bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk predictors as companion diagnostics for ER positive, HER2 negative early staged breast cancers from India.
Authors: Ramshankar Vijayalakshmi , Gopalakrishnan Aravinda lochan , Krishnamurthy Arvind , Radhakrishnan Venkatraman , Iyer Priya
Published: June 2024

e13049

Background: Gene expression profiling tests can identify women with breast cancer most likely to benefit from chemotherapy providing accurate prognostic information than other non-genetic clinicopathological parameters. These derive specific molecular features of a tumour indicating an increased likelihood of rapid growth, metastasis risk, and response to chemotherapy. The tests are typically performed after surgery, in conjunction with other available information such as tumour size and grade. The objective of the current study was to evaluate the risk prediction as a companion diagnostic assay for women with early staged breast cancers (ER+,HER2-ve). Methods: The risk prediction was done evaluating quantitative gene expression profiling on Nanostring nCounter Flex platform using total RNA extracted from FFPE tissues (n = 81) obtained from trucut biopsy tissues and post MRM specimens after ensuring the tumour representation. The gene quantitations were derived after normalisation and using nSolver and Roselind software based statistical analysis. Results: We found 55.5% (45/81) and 44.5% (36/81) to be of intrinsic subtype Luminal A and Luminal B among our breast tumours respectively. The risk of recurrence score was high for luminal B (36.1% ; 13/36) compared to luminal A (13.4% ; 6/45). There was no difference pertaining to the Tumour Inflammation score (TIS score) among the luminal A and B that depicted good response to immunotherapy with 80% (36/45) among the luminal A and 72.3% (26/36) among the luminal B. We have identified top 38 differentially expressed genes that drive the high breast cancer proliferation score among the breast cancers in Indian women. The top 5 genes influencing the risk of recurrence with high BCP among the luminal A tumours were GNLY, CHRNA5, CDC20, MELK, RRM2 and among luminal B we got FGFR2, AURKA, MYBL2, CCNE2 and UBE2C. The top genes combining both types influencing the genomic risk of recurrence were FGFR2, MYBL2, AURKA, TTK, UBE2c and ORC6. The genomic risk of recurrence is based only on the gene expression unlike the risk of recurrence which includes the tumour size and nodal involvement. The top genes influencing a poor response to immunotherapy among luminal A was CNTFR, HAPLN1, FGF12, COL4A6 and CDH2 and the top genes influencing poor response to immunotherapy among luminal B was FGFR2, MYCN, AURKA and FAM198B. Conclusions: This is the first study from India using risk prediction test as a companion diagnostics assay for ER+ HER2-ve early staged breast cancer. The salient genes important to drive the breast cancer proliferation increasing the risk of recurrence scores in both luminal A and Luminal B intrinsic subtypes have been derived. We can validate these gene signatures as smaller panels of tests that can be low cost and more suitable for LMIC like India. The BCP panel of genes were relevant driving the recurrence.
Evaluating the impact of GLP-1 receptor agonists on weight management in patients with breast cancer undergoing endocrine therapy: A comparative analysis.
Authors: Urueta Portillo Daniela , Mazo- Canola Marcela , Alhaj Sara
Published: June 2024

e13063

Background: Obesity has been linked to increased risk of recurrence in postmenopausal patients with history of Hormone Receptor positive + (HR) breast cancer. making weight management very important in this patient population. The use of endocrine therapy with aromatase inhibitor (AI) or selective estrogen modulators (SERM) in this population has been linked to weight gain (PMID: 37831449). This study evaluates the effectiveness of GLP-1 medications (Semaglutide, Liraglutide, Dulaglutide, Tirzepatide) in these patients, comparing weight loss outcomes to those in non-cancer populations. Methods: A retrospective analysis was conducted on breast cancer patients who were receiving endocrine therapy (AI or SERM) in combination with GLP-1 medications. The study primarily focused on evaluating mean baseline Body Mass Index (BMI), the proportion of patients with a BMI ≥30, and the mean percentage change in BMI at the 12-month mark, including 95% confidence intervals (CIs) for these changes. Results: The study found that the mean percentage changes in BMI at 12 months for the GLP-1 medications were as follows: Semaglutide resulted in a -4.34% change (95% CI [-7.66%, -1.02%]), in stark contrast to a -14% change reported in the general population (PMID: 33567185); Liraglutide showed a -3.51% change (95% CI [-8.48%, 1.45%]), compared to -8.4% (PMID: 26132939); Dulaglutide led to a -2.33% change (95% CI [-6.80%, 2.13%]), against -10.0% (PMID: 34189841); and Tirzepatide recorded a 2.31% change (CI [-11.47; 20.54]) relative to -15.0% (PMID: 35658024). These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population. Conclusions: The study concludes that breast cancer patients on endocrine therapy exhibit less significant weight loss with GLP-1 medication treatment than what has been observed in the general population. This suggests that endocrine therapy may reduce the weight-loss efficacy of GLP-1 medications in this particular patient group. Further prospective research is essential to elucidate the mechanisms behind this attenuated response and to develop effective weight management strategies tailored for breast cancer patients undergoing endocrine therapy.
The impact of vitamin D levels on the progression-free survival of women with hormone receptor-positive, HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors.
Authors: Aranda-Gutierrez Alejandro , Meraz-Brenez Andres , Gonzalez-Sanchez Hector Raul , Verduzco-Aguirre Haydee Cristina , Martinez-Cannon Bertha Alejandra
Published: June 2024

