bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of beta 2-microglobulinin (β2MG) in cerebrospinal fluid (CSF) in primary central nervous system lymphoma (PCNSL).
Authors: Bertucci Alexandre , Boucard Celine , Harlay Vincent , Chinot Olivier L. , Tabouret Emeline
Published: June 2022

e14047

Background: Prognosis and response assessment are crucial to guide PCNSL patient therapeutic management. β2MG is a well-known prognostic factor of systemic lymphoma but its prognostic value in PCNSL remains uncertain. Objective is to evaluate the prognostic value of β2MG in CSF in PCNSL patients. Methods: We prospectively analyzed the CSF β2MG concentration in all newly PCNSL patients referred to our institution between March 2014 and November 2021 for whom lumbar punction was allowed. β2MG analysis was performed at diagnosis before the first treatment administration, after 2 and 4 treatment cycles. The clinical, radiological, histological, biological and treatment data were retrospectively collected. Results: Thirty-six patients were included with a median age of 71.8 (range 42.5 – 85.3). All patients presented with DLBCL CD20+ lymphoma. Median KPS was 70 (range, 30 – 100). Median dose of prednisone at diagnosis was 60 mg (range, 0 – 1000). Thirty-two patients (88.9%) received polychemotherapy with high-dose methotrexate as first line treatment. In CSF, median β2MG was 3.55 mg/L (range, 0.88 – 19.24), median IL10 was 35.0 pg/mL (range, 3.0 – 2843) and median IL6 was 22.1 pg/mL (range, 2.0 – 120). Only 14% and 16% of patients presented with normal CSF and blood β2MG rate at diagnosis, respectively. Five patients presented with meningitis involvement. CSF β2MG was independent from blood β2MG (p = 0.861), from CSF IL10 (p = 0.379), from CSF IL6 (p = 0.479) and from blood LDH (p = 0.685). Complete, partial responses or progressive disease were observed in 18 (54.5%), 10 (30.3%) and 5 (15.2%) patients respectively. CSF β2MG concentration tended to be correlated to patient response (p = 0.129). The rates of complete response were 65% and 44% for low (< median) and high (> median) CSF β2MG rates, respectively. At last follow-up, 17 patients (47%) had relapsed, and 11 patients (31%) died. Median progression-free survival (PFS) and overall survival (OS) were 21.2 months (95%CI: 5.9 – 36.4) and 47.6 months (95%CI not estimable due to the low number of events), respectively. In univariate analysis, low KPS and high CSF β2MG were associated with poor PFS (p = 0.002 and p = 0.008, respectively) with no detectable impact of blood β2MG. CSF IL10 and IL6 were not associated with patient outcome. In multivariate analysis high CSF β2MG tended to remain associated with worse PFS (p = 0.087, HR: 2.784, 95%CI: 0.862 – 8.987). In responder patients, CSF β2MG was significantly decreased at 4 months after first line treatment initiation (p = 0.005). Conclusions: CSF β2MG may exhibit a prognostic value in PCNSL patients. These results need to be validated in a larger prospective study.
Utilization of immortalized B cells to identify SDCBP as a novel therapeutic target in ovarian carcinoma.
Authors: Handley Katelyn , Mehta Sumit , Martin Alexandra , Biswas Subir , Maharaj Kamira Karen , Mine Jessica A. , Cortina Carla , Nagy Mate , Sprenger Kimberly , Mandal Gunjan , Innamarato Patrick , Powers John Joseph , Harro Carly M. , Chaurio Ricardo A. , Anadon Carmen M. , Pinilla-Ibarz Javier , Shahzad Mian M. , Flores Idhaliz , Conejo-Garcia Jose
Published: June 2022

e14507

Background: We hypothesized that tumor-infiltrating B cells in endometriosis and endometriosis-associated ovarian cancer can be used to identify novel, targetable antigen domains to inhibit the progression of ovarian carcinomas. We aimed to identify targets that are spontaneously recognized by B-cell-derived antibodies within ovarian clear cell carcinoma (CCC), endometrioid carcinoma (EC), and endometriosis and to determine the preclinical anti-cancer efficacy of a candidate antibody that recognizes the extracellular domain of an identified target. Methods: B cells from freshly dissociated CCC (n = 2), EC (n = 2), and endometriomas (n = 2) were isolated, activated, and EBV-immortalized. Antibodies were purified from B cell supernatants and used for screening in a proteome array. Targets were prioritized based on accessibility (transmembrane or secreted proteins), expression in endometriosis and cancer, and concurrent IgA and IgG responses. Tumor-promoting syndecan binding protein (SDCBP) was identified and SDCBP-reactive B cells were FACS-sorted and subjected to single cell B cell receptor sequencing to determine the variable heavy and light chain sequences of enriched clonotypes. We then generated a recombinant IgG4 antibody targeting SDCBP with the dominant VH/VL matching sequences. Immunoblots and qPCR were performed to assess SDCBP expression in ovarian cancer cell lines and tumor samples. In vivo studies compared anti-tumor potential of the α-SDCBP IgG4 with controls using immunodeficient mouse models of human CCC and high-grade serous ovarian carcinoma (HGSOC). Results: Nine accessible proteins were detected by both IgA and IgG in all samples, including SDCBP. SDCBP is expressed in ovarian cancer cell lines and tumor samples of multiple histologies, including CCC, EC, and HGSOC. Administration of α-SDCBP IgG4 in TOV21G (CCC) tumor-bearing mice significantly decreased tumor volume compared to non-antigen-specific irrelevant IgG4 (iIgG4, p = 0.002) and vehicle (0.001), and correspondingly trended toward decreased tumor weight compared to vehicle (p = 0.06). Likewise, administration of α-SDCBP IgG4 in OVCAR3 (HGSOC) tumor-bearing mice significantly decreased tumor volume compared to iIgG4 (p = 0.03) and trended toward decreased tumor weight (p = 0.06). Conclusions: An α-SDCBP IgG4 has demonstrated anti-tumor efficacy in SDCBP+ CCC and HGSOC, and SDCBP-targeted therapy for endometriosis and associated malignant conditions, as well as HGSOC, warrants further investigation.
The landscape of ACVR2A mutations in Chinese solid tumor patients.
Authors: Li Xin , Ren Yaoyao , Li Caifeng , Luo Cui , Ma Juan , Bian Zhengying , Ge Minghui , Lu Guanghua , Ding Ran , Bu Fanfeng
Published: June 2022

