophosphamide, and nab-paclitaxel prior to CT041 CAR T cells. The primary objective was to assess the safety, efficacy and cytokinetic profile of CT041. Adverse Events (AEs) were graded according to CTCAE 5.0, and tumor response was assessed per RECIST 1.1. Results: As of February 15, 2022, 11 patients (5 gastric and 6 pancreatic) with a median of 2 prior lines of therapy (range 1- 4) were treated with CT041 at a dose between 2.5 and 4 x 108 cells. There were no dose limiting toxicities, treatment-related deaths, severe cytokine release syndrome (CRS), immune effector cell-associated neurologic syndrome (ICANS), or severe gastrointestinal (GI) related AEs. All CRS were grade 1 or 2. Only one patient received tocilizumab. No grade 4 AEs were observed except for hematologic toxicities related to conditioning. The first eight patients were evaluable for response by the date of data cut-off: 1 patient achieved a complete response after two CT041 doses (gastric), 2 had partial response (gastric), 2 had stable disease with tumor shrinkage (pancreatic) and 3 (pancreatic) had progression of disease after an initial biochemical response. ORR was 37.5% (3/8) in all patients including 100% (3/3) in the gastric subgroup (all ≥ 3 prior lines). The last three patients had not reached the time for response assessment. CAR T cell expansion correlated with ctDNA reduction. The median duration of response and the progression-free survival had not been reached. Conclusions: These preliminary results indicate that CT041 therapy was safe and had therapeutic efficacy in patients with advanced GI cancers. In heavily pre-treated gastric cancer, CT041 may have significantly improved anti-tumor activity compared to historical treatment regimens. Clinical trial information: NCT04404595.
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.
A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: Interim results.
Authors: Van Tine Brian Andrew , Hubbard Joleen M. , Mita Monica M. , Barve Minal A. , Hamilton Erika P. , Brenner Andrew J. , Valdes Frances , Ahn Daniel H. , Starr Jason S. , Pelham Joshua , Strack Thomas , Yuet Amy , Yurewicz Diana , Smith Taunya J. , Machado Andres , Edenfield William Jeffery , Morikawa Aki , Okera Meena , Abdulla Nihal E. , Wainberg Zev A.
Published: June 2022

2583

Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.
Extended duration of anti-PD-1 therapy, using reduced frequency dosing, in patients with advanced melanoma and Merkel cell carcinoma.
Authors: Tachiki Lisa May Ling , Williams Silva Karly , Hippe Daniel S , Fritzsche Dane , Raczka Aleksandra , Perdue Andrea , Majovski Julia , Spallone Alexandra , Goldstein Daniel A , Nghiem Paul , Thompson John A. , Hall Evan Thomas , Bhatia Shailender
Published: June 2022

2588

Background: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in patients with metastatic melanoma (Mel) and Merkel cell carcinoma (MCC) is unclear. ICI discontinuation in Mel patients, especially those without CR, may be associated with a higher rate of progression over time, as compared to ICI continuation. Thus, extending DoT could improve outcomes. However, indefinite continuation at standard frequency doses (SFD) is not logistically or financially viable. Based on data from phase I studies suggesting sustained PD-1 receptor occupancy beyond 3 months after a single dose of nivolumab, we employed reduced frequency dosing (RFD) of anti-PD-1 antibodies every 2-3 months, to extend ICI duration beyond 2 years. Methods: This retrospective study analyzes patients in our skin cancer clinic with metastatic Mel and MCC who experienced initial clinical benefit with anti-PD-1 administered at SFD and then transitioned to RFD. We analyzed safety and efficacy endpoints including progression free survival (PFS) and rates of immune-related adverse events (irAE) with RFD. We also compared the pharmaceutical costs and patient-centered costs between 2 years of treatment at SFD versus extended DoT at RFD. Results: From 2014 – 2021, 23 patients with either metastatic Mel (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT at SFD in this cohort was 1.1 years (range 0.2 – 2.2) with best objective tumor responses of CR (N =6), PR (N = 11), SD (N = 6). Median DoT at RFD was 1.2 years (range 0.2 – 3.5). The median follow-up for the entire cohort is 3.7 years (range 0.7 – 6.3) after ICI initiation. The 3-year PFS in Mel patients was 100% in those with CR (3/3), 89% with PR (8/9), and 50% with SD (3/6). The 3-year PFS in MCC was 100% in all 5 patients, including patients with CR (3/3) and with PR (2/2). Any-grade irAEs occurred in 43% of patients by 3 years on RFD, and grade 3/4 irAEs presented in 15%. Among the subset of 15 patients with DoT >2 years (median 3.4 yr, range 2.0 – 5.0), total savings amounted to $1.1 million in drugs costs and 384 hours of clinic and travel time despite the increased DoT, as compared to the calculated values for 2-year DoT at SFD. Conclusions: RFD may provide an alternative approach to extending DoT in patients receiving ICI without additional logistical and financial burden, while preserving outcomes. Efficacy and safety data suggest sustained biologic activity of ICI with RFD administration. PK/PD analyses on patient samples are ongoing to further characterize the RFD approach. The RFD approach could be utilized to expand ICI access to communities with limited healthcare resources, thereby impacting cancer outcomes at a global scale.
A phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody, in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Coward Jermaine , Markman Ben , Nagrial Adnan , Abed Afaf , Walpole Imogen
Published: June 2022