e13075

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) halt the transition from the G1 to the S phase, a process governed by the hyperphosphorylation of the retinoblastoma (Rb) protein. Similarly, vitamin D3 has been demonstrated to induce cell cycle arrest through the inhibition of various cyclin-dependent kinases, including those responsible for phosphorylating the Rb protein. Therefore, we hypothesized that suboptimal vitamin D levels may compromise the efficacy of CDK4/6i used to treat hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). Methods: We conducted a retrospective single-center study of women diagnosed with HR-positive, HER2-negative MBC and treated with any CDK4/6i between 2020 and 2023. Eligible patients were those who received at least one cycle of CDK4/6i, had a baseline 25-OH vitamin D measurement, and had a follow-up period of more than three months. Independent samples T-test, X2, and Fisher’s exact tests were used to evaluate associations between variables. Progression-free survival (PFS) was calculated using the Kaplan-Meier method and compared according to vitamin D levels using the log-rank test. Results: Among 31 patients, the mean age at diagnosis was 53 years (SD 14), 24 (77%) received CDK4/6i in the first-line setting, and 9 (29%) had suboptimal vitamin D levels (<20 ng/ml). Clinicopathological features based on vitamin D levels are shown (Table). The type of iCDK was different according to vitamin D levels (p = 0.036), with no other observed differences between groups. With a median follow-up of 26 months (95% CI 17-35) since iCDK initiation, median PFS was not reached for the entire cohort. A univariate analysis revealed that patients with suboptimal vitamin D levels had an inferior median PFS compared to patients with optimal levels (14 months [95%CI 4-24] vs. not reached [p=0.016]). Notably, no other parameter was associated with PFS in univariate analyses. Conclusions: In this cohort of Mexican patients with HR-positive, HER2-negativeMBC, suboptimal vitamin D levels adversely impacted PFS. Given the retrospective nature of this study and the limited number of patients, we emphasize the importance of studying these findings prospectively. [Table: see text]
Real-world comparison of the efficacy of three CDK4/6 inhibitors (CDK4/6i) in the first-line treatment of endocrine-sensitive advanced breast cancer (aBC): Single institution experience.
Authors: Dedic Plavetic Natalija , Čular Katarina , Gudelj Dora , Kaceljak Kristina , Križić Marija , Popovic Marina , Bulimbašić Stela , Sirotković-Skerlev Maja , Bubanović Sanda , Silovski Tajana
Published: June 2024

e13080

Background: The combination of CDK4/6i and endocrine therapy (ET) is the standard of care in the first-line treatment of hormone receptor positive (HR+), HER2- aBC. In registrational studies, the progression-free survival (PFS) of all three CDK4/6i ranged from 23.8 to 28.12 months and overall survival (OS) from 53.9 to 66.8. In Croatia, both ribociclib and palbociclib were approved for clinical use in August 2018 and abemaciclib in November 2019. Methods: This retrospective study included patients with endocrine-sensitive HR+, HER2- aBC treated with aromatase inhibitor (AI) and CDK4/6i in the first-line setting between August 2018 and October 2023 at University Hospital Centre Zagreb. Ethics committee approval was obtained before the study was commenced. Patient demographics, clinical presentation, tumor characteristics and treatment data were collected. Real-world PFS (rwPFS) and OS analyses were done with the final data cut-off date of December 31, 2023, using type 1 right censoring. Data were analyzed using the Kaplan-Meier method. Results: Of the 274 patients treated with a combination of CDK4/6i and ET in the first-line setting, 172 with endocrine-sensitive tumors (98 de novo metastatic and 74 with treatment-free interval longer than 12 months) were eligible for the study, of which 41.86% (72/172) received ribociclib, 44.19% (76/172) palbociclib, and 13.95% (24/172) abemaciclib. Overall rwPFS was 48 months (95% CI:35-53). In the abemaciclib group, median rwPFS and OS were not reached in the follow-up period. The rwPFS was 48 (95% CI:27-53) for ribociclib and 47 (95% CI:30-49) for palbociclib. The overall OS was 62 months (95% CI:47-62). Median OS in the ribociclib group was 62 months (95% CI:40-62) and in the palbociclib group 52 (95% CI:42-54) months. Conclusions: The PFS and OS results for palbociclib and ribociclib in this retrospective real-world study correlate with results from randomized clinical trials, confirming some inferiority of palbociclib compared to ribociclib in the context of OS. Due to the later availability of the drug, larger sample size and longer follow-up will be needed to make definitive conclusions on the efficacy of abemaciclib.
Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multicenter, open-label, single-arm, phase II study.
Authors: Peng Peijian , Xu Xiaolu , Zhong Jincai , Ye Jin-Hui , Wang Zhi-Hui , Wang Hong , Lin Hong , Du Caiwen , Zou Guorong , Ouyang Jie , Shi Ying-ying , Xu Fei , Yu Gengsheng , Lu Yongkui , Wang Yong-Xia , Cui Shi-En , Li Lu-Zhen
Published: June 2024