e14523

Background: ACVR2A (activin A receptor type 2A) encodes a receptor that mediates the functions of activins, and it contains two polyadenine (A8) microsatellite loci, which are located in exon 3 and exon 10. Recent studies have shown that ACVR2A mutant was associated with microsatellite instability-high (MSI-H) and high tumor mutational burden(TMB-H) in gastrointestinal cancers. However, this association remains unclear in other solid tumors. Methods: We retrospectively analyzed the ACVR2A mutations from comprehensive 539-gene profiling of 10434 Chinese patients with pan-cancer. Somatic mutations in tumor tissue were assessed. We screened out ACVR2A mutations, calculated the mutation frequency, TMB in different types of cancer. Results: ACVR2A mutants were detected in 340 (2.9%) samples. The top 5 frequently cancers were colorectal cancer (98, 28.8%), lung carcinoma (68, 20%), hepatocellular carcinoma (64, 18.8%), gastric cancer (48, 14.1%) and biliary tract cancers (19, 5.6%). And 12.7% were other cancers (e.g., pancreatic cancer, small bowel adenocarcinoma, brain cancer). ACVR2A variants included truncation (50%), splicing site variant (9.0%), and other mutant types(41.1%). Truncation was the most common type, recurring in a few hot spots (K437Rfs*5/ K437Rfs*19, D96Tfs*54/ D96Rfs*4, V433del, R438Efs*19). The TMB in ACVR2A mutation group was significantly higher than that in ACVR2A wild-type group (p < 0.001). In addition, TMB ≥10 muts/Mb was seen in 76.7% tumors with ACVR2A truncation or splicing site mutant(INACT) and 20.6% tumors with other mutant types(VUS)(p = 0.002). The median TMB of INACT group and VUS group was 35.46 muts/Mb (0.74-344.12) and 6.62 muts/Mb(0.5-598.53), respectively. Conclusions: We analyzed the distribution of ACVR2A mutants in Chinese patients with solid tumors. Our data shows that ACVR2A truncation or splice site mutant type is significantly associated with TMB-H, and this may be potential molecular marker of immunotherapy.
Correlation of circulating tumor cells as a positive interventional biomarker in cancer patients.
Authors: Khandare Jayant , Aland Gourishankar , Jayant Sreeja , Chakraborti Pratim , D'Souza Alain , Kadam Avinash , Birari-Gawande Poonam , Bendale Yogesh Narayan
Published: June 2022

e14527

Background: Circulating Tumor Cells (CTC) is a predictive biomarker for accounting disease progression and for minimal residual disease (MRD). Effect of conventional anticancer therapy on CTC count is well documented, however there is paucity of data related to effect of CAM based modality on CTC count in cancer patients. This study provides a preliminary observation about the effect of Ayurveda therapy on CTC count. Methods: The retrospective study involved stratification of 72 cancer patients undergoing cancer and maintenance treatment in a non-conventional, Ayurveda cancer treatment in India. For monitoring of prognosis in cancer patients, CTC count was assesed in patients attending Rasayu Cancer clinic. 17 cancer types, namely, breast cancer, cervix and ovarian cancer, bladder, lung, Head and neck squamous carcinoma, follicular thyroid, diffuse B-cell lymphoma, Hodgkin’s and non-Hodgkin’s, colorectal, Hepatocellular, stomach with abdominal metastasis, metastatic prostate cancer, SCC with lung and skeletal metastasis etc. Total 33 (46%) males and 39 (54.1%) female patients of various types and stages were analyzed for the presence of CTCs retrospectively. CTCs were isolated and renumerated from 1.5 ml of patient’s blood sample using OncoDiscover Liquid Biopsy Technology platform enriched with anti-EpCAM antibody immunomagnetic kit, approved by Drug Controller General of India (DCGI). CTCs were confirmed for cytokeratin+ 18 (CK18), DAPI+ and CD45-. Subsequently CTCs were imaged using Zeiss Axio Observer 7 fluorescence microscope. In 28 patients (50%), CTC was accounted for at both pre and post treatment in duration of 3-6 months. 28 patients were assessed for quality of life measured by FACT-G questionnaire. The outcome was quantified for clinico-pathological parameters; age / gender, cancer types, and CTC distribution. Results: The mean and median CTC distribution was observed to be 15.34 and 12.5, respectively. 8% patients showed the absence of any CTCs (6 subjects (1 male and 5 females). While 32 males (96%) and 34 females (87%) showed presence of CTCs. The correlation coefficient of CTC presence in male and female was significant 0.4799 (p < 0.05). The Ayurveda Rasayana therapy showed significant reduction in post interventional CTC count (-3.94±1.2) (P=0.02). In addition, this group of patients also showed significant improvement in health-related quality of life as measured by the FACT-G questionnaire (P<0.05). Conclusions: CTC is a validated predictive biomarker for accounting minimal residual disease, both in pre and post cancer treatments. The enumeration of CTCs represents an effective prognostic biomarker in assessing the disease progression. Reduction in CTC count was seen to be associated with improvement in health-related quality of life (QoL) which needs to be investigated further to establish correlation.
Isoflavonoid-based therapeutics to remodel immunologically cold tumors in nasopharyngeal carcinoma.
Authors: Kam Ngar Woon , Laczka Olivier , Hung Desmond , Li Xiang , Dai Wei , Tsao George , Lee Victor Ho-Fun , Kwong Dora Lai Wan
Published: June 2022