2603

Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study conducted in Australia using an accelerated "3+3" design. Patients (pts) with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles. Treatment continuation beyond cycle 4 is possible if subject is deriving an ongoing clinic benefit. The safety, tolerability and preliminary efficacy data will be analyzed. Results: Between 29 Jul 2020 and 30 Dec 2021, a total of 20 patients with various advanced solid tumors were enrolled including 0.03 mg/kg (n = 3), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 1.0 mg/kg (n = 8) and 3.0 mg/kg (n = 3). The median age was 60 years (range 33-75). Baseline ECOG scores were 0 (13 pts) and 1 (7 pts). 8 pts had received prior immunotherapy (anti-PD-1/PD-L1 or anti-PD-1+CTLA-4mAb). Dose escalation has been completed and only one dose-limiting toxicity relating to YH003 was observed at 1.0 mg/kg (grade 3 transaminitis). The maximum tolerated dose (MTD) was not reached. 13 (65%) pts experienced any grade treatment related adverse events (TRAEs). The most common (≥ 10%) TRAEs were infusion reaction, pyrexia, fatigue, nausea, diarrhea, transaminitis. Most TRAEs were grade 1 or 2. Only 3 (15.0%) pts experienced Grade 3 TRAEs including one each of neutropenia (YH003 0.3 mg/kg), transaminitis (YH003 1.0 mg/kg) and elevated lipase (Toripalimab 0.1 mg/kg). Only 2 pts have permanently discontinued treatment due to TRAEs including grade 3 transaminases increased and grade 2 hepatitis. There were no ≥grade 4 TRAEs and drug related serious adverse events (SAEs) were not observed. Among 14 pts assessable for response, the overall response rate (ORR) was 14.3% (2/14) and disease control rate (DCR) was 35.7% (5/14). One partial response (PR) occurred in a pt with anti-PD1/anti-CTLA4 refractory ocular melanoma with liver metastases (YH003 0.1 mg/kg) who continued on treatment for > 1 year. The other PR occurred in a pt with Non-Small Cell Lung Carcinoma (YH003 1.0 mg/kg) who continued on treatment for almost 9 months. Conclusions: YH003 was well tolerated up to 3.0 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.
Molecular predictors of response among patients with MMRd tumors treated on NCI-MATCH Arm Z1D.
Authors: Schoenfeld Jonathan Daniel , Azad Nilofer Saba , Lee Jennifer , Gross Jacob , Overman Michael J. , Kao Katrina , Steinfeld Anna , Brunnquell Donna , Bu Xiangning , Guan Ping , Weirather Jason L. , Pfaff Kathleen L. , Ranasinghe Srin , Wang Victoria , O'Dwyer Peter J. , Wu Catherine J. , Rodig Scott J. , Patton David R. , Harris Lyndsay
Published: June 2022