e13139

Background: The combination of eribulin and gemcitabine has demonstrated a similar progression-free survival (PFS) benefit as paclitaxel plus gemcitabine, with less neurotoxicity, for patients with MBC who have not received prior cytotoxic chemotherapy. However, the effect of eribulin plus gemcitabine on PFS in second line or beyond remains unclear. Methods: This open-label, single-arm, phase II study (NCT05263882) was conducted at 14 institutions in China. Eligible patients had histologically confirmed HER2-negative MBC and had received at least one prior taxane-containing chemotherapy regimen for advanced disease, and anthracycline-containing regimens in the adjuvant setting. Patients received intravenous infusions of eribulin (1.4 mg/m2) and gemcitabine (1.0 g/m2) on days 1 and 8 of a 21-day cycle. Efficacy outcomes, including PFS, objective response rate (ORR), and disease control rate (DCR), were assessed using RECIST v1.1. Adverse events (AEs) were graded according to NCI-CTC version 5.0. Results: A total of 70 patients were enrolled from November 2021 to October 2023; 47 (71.4%) had HR+HER2- and 18 (28.6%) had triple-negative MBC. The median patient age was 50 years (range: 31-68), and the sites of metastasis were the bone (68.6%), liver (52.9%), lymph nodes (48.6%), lung (44.3%) and brain (10.0%). Patients had received a median of 3 prior lines of systemic treatment, 2 lines of chemotherapy, and 1 line of endocrine treatment. Among all patients, the ORR was 48.6%, the DCR was 92.9% and the median PFS was 7.2 months. For the HR-positive subgroup, the median PFS was 8.4 months, while for the triple-negative subgroup, it was 6.3 months. Among HR+ patients who had received prior CDK4/6 inhibitor treatment, the median PFS was 7.2 months. In the subgroup of HR+ patients who had not received CDK4/6 inhibitor treatment, the median PFS had not been reached. For the HR+ HER2-low subgroup, the median PFS was 8.4 months. The most common grade 3-4 AEs were hematological, including neutropenia (38.6%), leukopenia (31.4%), anemia (24.3%), and thrombocytopenia (15.7%). Grade ≥3 perceived AEs were relatively low. Conclusions: Eribulin plus gemcitabine was effective in heavily pretreated patients with HER2- MBC, while maintaining a predictable and manageable safety profile. Clinical trial information: NCT05263882 . [Table: see text]
Association between GPRC5A expression and carboplatin efficacy in triple-negative breast cancer patients.
Authors: Li Lei , Tang Jinhai , Zhou Honglei
Published: June 2024

e13142

Background: Triple-negative breast cancer (TNBC) patients often face a grim prognosis, primarily due to their resistance to chemotherapy. Carboplatin is a common treatment for TNBC, particularly effective in BRCA1/2 mutations, but its efficacy varies in BRCA1/2 wild-type patients. A previous study identified GPRC5A expression as a biomarker for carboplatin chemotherapy in ovarian cancer, yet its association with carboplatin efficacy in TNBC remains unknown. This study aims to investigate whether GPRC5A can serve as a biomarker for predicting carboplatin efficacy in TNBC and to elucidate the underlying mechanisms. Methods: Analyzing clinical data from the past 5 years in Division of Breast & Thyroid Surgery in Jiangsu Province Hospital, we identified 199 TNBC patients treated with carboplatin. GPRC5A expression in TNBC tumors was assessed via immunohistochemistry (IHC) and evaluated by three individual pathologists. Expression levels were categorized as low (low), low (mild), high (moderate), and high (high). The Chi-square test was employed to assess the correlation between GPRC5A expression and carboplatin efficacy. TNBC-derived organoids were used to validate the relationship between GPRC5A expression and carboplatin sensitivity. Results: Among the 199 TNBC patients, 31 (17.2%) had BRCA1/2 mutations. The pathologic complete response (pCR) rate in BRCA1/2 mutation patients receiving carboplatin was 83.9%, compared to 61.3% in BRCA1/2 wild-type patients (p=0.016). Analyzing the relationship between GPRC5A expression and BRCA1/2 gene mutations in 145 patient samples revealed no significant association (p=0.37). Irrespective of BRCA1/2 mutation status, patients with low/mild GPRC5A expression had a higher pCR rate (74.1%) compared to those with moderate/high GPRC5A expression (45%, p<0.001). TNBC-derived organoids treated with carboplatin showed a cell survival rate of 31.25% (±8.5%) in low GPRC5A expression organoids and 56.25% (±12.6%) in high GPRC5A expression organoids (p=0.017). Conclusions: Our study demonstrates a correlation between GPRC5A expression and BRCA1/2 mutation status in TNBC. Furthermore, TNBC patients with low GPRC5A expression exhibited a more favorable response to carboplatin treatment, suggesting GPRC5A could be a potential biomarker for predicting carboplatin efficacy in TNBC patients.
Landscape of HER2-low breast cancer: Insights from a six-year study on incidence and clinicopathological characteristics.
Authors: Abou Khalil Michel , Habibian Lea , Martin Christine , Semaan Karl , Khaddage Abir , EL Kassis Nadine , Kesrouani Carole , Kourie Hampig Raphael , Atallah David M.
Published: June 2024