e14534

Background: Nasopharyngeal carcinoma (NPC) is endemic in Southern China and is well-known to be heavily infiltrated by lymphocytes and constitute a unique but poorly defined tumor microenvironment. We aimed at delineating and defining the contribution of idronoxil (IDX), a synthetic flavonoid derivative, in restoring sensitivity to apoptosis and potentially modulating the immune microenvironment of NPC. Methods: Using multiplexed staining, we measured the levels of ENOX2 (IDX’s target), CD8 (cytotoxic T cell) and pan-cytokeratin (tumor marker) in 86 NPC patients’ cancerous specimens in tissue microarray format. NPC tissue bulk RNA-Seq and affymetrix microarray public datasets were gathered to examine ENOX2 significance. Interaction between ENOX2-expressing tumor cell lines (C17 and NPC43) and T cells were also studied. In vivo, antitumor effects of IDX on the growth of NPC43+ve tumors in nude mice and humanized mice were studied. Results: We performed median density as cut-off and tumors can be classified as hot or cold. 68.6% “cold”-phenotype tumors were observed in our cohort and the top 20% patients with highly positive ENOX2-expresing tumor cells showed lower number of CD8 infiltrates. Publicly dataset showed that highly expressed ENOX2 group associated with poorer prognosis (log-rank test p = 0.041). In vitro, we observed increased migration of T cells towards cancer cells when tumor cells were pre-treated with the combination of IDX and cisplatin (IDX+Cis) compared with monotherapy (IDX or cis alone) or untreated. We also observed increased susceptibility of tumor cells to T cell cytotoxicity when both IDX and Cis were added. In nude mice, IDX+Cis significantly decreased the tumor growth compared to saline-treated group. In humanized mice, upon treatment, we found 1.69-fold (p = 0.039) more CD3+ T cells in the tumor than in the blood when compared to control group. In humanized mice, the ratio between human T cell levels in tumor and blood was increased by the IDX+Cis compared to control group (1.67-fold, p = 0.01 by t-test). Conclusions: Distinct immunospatial profiles could be associated with clinicopathologic characteristics. The ability of IDX to modulate T cell populations indicates the potential of IDX to enhance the efficacy of current chemotherapy treatments in NPC by upregulating cellular trafficking toward tumor.[Table: see text]
Biodegradable nanoparticles inhibit tumor growth by altering tumor-associated macrophages and cancer-associated fibroblasts.
Authors: Murthy Tushar , Podojil Joseph , Kwak Taekyoung , Vonteddu Prashanthi , Elhofy Adam , Boyne Michael , Puisis John , Veglia Filippo , Singh Surya , Dotiwala Farokh , Montaner Luis , Gabrilovich Dmitry , Donthireddy Laxminarsimha , Eraslan Rukiye-Nazan
Published: June 2022

e14553

Background: The tumor microenvironment (TME) plays a crucial role in tumor growth and progression and has a significant influence on response to therapy. The TME consists of myeloid-derived cells, stroma (e.g. fibroblasts and extracellular matrix (ECM)), and the vasculature that together support tumor growth and progression. Studies in animal models and in humans show that myeloid- derived cells such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) engage in activities that support tumor growth and progression. These cells also promote immune suppression in the TME that blunts the efficacy of the anti-cancer drugs and immune-targeted therapies such as immune checkpoint inhibitors. In addition to MDSCs, cancer-associated fibroblasts (CAFs) in the TME support tumor progression via production of pro-tumor and pro-angiogenic growth-factors, remodeling of the ECM via production of proteases, and suppression of anti-tumor immune function. CAF abundance in the TME is a negative prognostic factor for several solid tumors and is associated with negative outcomes and poor response to immune-targeted therapies like immune checkpoint inhibitors. ONP-302 nanoparticles fabricated from biodegradable poly (lactic-co-glycolic acid)(PLGA) polymer have been previously described in the literature for the treatment of acute inflammatory conditions via immuno-modulatory effects on myeloid derived cells. Here, we evaluated the efficacy of ONP-302 nanoparticles at inhibiting tumor growth via targeted inhibition of myeloid-derived cells and reshaping of the TME. Methods: ONP-302 anti-tumor efficacy was evaluated in syngeneic mouse tumor models using both immunocompetent and immunodeficient mice. We examined the effect of ONP-302 treatment tumor growth kinetics and effects on the major cellular constituents of the TME such as myeloid-derived cells and CAFs. Results: Therapeutic treatment with ONP-302 in vivo resulted in a marked delay in tumor growth in three different syngeneic tumor models in immunocompetent mice. ONP- 302 efficacy persisted with depletion of CD8+ T cells in immunocompetent mice and also was effective in immune deficient mice. We found ONP-302 treatment caused a gene expression shift in TAMs toward the pro-inflammatory M1 type and substantially inhibited the expression of genes associated with the pro-tumorigenic function of CAFs. ONP-302 also induced apoptosis in CAFs in the TME. Conclusions: Our data indicate that the slowing of tumor growth after ONP-302 treatment is due to disruptions in known signaling pathways involving TAMs and CAFs, pathways typically supporting tumor growth. These data taken in concert indicate the activity of ONP-302 is pleotropic and affects multiple pathways.
Safety and efficacy of YBL-006, an anti-PD-1 monoclonal antibody in advanced solid tumors: A phase I study.
Authors: Oh Do-Youn , Park John J. , Lee Keun Wook , Kim Seung Tae , Sriuranpong Virote , Rha Sun Young , Yoo Changhoon , Keam Bhumsuk , Sabanathan Dhanusha , Kim Se Hyun , Park Joon Oh , Parinyanitikul Napa , Kim Min Hwan , Kim Kyu-Pyo , Kim Myungsuk , Yoon Jaebong , Lee Han Seung , Ock Chan-Young
Published: June 2022