2616

Background: On arm Z1D of the NCI-MATCH trial, the PD-1 inhibitor nivolumab was found to have activity among patients with mismatch repair-deficient (MMRd) tumors as defined by complete loss of MLH1 or MSH2 nuclear expression determined by immunohistochemistry, with 6-month progression free survival of 51%. We aimed to identify molecular predictors of response in this population. Methods: Among patients treated on NCI-MATCH Z1D, we evaluated genomic and tissue predictors of clinical benefit (CB), defined as patients with RECIST v1.1 complete or partial response or stable disease for ≥ 6months. WES files were processed and filtered using GATK best practices preceding TMB and MSI calculations according to MSI sensor score, a WES-based MSI rating system. Cutoffs were set to define TMB (TMB-Low: ≤10 mutation/Mb; TMB-High: >10) and MSI (MSS: ≤10% unstable loci; MSI-Low: 10 > x ≤ 20; MSI-High: >20). Multiplex immunofluorescence (mIF) used formalin-fixed paraffin-embedded slides stained using a BOND RX automated stainer. Expression analyses followed normalization in DEseq2's median of ratios method. Gene set enrichment analysis was conducted by “empirical phenotype-based permutation test.” Additional RNA, WES, and mIF comparisons used the Wilcoxon rank-sum test. Results: Among 36 patients accrued to NCI-MATCH Z1D with pretreatment correlative samples available, 7 were unevaluable for response, and 1 was misclassified as having an MMRd tumor. Of the remaining 28, 15 had CB (2 CR, 10 PR, 3 SD ≤ 6 months) and correlative data were available for 26 (WES), 27 (RNAseq), and between 10-20 for mIF based on the marker assessed. According to MSI-sensor score, 11 were MSI-high, 8 were MSI-low, and 7 were MSS. MSI-sensor status, but not TMB was associated with CB (p=0.037 and p=0.185, respectively). Similar results were seen when using CR+PR vs SD+PD evaluation. Using RNAseq gene set enrichment analyses, CB patients had increased expression of interferon alpha (p=0.01), interferon gamma (p=0.03), PI3K-AKT-mTOR (p=0.02), cytotoxicity (p=0.05) and antigen processing (p=0.01) gene sets, while hedgehog signaling genes were increased in non-CB patients (p=0.04). The ESTIMATE immune index and infiltration of CD4+/PD1+/Ki67+ cell populations as determined by mIF were nominally higher in patients with CB (p=0.051 and p=0.075). Conclusions: Among patients with MMRd tumors treated with PD-1 checkpoint blockade, correlative analyses demonstrate associations between CB and MSI-sensor score as well as biomarkers indicative of immune infiltration and antigen presentation. This suggests that these measures may help differentiate patient response in MSI tumors. Clinical trial information: NCT02465060.
Association between tumor mutational burden (TMB) and mutational profile and its effect on overall survival: A post hoc analysis of patients with TMB-high and TMB-low metastatic cancer treated with immune checkpoint inhibitors (ICI).
Authors: Xavier Camila Bragança , Guardia Gabriela , Lopes Carlos Diego Holanda , Awni Beatriz Mendes , Campos Eduardo Felicio , Alves João Pedro , Camargo Anamaria Aranha , Galante Pedro Alexandre Favoretto , Jardim Denis L.
Published: June 2022

2632

Background: High-TMB was recently approved as an agnostic biomarker for pembrolizumab in advanced cancers. Still, several patients with high-TMB do not respond to ICI, while some patients with low-TMB benefit from immunotherapy. Methods: We collected genomic (MSK-IMPACTassay) and survival data from 1,661 patients and assessed OS (Kaplan-Meier method) according to the mutational status. To better qualify patients with TMB ≥ 10 mut/Mb (TMB-H) (N = 488, 29%) and TMB < 10 mut/Mb (TMB-L) (N = 1,173, 71%) for ICI treatment, we analyzed single gene alterations impacting OS (P < 0.05). For all genes exhibiting a correlation with OS, we conducted a Cox multivariate analysis stratified by median TMB, sex, median age, microsatellite instability (MSI) status, and histology. Results: Survival to ICI increased with higher TMB. Median OS was 42 and 15 months for TMB-H and TMB-L (P < 0.05), respectively. For TMB-H tumors, 5 genes ( STK11, KEAP1, CIC, E2F3, TP53) exhibited reduced OS on ICI, and 22 genes ( NTRK3, TERT, NOTCH3, RNF43, TET1, PTPRD, NCOA3, TENT5C, ZFHX3, RIT1, CCNE1, PPM1D, GATA2, ALK, DNMT1, PTPRT, MET, EPHA7, BCL6, SMO, CDK6, MED12) were associated with better OS, P < 0.05. Cox multivariate analysis confirmed a correlation between mutations in STK11 and E2F3 with worse OS, while mutations in NTRK, PTPRD, RNF43, TENT5C, TET1, and ZFHX3 were associated with better OS (P < 0.05). Histology did not play a relevant role in ICI response except for melanoma (better OS; P < 0.05). MSI status did not significantly affect OS. For TMB-L tumors, 20 genes were related with reduced OS ( TP53, H3C2, DAXX, SMARC4, STK11, SOX17, RB1, PIK3CA, CTNNB1, KMT2D, HLA-A, FBXW7, CDH1, RBM10, KEAP1, IGF1R, H3C11, EGFR, RUNX1, B2M), while 8 genes were associated with better OS ( VHL, SETD2, PBRM1, BRAF, KDM5C, MAP2K1, CSF1R, RET), P < 0.05. Cox multivariate analysis confirmed 15 genes associated with superior ( KDM5C, PBRM1, and VHL) and inferior ( CTNNB1, DAXX, FBXW7, H3C2, H3C1, IGF1R, KMT2D, PIK3CA , RB1, SMARC4, SOX17, TP53) OS (P < 0.05). In the TMB-L context, melanoma histology and MSI status (except among VHL-mutated tumors) were independently associated with better OS. Conclusions: This pan-cancer analysis demonstrates that genomic alterations in single cancer genes can help define outcomes of TMB-H and TMB-L patients treated with ICI. [Table: see text]