e13148

Background: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+ or 2+ in immunohistochemistry (IHC) and the absence of the ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2 breast cancer to novel anti-HER2 antibody-drug conjugates, rising interest in the HER2-low subtype. To date, data on characteristics of HER2-low breast cancer subtype is limited. Herein, we describe the clinicopathological characteristics of HER2-low breast cancer subtype compared HER2-zero/negative breast cancer. Methods: Real-world data from the Anatomic Pathology Division of Hotel Dieu de France, spanning 2017-2022, was retrospectively collected. Patients with HER2-IHC 3+ and HER2-IHC 2+ with ISH-amplified (HER2-positive) were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Patients were then categorized based on their hormone receptor (HR) status. Clinicopathological characteristics between the groups were compared using a Chi-Square and Mann–Whitney U tests. Results: Out of 1195 patients, we observed 341 (28.5%) HER2-low breast cancers cases. HER2-positive breast cancer cases (n=178; 14.9%) were subsequently excluded. There was no significant difference in age and sex between the HER2-low and the HER2-zero group (p=0.3 and 0.8, respectively). HER2-low breast cancer was associated with positive estrogen receptor (ER) status and positive progesterone receptor (PR) status (p<0.001 and p=0.01, respectively). Ductal adenocarcinomas were more frequently observed in the HER2-low group, whereas lobular and metaplastic adenocarcinomas were especially prevalent in the HER2-zero group (all p<0.001). When stratified by HR status, 87.4% of patients had HR-positive status and 12.6% were HR-negative. Furthermore, the occurrence rate of tumors with a low Ki-67 labeling index was comparable between the two groups (p=0.9). However, among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (p = 0.04; Table). Conclusions: In conclusion, this study showed that HER2-low is a distinct from HER2-zero and is frequently present among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Our findings suggest that, within HR-negative breast cancer, breast cancer with low HER2 expression exhibits a less aggressive profile when compared to HER2-zero tumors. [Table: see text]
Analysis of regulation of cell death pathway genes in CSC-enriched TNBC after treatment with doxorubicin: A potencial biomarker.
Authors: Andrade Warne Pedro , Barbosa Isabela Nery Tavares , Silva Luciana Maria , Moreira Milene Pereira
Published: June 2024

e13154

Background: Breast cancer is one of the most common cancers in women worldwide, and triple-negative breast cancer (TNBC) accounts for approximately 10-20% of all cases globally. TNBC has the worst prognosis among other types of breast cancer due to the lack of targeted therapy. In addition, TNBC tumors exhibit significant cellular and molecular heterogeneity, along with the presence of cells with cancer stem cell (CSC) characteristics, which contribute to the low response to available chemotherapy treatments, leading to chemoresistance, recurrence and metastasis. objective of this study is to evaluate the expression of genes related to cell death and survival pathways in CSCs-enriched spheroids DOX-treated obtained of BT-549 cells, a human TNBC cell line. The death receptor genes include TNFRSF10B, TNFRSF10C, CFLAR, RIPIK1, CASP8, NFKB1, RELA, and MLKL. Methods: To achieve this, gene expression was analyzed through RT-qPCR, comparing the expression in DOX-treated CSCs-enriched spheroids (IC50 55.7 μM/ 48h incubation) and untreated CSCs-enriched spheroids. Preliminary results indicated that, among the evaluated genes, only CFLAR, NFKB1, and RELA were expressed in the untreated CSCs-enriched spheroids, while the others were not expressed under any condition. Results: The genes CFLAR, NF- κ B and RELA showed considerable Ct values, while the remaining genes did not exhibit a Ct value in one or more samples. The gene CFLAR showed an overexpression, both in monolayers vs. spheroids and in treated spheroids vs. untreated spheroids, which can be related to the inhibition of Caspase 8 and consequently, the apoptotic activity of cells. The overexpression of the RELA, same as CFLAR, suggests increased inflammation pathway activation in the tumor microenvironment. However, the lower expression of the NF-κB1 gene in treated spheroids vs. untreated spheroids may be related to the production of ROS, suppressing its activation. Conclusions: The expression of NFKB1 and RELA genes is associated with the cellular survival pathway, which may be linked to the resistance to the drug observed in many patients. Previous studies of our group have shown that achieving a satisfactory result of DOX action on CSCs-enriched spheroids requires using a dose 100 times higher than that used in monolayer cells. This may be related to the non-expression of the TNFRSF10B, TNFRSF10C, RIPIK1, CASP8, and MLKL genes in CSCs-enriched spheroid DOX-treated. Thus, the results obtained so far indicate that DOX may have an impact on the expressed genes in CSCs-enriched spheroids and demonstrate the expression of apoptosis inhibitors in treated breast spheres. Consequently, the expression of these genes in BT-549 cells TNBC indicates a pro-inflammatory, anti-apoptotic, and pro-cell survival profile of CSC-enriched spheroids.
Dose escalation of KY-0118, PD-1, and IL-2v due-target fusion protein in patients with advanced renal clear cell carcinoma, urothelial carcinoma, and malignant melanoma.
Authors: Wu Guoxiang , Ju Dianwen , Su Yahui , Yu Helen
Published: June 2024