e14557

Background: YBL-006 is a fully human anti-programmed death-1 (PD-1) antibody under evaluating its safety and efficacy in phase I clinical trial. We have reported interim analysis of dose escalation cohort which showed a tolerable safety profile. Here, we present the updated clinical activity of YBL-006 in dose escalation and expansion cohorts. Methods: Dose escalation (0.5, 2, 5, 10 mg/kg) and dose expansion (flat doses of 200 mg every 2 weeks [Q2W] and 300 mg every 3 weeks [Q3W]) cohorts explored the safety, pharmacokinetics (PK) and objective response rate (ORR) in the patients with advanced solid tumors who failed or were ineligible to the standard of care. Adverse events (AEs) were graded using the CTCAE v5. ORR was assessed using the RECIST (v1.1). Lunit SCOPE IO, an H&E analysis tool, was applied as an exploratory biomarker, and samples with “Immune inflamed phenotype” were defined as those with high intratumoral TIL density in ≥ 20% of the tumor microenvironment. The cut-off date for analysis was Jan 4th, 2022. Results: A total of 67 patients (safety set) with advanced solid tumors were enrolled in the study. Median follow-up duration of the safety set was 1.6 months (range 0.2-16.8). There was no dose-limiting toxicity during dose escalation phase. Most frequent AEs were grade 1 or 2; fatigue (19.4%), pruritus (10.4%), and fever (7.5%), and two hypothyroidism (3.0%), one pneumonitis (1.5%), and one cytokine-releasing syndrome (1.5%) were observed. One subject experienced grade 3 diarrhea in the safety set. PK study showed that half-life was 8.0 days, and mean Cmax and AUC0-inf were 4.15 x 104 ng/ml and 1.12 x 107 ng/ml*h for 200 mg dose, and 6.26 x 104 ng/ml and 1.53 x 107 ng/ml*h for 300 mg dose, respectively. A total of 52 patients were evaluable for efficacy. ORR was 15.4%, including 1 complete response (penile squamous cell carcinoma [SqCC]), and 7 partial responses (two gastric adenocarcinomas, anal SqCC, paranasal sinus SqCC, nasopharyngeal carcinoma, neuroendocrine carcinoma, and thyroid Hurthle cell carcinoma). Durable responses were seen in 2 patients for over 12 months. Median duration of response was 4.9 weeks (range 1-65). Among efficacy set, 32 samples were available for Lunit SCOPE IO. ORR was significantly higher in inflamed immune phenotype compared to non-inflamed samples (62.5% vs 8.3% p = 0.005). Conclusions: Interim analysis of phase I trial of YBL-006 shows a tolerable safety profile and clinical activity. Notable anti-tumor efficacy was observed in inflamed immune phenotype. Clinical trial information: NCT04450901.
A novel nomogram could predict prognosis for multiple cancer patients with primary resistance to immune checkpoint inhibitors.
Authors: Li Xuanzong , Fan Xinyu , Wang Linlin
Published: June 2022

e14561

Background: Cancer patients with immune checkpoint inhibitors (ICIs) treatment often experience unique progression response patterns, accounting for the discordance of short-term and long-term benefits. Identifying the specific characteristics of different quality progression disease (PD) events can maximize the curative effect of ICIs and further improve the prognosis of the patients with immunotherapy. In this study, we established a neutrophil-to-lymphocyte ratio (NLR)-based nomogram model which could predict survival for NSCLC patients with primary resistance to ICIs. Methods: Univariate and multivariate Cox regression analysis were used to evaluate the ability of each parameter to predict overall survival (OS). The regression coefficients obtained in multivariate analysis were visualized in the form of a nomogram, thus a new nomogram and risk classification system were established. The discrimination ability of the new model was evaluated using area under the curve (AUC) in receiver operating characteristic curve (ROC) analysis. Survival curves were made by the Kaplan-Meier method and compared by the Log-rank test. Results: A total of 1235 patients with multiple cancer types who accepted at least one dose of ICIs treatment between 2015 and 2018 at Memorial Sloan Kettering Cancer Center were included in our study. Among them, 624 PD-patients (obtaining PD as their best response) were used to identify potential survival-related characteristics and build a nomogram model. Univariate and multivariate analysis demonstrated that pretreatment NLR, treatment lines and Eastern Cooperative Oncology Group performance status scores were independent prognostic factors and were included in the predictive model. The ROC curves implied the good discrimination ability of the predictive model with the AUC value for 1-year OS was 0.756. And, the calibration curves showed that the predicted value of the 1-year survival rate by the nomogram was in good agreement with the actual observed value of it. Based on the nomogram, we divided PD-patients into high-, med- and low-risk subgroups. The OS of cancer patients in three risk groups were accurately differentiated either in all PD-patients or PD-NSCLC-patients, but not in the patients who responded to ICIs. Importantly, the prognosis of the low-risk PD-patients was significantly better compared with the patients in med- and low-risk groups (P < 0.001). Moreover, in the PD-patients with NSCLC, similar results were also found that patients had a worse OS in the high-risk group (P < 0.001). Interestingly, in contrast to the results in PD-patients, a comparable OS between high-, med- and low-risk groups based on our model was verified in the patients who responded to ICIs. Conclusions: The pretreatment NLR-based nomogram could predict the prognosis for pan-cancer patients with primary resistance to ICIs treatment.
Response assessment and toxicity in patients treated with immune checkpoint inhibitors in solid tumors : A comprehensive cancer care center experience from India.
Authors: Mehta Prashant , Sushmitha Cheemala , Sood Siddarth , Anand Shekhar , Badola Amit , Raju Anisha , Gupta Raman
Published: June 2022