e14505

Background: KY-0118 is an anti-PD1 and IL-2v(variant) fusion protein for advanced solid tumors. The non-α biased design reduces the binding to IL2-Raβγ and enhanced binding to PD-1 & IL2-Rβγ positive TILs to drive increased proliferation and activation of NK and CD8+ T cells without unwanted expansion of Tregs. KY-0118 adopts specific single design, only 67kDa MW thus obtains excellent tumor penetration activity. The preclinical data shows higher antitumor activity in several CDX models compared with nivolumab and IL2wt. KY-0118 monotherapy is currently in Phase I escalation. Methods: The phase I dose escalation is a traditional 3+3 design, KY-0118 on Days 1, 8 and 15, 21-day treatment cycle, 9 dose levels (0.3μg/kg-64μg/kg) or higher doses of 3 to 6 patients are planned. The dose expansion cohort is currently enrolling. The primary endpoint was to evaluate the safety, tolerability, and determine the DLT, MTD, RP2D of KY 0118 when given alone. Secondary objectives are PK/PD characteristics and preliminary evidence of efficacy via ORR per RECIST v1.1 and iRECIST. Results: Up to Jan 31, 2024, 21 patients have been treated, the median number of prior lines of systemic therapy was 2. The dose level 8 (48µg/kg) of DLT observation period is ongoing, no DLT was observed in the administered dose groups. Most of TEAEs are transient grade 1-2, no TEAE led to withdrawal from this study. The most common nonhematologic TRAEs were pyrexia, flu-like symptoms, nausea, fatigue. 2 patients had grade 3 hematologic toxicity. Treatment-related sAEs were observed in one patient (include nausea, vomiting, and pulmonary embolism, now recovered and continuing treatment). No patients experienced complete or partial response, but several showed evidence of antitumor activity, at the dose of 36 ug/kg, 21% shrinkage of target lesions in a patient with RCC, the DCR for the 12, 24, and 36μg/kg dose levels are 33%, 75%, and 67%, respectively. Conclusions: These preliminary data suggest that KY-0118 demonstrated a manageable safety profile and encouraging early evidence of activity has been observed in locally advanced and/or metastatic solid tumors. Enrollment is ongoing, further results are forthcoming. Pts: 21; AEs: 399; TEAEs: 289 (100%); AESI: 13; sAEs: 8. Clinical trial information: NCT06175780 .
Risk stratification for immune effector cell-associated neurotoxicity syndrome in patients receiving chimeric antigen receptor T cell therapy.
Authors: Chishinga Nathaniel , Mapalo Martha Tendai , Bodine Charles Douglas
Published: June 2024

e14534

Background: Chimeric Antigen Receptor-T (CAR-T) cell therapy is a novel immunotherapy that has successfully been used to treat hematological cancers. However, CAR-T cell therapy has significant neurotoxic adverse effects including immune effector cell-associated neurotoxicity syndrome (ICANS). There is limited data that stratifies patients undergoing CAR-T cell therapy that are at increased risk of ICANS. We therefore investigated characteristics among patients receiving CAR-T cell therapy associated with increased risk of ICANS. Methods: We used ICD-10 codes to query the National Inpatient Sample database from the year 2016 to 2020 to identify patients receiving CAR-T cell therapy, aged 18 years and older. We used logistic regression models with random-effects to adjust for age, gender, race and chronic comorbidities at individual-level and clustering at hospital-level and obtained adjusted odds ratios (aORs) and 95% confidence intervals of factors associated with ICANS among patients receiving CAR-T cell therapy. Results: Of 467 patients receiving CAR-T cell therapy included (median age in years [interquartile range], 60 [54 -70]; 40.0% female; 75.6% White, 7.3% Black, 8.4% Hispanic), 29 (6.2%) had ICANS. Having acute kidney injury (AKI) [aOR = 4.2, 95%CI: 1.6–10.1] or sepsis [aOR = 6.1, 95%CI: 1.9 - 19.4] were significantly associated with ICANS compared to those without these risk factors. Conclusions: In patients receiving CAR-T cell therapy, having AKI or sepsis was found to be associated with an increased risk of ICANS. These findings suggest that identifying patients who have AKI or sepsis preceding or during CAR-T cell therapy infusions may help predict which patients are at increased risk of ICANS.
Effect of tobacco use on response to immunotherapy in patients with cancer.
Authors: Zubair Hina , Ferrick James P , Welch Christine A , Davis Elaine A , Kamran Amir Shahzad
Published: June 2024