e14562

Background: Checkpoint inhibitors are approved in various solid malignancies in either first-line or following progression on chemotherapy. These have shown good efficacy with low toxicity. However, there are very few studies from Indian centers. The purpose of the study was to assess the real world efficacy and toxicity in patients treated with Immunotherapy (IO) in various solid malignancies. Methods: The present study is a retrospective single-center hospital-based registry study that included 94 patients treated with immune checkpoint inhibitors in various solid malignancies from January 1, 2017 to December 31, 2020. The investigator assessed response at 3-months post-initiation of treatment has been reported. Patients who received less than two months of Immunotherapy were excluded in response analysis. Adverse events during IO were documented and graded using CTCAE (Common terminology criteria for adverse events), v.5.0. All statistical analysis was performed using Microsoft Excel 2016 and R software (Rx 64 version 3.6.2). Results: Sixty-nine patients who received more than 2 months of IO were assessed. Baseline characteristics of patients are listed in table 1. Lung cancer 29% (n= 27) Head and neck cancer 22% (n=21) and metastatic renal cell carcinoma 10% (n=9) were the common cancers where IO was given. Overall response rate at 3 months was 55% (n=38). Progressive disease and stable disease were seen in 39% (n=27) and 6% (n=5) patients respectively. The reported severe adverse events were pneumonitis, colitis, and hepatitis, with Grade 3 or more toxicities were in 7% (5/69) patients. Conclusions: IO was associated with clinical benefit and fewer toxic effects; however, increased treatment cost remains a significant concern in developing countries like India.[Table: see text]
Feasibility of next generation sequencing (NGS) from Uzbekistan: A preliminary data analysis.
Authors: Olimova Zilola Avazovna , Pendharkar Dinesh
Published: June 2022

e14579

Background: Molecular testing has become an important part of management of cancer patents. Due to local nonavailability and financial constrains NGS is picking up slowly in Uzbekistan. An attempt was being made to see feasibility and analyze next generation sequencing data from local population. Here we report data from first such big analysis. Methods: 76 advanced cancer patients were enrolled and tissue samples were sent for NGS. The analysis were sent to the lab for performing FOUNDATIONONER CDx (F1CDx) - the NGS based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations(indels), and copy numbers alterations(CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability(MSI), tumor mutational burden(TMB), and for selected forms of ovarian cancer, loss of heterozygosity(LOH) score, using DNA isolated from formalin-fixed, paraffin-embedded(FFPE) tumor tissue specimens. Results: Out of 76 patients (35 male 41female) there were 15/76 lung cancer patients, 13/76- breast cancer, 12/76 - colorectal, 5/76 - ovarian and other malignancies. In cohort of lung cancer, the multiple gene abnormalities detected were - EGFR-5/15; ALK-3/15; ROS-0; KRAS-1/15; NRAS-0; BRAF-1/15; MET-1/15; NTRK-3/15. In breast cancer population - BRCA1 mutation was found in - 3/13; BRCA2 in 1/13; ERBB-3/13; and ESR-1/13. In group with colorectal cancer the gene abnormalities located were - BRAF-1/12; KRAS-7/12: G12D-1; G12V-1; G12C-1; NRAS-0; MSI-3/7; MMR: MLH-1; MSH2-2; MSH3-2; MSH6-2. In ovarian cancer findings included - BRCA1 in 0/5; BRCA2-1/5; PALB-1/5; CHEK-1/5; PARP1-1/5. The most frequent genetic alteration observed in the whole group was TP53 (50/76). Commonest hereditary gene alterations besides TP53 were seen in ATM gene -12/76. A large number of Variant of Unknown Significance were also recorded. Conclusions: It is feasible to perform NGS analysis using reference laboratories. There is population of patients, willing to undergo specialized tests. Actionable molecular data information can be collected and utilized for patient care. No unique markers could be found due to small sample size.
A bivalent Tim-3/PD-1 bispecific antibody for the treatment of PD-1 antibody resistant or refractory NSCLC.
Authors: Liu Jiajian , Luan Y. , Deng H. , Wang F. , Wang C. , Zhang Z.
Published: June 2022

e14597

Background: Immune checkpoint inhibitors (ICI) PD-1/PD-L1 antibody are key drugs for the treatment of non-small cell lung cancer (NSCLC). Bispecific antibody is one of the strategies aimed at the clinical needs for NSCLC patients who are resistant to or refractory from ICI treatment. Tim-3, one of the next generation of ICB targets, is co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. Methods: A bivalent to both Tim-3 and PD-1 bispecific antibody (Bis5) was developed and is in Phase I clinical trials for NSCLC patients who are resistant to or refractory from PD-1 antibody treatment. Results: Bis5 showed affinity of 5-8 nM to both Tim-3 and PD-1. Moreover, Bis5 showed better cell activity than Tim-3 and PD-1 antibody combination to activated T cell as well as NK and DC. Bis5 showed 77%-88% tumor inhibition which is close to PD-1 antibody alone in MC38 model. Neither PD-1 antibody or PD-1 and Tim-3 antibody combination show any activity in CT26 model while Bis5 showed significant tumor inhibition activity and doubled the survival rate. The highest non-severe toxicity dose (HNSTD) was 200mpk in monkeys. ADA were 33.3% (2/6), 83.3% (5/6), and 0.0% (0/6) at doses of 2, 10, and 50 mpk, respectively. The T1/2 were 31.7-66.5 h for doses 2-50 mpk. Conclusions: A Phase I, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of Bis5 in patients with advanced and/or metastatic solid tumors has started. Seven cohorts (0.1, 0.3, 1, 3, 6, 10, 15 mg/kg) are planned to be enrolled sequentially in the dose escalation part. In the expansion part, a cohort group of 10 patients is planned for post PD-1 treated NSCLC as the second or third line treatment.
Ground-glass opacity showed response to immunotherapy in cancer patients.
Authors: Wu Fang , Hu Chunhong , Liu Xiaohan , Li Yizheng , Zeng Yue , He Liuer , Liu Junqi
Published: June 2022