e14537

Background: Evidence from existing literature suggests that it remains unclear if tobacco usage affects the efficacy of immune checkpoint inhibitors (ICI). This research aims to evaluate the connection between smoking and the effectiveness of immune checkpoint inhibitor (ICI) therapy in specific cancer types treated at our institution. Methods: This is a retrospective cohort study where cancer patients >18 years old who received immunotherapy from 2017 to 2023 were identified through our center’s Cancer Registry. This study focuses on three major cancer types: lung, head and neck, and melanoma. 458 patients with their demographics, staging, duration of treatment and last contact have been assessed. SAS 9.4 was used for analysis with Chi-square/Fisher’s Exact testing, Student’s T-test, life tests and the Cox proportional hazards model to discern the effects of tobacco use and overall survival. Results: Among 458 patients, 48 (10.48%) are never-smokers, and 410 (89.52%) are smokers (current or former). Overall, 211 (46.06%) have stage 0-IIIA, while 247 (53.93%) have IIIB-IVB tumors. The mean age is 66.08 years. Additionally, 330 patients (72.05%) received chemotherapy as part of their treatment regimen in addition to immunotherapy. Non-tobacco users exhibit a higher survival probability compared to tobacco users. At five years, non-tobacco users showed a survival rate of 41%, whereas tobacco users had a survival rate of 28% (p=0.01) and hazard ratio [HR] of 1.55 (95% confidence interval, 1.00–2.39). The median survival for all patients is 40 months among non-tobacco users and 19 months among tobacco users. Moreover, there is no difference in the survival rates between current and former smokers. Conclusions: The study demonstrates that immunotherapy has better outcomes and increases survival probability in non-tobacco users. Also, there is no difference in survival between current or former tobacco users. However, these findings warrant future prospective studies.
The clinical application of circulating tumor cells (CTCs) for immunotherapy in advanced pancreatic cancer.
Authors: Chen Jianhua , Zhang Li‘Na , Li Junjian , Wang Jing , Lin Ping , Wang Hongxia
Published: June 2024

e14541

Background: Circulating tumor cell (CTCs) has the potential utility for screening, prognostic and predictive assessment, and offers the potential for personalized management. This trial aimed to evaluate the prognostic and predictive impact of programmed cell death ligand 1 (PD-L1) positive CTCs in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: Twenty-three heavily treated advanced PDAC patients were randomized to receive camrelizumab combined with apatinib or capecitabine, or placebo plus capecitabine until disease progression or unacceptable toxicity, and peripheral blood CTCs samples were collected at baseline and after treatment. Forty-nine CTCs samples from 23 recruited advanced PDAC patients were detected by subtraction enrichment and immunostaining-FISH (SE-iFISH). PD-L1 expression level also was evaluated in tumor tissue samples by Immunohistochemistry (IHC). Investigator-assessed 6-month overall survival (OS) rate and 3-month progression-free survival (PFS) rate was evaluated. Results: The positive detection rate of CTCs in 23 PDAC patients was 95.7%. The cell sub-types of sizes of CTC analysis showed that 58.6% CTCs was the small CTCs (Diameter < 5μm). CTCs karyotypes analysis exhibited that triploid small CTCs were the main karyotype (41.2%) in small CTC, and pentaploid large CTCs was the major karyotype (74.7%) in large CTCs. PD-L1+ CTCs were detected in 43.5% of PDAC patients. Tissue PD-L1 positive detection rate was 50% (CPS > 1%) in available tissue samples(n=10). The presence of PD-L1+ CTCs cohort exhibited a significant increase in 6-month OS rate (80% versus 38.5%, P < 0.05) and 3-month PFS rate (70% versus 23.1%, P < 0.05) compared to PD-L1- CTCs cohort. Compared with the PD-L1- CTCs patients, the combination therapy camrelizumab markedly improved the 6-month OS rates (75% versus 50%) and 3-month PFS rate (62.5% versus 25%) in PD-L1+ CTC patients. Conclusions: PD-L1+ CTCs could be considered as a favorable prognostic marker in advanced PDAC. These results suggest that PD-L1+ CTCs might be used as a predictor of the efficacy of cancer immunotherapy in advanced PDAC, and provide a new monitoring method for the precise treatment of advanced PDAC. The expanding sample size test is now ongoing. Clinical trial information: ChiCTR1900024095 .
Anti-TNFR2 monoclonal antibody LBL-019 in patients with advanced malignant tumors: A phase I, first-in-human, open-label, multicenter, dose escalation Study.
Authors: Zhou Fei , Li Wei , Chen Yu , Lin Jing , Chen Ling , Zhang Huishan , Dong Xiaorong , Tong Fan , Zhang Ruiguang , Yin Yongmei , Liang Yan , Yang Nong , Hu Sheng , Zhuang Wei , Li Tao , Cai Shengli , Zhou Caicun
Published: June 2024

e14580

Background: LBL-019 is a humanized monoclonal IgG1 antibody against TNF receptor 2 (TNFR2). It specifically binds to TNFR2 with high affinity, co-stimulates TNFR2 in Fc crosslinking-dependent manner, results in activation of NF-κB signaling and T cell activation and expansion, promoting antitumor immunity. Here we report the preliminary safety and efficacy of LBL-019 in patients with advanced malignant tumors. Methods: This is a phase Ⅰ, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and PK of LBL-019 in patients with advanced solid tumors that progressed after standard systemic therapy. The dose escalation phase consists of 7 dose cohorts of LBL-019 at 0.2, 0.8, 3, 10, 15, 20, and 30 mg/kg (iv Q2W), using accelerated titration design (first dose) followed by 3+3 design. The primary endpoints were tolerability and safety. The second objectives were pharmacokinetics, pharmacodynamics, and preliminary efficacy (per RECIST 1.1). Results: As of January 02, 2024, 26 patients [17 (65.4%) male, median age 57 years (range:27, 72), 22 (84.6%) ECOG score of 1] were treated in phase Ⅰ. Tumor types include 7 (26.9%) hepatocellular carcinoma (HCC), 4 (15.4%) melanoma, and 15 (57.7%) other tumors. 19 (73%) previously received anti-PD(L)-1 treatment. During the study, no DLT was observed, and the MTD was not reached. The median follow-up was 12.2 months (95%CI: 7.5, 15.9). 19 patients (73.1%) experienced TRAEs of all grades, with 2 (7.7%) having grade ≥3 TRAEs. The most common TRAEs (≥10%) included lipase increased (19.2%), anaemia (19.2%), aspartate aminotransferase increased (15.4%), pruritus (11.5%), rash (11.5%). Treatment interruption and permanent discontinuation due to TEAEs occurred in 12 (46.2%) and 1 (3.8%) patient, respectively. Thirteen patients (50.0%) experienced SAEs, and one of SAE was related to treatment. Out of 23 who underwent efficacy evaluation, 1 patient with HCC achieved PR, and 7 patients achieved SD. The patient with PR and 6 patients with SD received prior immunotherapy, the ORR and DCR were 4.3% and 34.8%, respectively. The DoR in the patient with PR has exceeded 10 months. Conclusions: LBL-019 is well tolerable and has demonstrated preliminary efficacy in patients with advanced malignant tumors. Clinical trial information: NCT05223231 .
Intravenous infusion (IV) or intracavitary perfusion (IP) of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody: Analyses of two phase 1 studies.
Authors: Niu Jiaxin , Barve Minal A. , Spira Alexander I. , Edenfield William Jeffery , Wang Kevin , Liu Gaiyun , McKean Meredith , Fu Wenmin , Qiu Meng , Cheng Peng
Published: June 2024

e14581

Background: T3011 is a recombinant HSV-1 oncolytic virus expressing both IL-12 and anti-human PD-1 antibody. Upon delivery, locally produced IL-12 and PD-1 induces IFN-γ production, enhances the oncolytic activity of NK cells and cytotoxic T lymphocytes, promotes anti-angiogenesis, and inhibits tumor growth. We present the results of T3011 monotherapy administered via IV in advanced solid tumors or IP for malignant pleural effusion/ascites. Methods: In a phase 1, dose-escalation and expansion study using a 3+3 design with 5 cohorts (1×106, 1×107, 1×108, 5×108, 1×109 PFU), T3011 was administered intravenously on Days 1, 4, 8, 11,15,18 of a 28-day cycle in pts with advanced solid tumors. The primary objective was to evaluate the safety and tolerability of IV T3011, characterize dose-limiting toxicities (DLTs), MTD or RP2D, pharmacokinetic and pharmacodynamic profiles. In another pilot study to evaluate the safety and efficacy of T3011 in pts with malignant pleural effusion or ascites, T3011 was infused into the pleural or peritoneal cavity through an indwelling catheter on Days 1, 4, 8, 11 with 2 cohorts (5×108, 2×109 PFU). The response of malignant pleural effusion or ascites was assessed by WHO criteria. Results: As of 15 Dec 2023, 18 pts were enrolled and treated with IV T3011,4 pts received IV T3011 therapy at the highest dose level, 1×109 PFU. T3011 was well tolerated without ≥ Grade 3 TRAEs or DLTs. MTD was not reached. The most common TRAEs (≥ 10%) were nausea and infusion-related reactions, diarrhea, etc. Among 14 evaluable pts with advanced solid tumors, 3 pts had confirmed SD per RECIST1.1 and tumor burden reduced significantly. All the pts had detectable T3011 DNA in blood within 0.5-2 hours after administration, which was cleared subsequently within 3-7 days. As of 5 Jan 2024, 6 pts (pleural effusion 3, ascites 3) were dosed with IP T3011. 2 pts received 5×108 PFU and 4 pts received 2×109 PFU. Most TEAEs were grade 1 or 2. Only 1 pt developed grade 3 leukopenia, which resolved with G-CSF. No SAE occurred. 3 pts with pleural effusion showed 1 CR, 1 PR and 1 SD. 3 pts with malignant ascites secondary to advanced colorectal cancer, 1 was evaluable with PR. Conclusions: IV T3011 monotherapy has a very manageable safety profile and some encouraging activity in advanced solid tumors. IP T3011 monotherapy is also well tolerated and demonstrates promising activity against malignant pleural effusion and ascites. Clinical trial information: NCT04780217 .
CRPA1A2: A novel TCR-based T-cell engager targeting MAGEA1-positive solid tumors.
Authors: Xie Xingwang , J Dong , Bi Jinglei , Zhai Jiahui , Yan Baoqi , Li Yonghong , Wang Jianghua , Zhu Yaping
Published: June 2024