e14605

Background: Ground glass opacities (GGO) are lesions with hazy density on CT. Immune checkpoint inhibitors (ICIs) achieved a significant improvement in the treatment of early and advanced non-small lung cancer (NSCLC). It is unclear whether ICI therapy show efficacy on GGO lesions. Methods: As the largest diameter of most lesions was less than 10mm, the definition of evaluable lesion we expanded the lower limit of the diameter to 4 mm. We retrospectively assessed cancer patients with GGOs who underwent at least two courses of immunotherapy between January 2016 and June 2021 in Second Xiangya hospital, China. Also, we evaluated GGOs that had been examined by low-dose thin-slice CT more than twice. Wilcoxon test was used to evaluate the length and diameter changes of GGO. We assessed the correlation between CT imaging features of GGO and the efficacy of immunotherapy through univariate and multivariate logistic regression. Results: Among eligible patients (n = 51), 35 were lung cancer patients and 16 were other tumor patients. Confirmed 95 GGOs were included. 68 GGOs were from lung cancer patients and 27 GGOs were from patients with other types of cancer (such as esophageal carcinoma, oral squamous cell carcinoma and hepatocarcinoma etc.). The diameter of GGO decreased significantly after immunotherapy (7.56 vs 4.31, P = 0.000). The same results were observed in lung cancer patients (7.98mm vs 4.92mm, P = 0.000) and in non-lung cancer patients (6.90mm vs 3.35mm, P = 0.001). The volume of GGO shirked significantly after immunotherapy in cancer patients (297.35mm3 vs 125.46mm3, P = 0.000) lung cancer patients (401.41 mm3 vs 164.91 mm3, P = 0.007) and non-lung cancer patients (137.93mm3 vs 65.04mm3, P = 0.000). Conclusions: GGO can response to immunotherapy, which indicates immunotherapy maybe potentially helpful for patients with multiple GGO lesions such as multiple primary lung cancer (MPLC) patients.
A phase 2 study of anlotinib in patients with metastatic pheochromocytoma/paraganglioma.
Authors: Tong Anli , Cui YunYing , Gao Yinjie , Cheng Yuejuan , Li Yuxiu
Published: June 2022

e15000

Background: Metastatic pheochromocytoma / paraganglioma (MPP) are rare while the prognosis was poor and the efficacy for current therapy was unsatisfactory. Anlotinib is a multikinase inhibitor targeting tumor angiogenesis and growth. Currently, there is no study evaluating the efficacy and safety of anlotinib in MPP pts. Methods: This is a prospective, single-arm phase 2 trial (NCT 04860700). Pts with histologically or radiologically confirmed MPP were enrolled. Main other inclusion criteria were 18-75 years old and ECOG PS 0-2. Anlotinib (8-12mg, QD) were given orally from d1 to d14 every 21 days until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included biochemical (catecholamine levels) response rate (BRR), progression-free survival (PFS) and safety. Results: 10 pts with MPP were enrolled and tumor response were evaluated in 6 patients. All these 6 patients had objective radiological evidence of progression within 6 months before enrollment. Tumor shrinkage was observed in 4 pts, 1 achieved partial response (PR) and 3 achieved stable disease (SD). The ORR was 16.7% (1/6). For 1 patient (p-1) with no measurable lesions, the pathological lymph nodes shrunk obviously and the rapid progression of bone metastatic lesion was well controlled. Among all 6 pts, catecholamine levels were obviously decreased in 4 pts, achieving a BRR of 67%. 1 patient who developed blindness at right eye caused by the progression of intracranial metastasis after chemotherapy had recovered the vision after anlotinib treatment. At the data cutoff date on February 1st, 2022, 1 patient terminated anlotinib since obvious elevation of catecholamine level and others were still in treatment with no radiographic disease progression. The median treatment duration was 7.5 cycles. The details of efficacy result were listed in table below. Overall, treatment of anlotinib blocked the rapid disease progression and achieved a durable disease control. The most common treatment-related adverse event (TRAE) was hypertension (5/6), which was well controlled, other TRAEs occurred in > 1 pts included grade 1 or 2 proteinuria (2/6) and palmar-plantar erythrodysesthesia syndrome (2/6). Conclusions: The preliminary results of this study indicated that anlotinib is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. Clinical trial information: NCT04860700. [Table: see text]
Antitumor pharmacological activity of hybrid organotin compounds on the Lewis epidermoid carcinoma model.
Authors: Dodokhova Margarita Avdeevna , Kotieva Inga Movlievna , Safronenko Andrey Vladimirovich , Alkhuseyn-Kulyaginova Margarita Stefanovna , Kotieva Elizaveta Мikhailovna , Kotieva Violetta Мikhailovna , Starostin Sergey Igorevich , Nikitin Evgeniy Aleksandrovich , Shpakovsky Dmitriy Borisovich , Milaeva Elena Rudolfovna
Published: June 2022

e15004

Background: New antitumor agents based on organic metal derivatives are intensively determined and created by now. Tin compounds are of great interest among them [Milaeva E.R.et al. Novel selective anticancer agents based on Sn and Au complexes. Pure & Applied Chemistry. 2020, 92, 1201-1216]. The results of studies on cell line models allowed us to conclude that cytotoxic effect of organotin compounds is pronounced, so it is advisable to hold their further studies on biological models in vivo [ Dodokhova M.A. et al. Pharmacotherapeutic potential’s evaluation of organotin compounds in vivo Biopharmaceutical journal, 13(3), 30 – 34 (2021); doi: 10.30906/2073-8099-2021-13-3-30-34]. For the specialists of experimental pharmacology and oncology is relevant to rate the antitumor activity of hybrid organotin compounds on experimental malignant tumors. Methods: The study was held on C57Bl/6 mice (females, n = 36, each cohort contained 12 mice) on a Lewis epidermoid carcinoma model (subcutaneous transplantation) [Kit O.I. et al. Influence of chronic neurogenic pain on the dynamics of the no-system functioning during melanoma B16/F10 growth in male mice. Siberian Journal of Oncology, 2021, 20(3), 67–75]. Bis-(3,5-di-tert-butyl-4-hydroxyphenyl)dimethyl tin(Me-3) and (3,5–di–tert–butyl–4–hydroxyphenylthiolate) triphenyl tin (Me-5) were used as chemotherapeutic agents. Groups of animals were formed as follows: I (experimental) - Me-3 at a dose of 75 mg / kg; II (experimental) - Me-5 at a dose of 50 mg / kg; III (control group) - without pharmacological substances. The doses were characterized as the most effective according to the results of a pharmacological activity screening study. The compounds were injected intraperitoneally daily for 5 days. All animals were euthanized since 21 days after the tumor cells transplantation. The antitumor effect was estimated by the percentage of tumor growth inhibition by weight (%). All manipulations were carried out in accordance with the European Convention for the Protection of Vertebrates Used for Experimental and Other Scientific Purposes (ETS 123). Results: After the intraperitoneal injection of chemical substances Me-3 and Me-5, there was revealed an inhibition of growth by weight of Lewis epidermoid carcinoma’s primary node for all experimental groups, 23.7% and 28% respectively. Conclusions: The injection of organotin compounds with different ligand groups allows us to suggest a biocidal activity of the organotin component on the primary tumor node cells.
Antibody-drug conjugate (ADC) joint disposition properties and their clinical utilities for comparative assessments in terms of favorable pharmacokinetic (PK) characteristics.
Authors: Williams Jason H. , Liao Kai H. , Palani Santhosh , Yin Donghua , Meng Xu
Published: June 2022

e15005

Background: PK characterization of ADCs is often fragmented using separate analyses of individual analytes. As such it is difficult to compare among ADCs in terms of PK characteristics critical for understanding the fate of an ADC complex as a whole and its clinical implications. While several integrated PK models have been applied to clinical datasets, these have been mostly for the purpose of identifying covariate effects on PK parameters. In this abstract, we propose 3 joint disposition metrics for integrated PK characterization of ADCs based on a combination of concentrations of ADC, payload (PL), conjugated payload (CPL), and total mAb (TAb, ADC plus unconjugated mAb) in the blood, and for defining what are favorable PK characteristics for ADCs. Methods: The joint disposition metrics representing linker stability (AUCmAb/AUCTab), therapeutic exposure ratio (CLPL/CLADC) and effective drug-antibody ratio (DAR) (AUCCPL/AUCADC), were derived mathematically from a framework of typical ADC designs and verified via modeling approaches using PK data of 3 clinical candidates, an anti-Trop2 ADC (PF-06664178) [King GT, et al. Invest New Drugs 2018;36(5):836-847], an anti-Notch3 ADC (PF-06650808) [Rosen LS, et al. Invest New Drugs 2020;38(1):120-130], and an anti-PTK7 ADC (PF-06647020) [Maitland ML, et al. Clin Cancer Res 2021;27(16):4511-4520]. Furthermore, the joint disposition metrics were calculated for a number of FDA-approved or otherwise well documented ADCs, which were selected as the information on ADC, payload and TAb analytes is available, to examine their clinical utilities in assessing among ADCs in terms of favorable PK characteristics. Results: The validity of the joint disposition metrics was demonstrated and verified for integrated PK characterization of ADCs. Estimates of the joint disposition metrics, for the linker stability, therapeutic exposure ratio and effective DAR, were obtained for the selected ADCs products and candidates (Table below), consistent with the expectation based on clinical experience. Conclusions: Three joint disposition metrics were derived for integrated PK characterization of ADCs using conventional PK analytes. Their clinical utilities were explored in assessing among ADCs in terms of favorable PK characteristics. Analyses of additional ADCs may be needed to further validate these metrics for broader usage.[Table: see text]
Integrative analysis of plasma cell-free DNA fragmentation and methylation patterns for colorectal cancer detection.
Authors: Shin Seungho , Jo Shin-Sang , Charton Clémentine , Kim Stephanie , Lim Hyeyeun , Kim Sol-yi , Chung Jongsuk , Hong Hye Kyung , Cho Yong Beom , Kim Jinho , Park Donghyun
Published: June 2022

e15022

Background: Recently, the analysis of epigenetic traits of cfDNA has been ben proven to be effective in early non-invasive cancer detection. Although integrating the DNA fragmentation and methylation information is expected to improve cancer detection performances, there are technical hurdles for effective integration of these data for detecting cancer non-invasively. In this study, we generated and analyzed targeted methylation sequencing data to develop a cancer detection method that uses both methylation and DNA fragment size patterns, optimized parameters for the model and evaluated the accuracy of the model in colon adenocarcinoma patients. Methods: Plasma cfDNA was collected from a total of 215 donors (111 COAD patients and 104 healthy adults) and targeted methylation sequencing data was generated using a customized panel covering 196k CpG sites containing robustly evaluated cancer specific markers. A total of 60 COAD and healthy samples, respectively, were used to train the model using elastic net and logistic regression. The remaining COAD 51 and healthy 44 samples were used as the test dataset in evaluating the model. Results: The integrative method achieved a high performance (94.12% sensitivity and 97.93% specificity) in classifying COAD patients and healthy individuals. Interestingly, when we decreased the bin size for cfDNA fragment length analysis, the performance of the model was significantly improved even with the same number of bins. Since the model with smaller bin size performed better, we could decrease the size target regions and data size. Our results proposed that analyzing fragment size at high resolution was an effective way to use the feature for cancer detection. By designing targeted Methyl-seq panel and generating high depth sequencing data (> 1000X), we could effectively integrate DNA methylation and fragmentation patterns for non-invasive cancer detection. Conclusions: In this study, we propose a novel non-invasive CRC detection method using targeted Methyl-seq data based on the integration of DNA methylation and fragmentation patterns. The adding of fragmentation features to the methylation information was effective in improving the sensitivity and specificity of CRC detection.
Blood based multigene testing using next generation sequencing to guide management in solid tumors: Experience from Augusta-Georgia.
Authors: Karki Nabin Raj , Parikh Jigar , Raval Priyanka , Nayak Asha , Abdel Karim Nagla Fawzy
Published: June 2022

e15023

Background: The pool of somatic alterations with prognostic and predictive significance in management of solid tumors is rapidly expanding. Multigene panel testing using next generation sequencing (NGS) technology from peripheral blood specimen is convenient and readily available in most oncology practices. Widespread adoption is lagging, in part due to anticipation of low probability of finding an actionable information. We share our experience of real-world utilization of this technology. Methods: Blood based next generation testing ordered by providers in Georgia (outside Atlanta) between January 1, 2015, and December 31, 2021, via Guardant platform for all solid tumors was included in this analysis. Guardant360 and Guardant360CDx assays sequenced circulating cell-free DNA to detect somatic alterations in up to 83 cancer associated genes. Data was obtained from Guardant360 on site of cancer, comprehensive genomic profile, and therapeutic options at the time of report. Results: 25 providers in Georgia from 11 institutions sent 335 blood samples from solid cancer patients. There were 192 males and 143 females. Most common cancers were lung and bronchus (45%), prostate (13%), breast (11%), pancreaticobiliary (8%), colorectal (4%), melanoma (3%) and kidney (3%). Any somatic mutations were detected in 85% (285/335) patients. A total 1524 alterations comprising of 977 unique alterations involving 83 genes were detected, with an average of 5.3 unique genomic alterations per patient. The genes that were altered at least 2% of times were TP53 (20%), ATM (5.5%), PI3KCA (4.3%), KRAS (3.8%), APC (3.5%), AR (2.8%), PDGFRA (2.8%), ARIDIA (2.5%) and BRAF (2.2%). Of all alterations, 11% (170/1524) were synonymous and 31% (474/1524) were variant of unknown significance. 85 samples had tumor mutational burden (TMB) results available, with 55% (47/85) having TMB > 10 mut/Mb. The average TMB was 14.9 mutations/Mb. Out of 252 specimens evaluated for microsatellite instability (MSI), 1 had high MSI. An FDA approved drug targeting the alteration/pathway was available for the same cancer in 4% (77/1524) and for other cancers in 19% (291/1524) of alterations. An approved drug matched to the alteration was available for the same cancer in 16% (54/335) patients and for other cancers in 45% (153/335) patients. 12.5% (42/335) patients were predicted not to benefit from certain drugs. 74% (249/335) had a clinical trial available for the mutations present. Conclusions: Eighty five percent solid tumor patients had a positive result in blood based NGS. Seventy four percent patients had at least one therapeutically applicable (suggestion for a drug to target the alteration approved for the same/different cancers or lack of benefit due to the alteration) information. Thus, blood based NGS yields clinically relevant and actionable information to guide management in solid tumors.
Real-world frequency of non-small cell lung cancer with ERBB2 exon 20 insertion (Exon20ins) mutations by site of insertion.
Authors: Yang Li , Huang Tanxiao , Qu Yuan , Wang Qichen , Teng Jiaman , Yang Bo , Chen Shifu , Kong Feng-Ming Spring
Published: June 2022

e15026

Background: ERBB2 Exon20ins mutations are in-frame insertions or duplications clustered around 2 key regions of Exon 20: the α-C helix (amino acid [AA] 770-774), the loop following the α-C helix (amino acid [AA] 775-783). The site of insertion can influence the outcome to selective EGFR/ERBB2 tyrosine kinase inhibitor therapy; ERBB2 exon 20 insertion mutation remains an unmet clinical need. The next-generation sequencing technology is a powerful tool to investigate the detailed ERBB2 mutations sites. Methods: We used real-world HaploX genomic data from patients (pts) with non-small cell lung cancer (NSCLC) to determine the frequency of ERBB2 Exon20ins mutations by site of insertion.The tumor tissue or serial blood sample was collected for each individual and the next-generation sequencing was performed using customized target captured HapOncoCDx panels. Results: From HaploX genomic data, 284/18205 pts (1.56%) with NSCLC had ERBB2 Exon20ins mutations: 72.2% were located in the helix, 27.8% in the loop (Table). The top 3 most frequent sites of insertion were Y772_A775dup (71.5%), G776delinsVC (11.3%), and G778_P780dup (6.0%). Conclusions: This real-world databases identified the helix as the most frequent insertion region of Exon 20 (∼72%). Exon20ins mutations were found less frequently in the loop (∼28%).[Table: see text]