e14589

Background: MAGEA1, identified as a cancer/testis antigen, is highly expression in various solid tumors, including hepatocellular carcinoma, non-small cell lung cancer, but absent in normal tissues except male germ cells and placenta, both of which lacking HLA class molecules. This selective expression of HLA-MAGEA1 epitope makes it a promising target for cancer therapy. However, its intracellular localization poses a challenge for conventional antibodies designed to target surface-expressed antigens. TCR-based T-cell engagers, such as Tebentafusp, overcome this hurdle by targeting intracellular protein-derived peptides presented on cancer cell surfaces via HLA, enabling precise cytotoxic T cell attacks. Notably, Tebentafusp has shown significant clinical benefits by improving survival rates in metastatic uveal melanoma, underscoring the efficacy of TCR-based T-cell engagers in treating MAGEA1-positive tumors. Methods: We have developed an advanced structural format, CR62, consisting of a anti-CD3 single chain fragment, a soluble modified TCR, and an Fc region. Additionally, the use of CorreGene's SMART-TCR system has facilitated the acquisition of TCRs with high affinities in the pico-molar range. By leveraging CR62 and a high-affinity TCR, we have conceptualized the TCR-based T-cell engager, CRPA1A2. Comprehensive preclinical assessments have been conducted to evaluate CRPA1A2's safety and efficacy. Results: CRPA1A2 is designed to specifically target the HLA-A*02:01-restricted MAGEA1 epitope, effectively inhibiting tumor growth. CRPA1A2 is characterized by its exceptional soluble expression in CHO cells, minimal homodimer miss-assembly and simplifying purification. It is strategically engineered with a high-affinity TCR and a low-affinity anti-CD3 scFv to optimize the efficacy and safety. In vitro studies, CRPA1A2 showed strong ability to eliminate tumor cells and induce IFN-γ release, effective even at low MAGEA1 epitope densities, with a therapeutic window that spans over three orders of magnitude, suggesting a 1000-fold greater activity against antigen-positive cancer cells compared to antigen-negative cells. In vivo, using a tumor-bearing mouse model, CRPA1A2 has been shown to recruit T cells into subcutaneous solid tumors, expand CD8+ T cell populations, and significantly reduce tumor mass. Notably, CRPA1A2 has an extended half-life of 120 hours and demonstrates preferential accumulation in tumor tissues, thereby enhancing its therapeutic potential. Moreover, the safety assessments for CRPA1A2 highlight its exceptional specificity, with in vitro studies showing no evidence of off-target toxicity, on-target off-tumor toxicity, or alloreactivity and favorable tolerance in mice during in vivo studies. Conclusions: CRPA1A2 has emerged as a superior TCR-based T-cell engager with exceptional antitumor efficacy and promising safety profile.
Effect of aberrant N-glycosylation of PD-L1 on the potency of anti-PD-1 treatments.
Authors: Kaufman Bar , Erlichman Nofar , Meshel Tsipi , Ben-Baruch Adit , Elkabets Moshe , Porgador Angel
Published: June 2024

e14599

Background: Immune checkpoint inhibitors (ICIs) targeting the PD1/PDL1 axis have revolutionized the way we treat cancer patient. Yet, response rate to these treatments remains low. Post translational modifications of PD-L1 in the form of N-glycosylation play a crucial role in both receptor-ligand interaction and in the potency of PD1/PDL1 ICIs. Understanding the effect of each N-glycosylation site is crucial for patient stratification for treatment groups and may help to increase response rate to anti-PD1/PDL1 ICIs. We recently developed the Immune-Checkpoint Artificial Reporter (IcAR) technology to assess specific ICI potency for target tumors including clinical samples. Using IcAR expressing recombinant human PD1 receptor we can analyze clinical response of patients to PD1-PDL1 blocking drugs and analyze the glycan-modified PDL1 expressing cancer cells. Methods: We have created two cell lines (MDA-MB231 and MCF7) overexpressing PD-L1 in its wildtype form, single mutated glycosylation sites (N35A, N192A, N200A, N219A) and all sites mutated together (Nx4). Using IcAR-PD1 we measured the functional binding of the different mutated cell lines, cell derived xenografts (CDX) and fixed cell samples to evaluate baseline binding. Later we have incubated IcAR-PD1 and mutated cell liens together with multiple clinically used PD1/PDL1 ICIs to evaluate the inhibition of interaction of each ICI. Results: While staining and functional interaction of PDL1 and single mutants is similar, removing all four N-glycosylation sites (Nx4) decreased both the staining of PDL1 and functional binding. Interestingly, blocking capacity of different ICIs was impaired by N35A PDL1 mutation, and was absolute through all concentration (2.5 to 40 ug/mL) when employed on the Nx4 cell lines. While anti-PDL1 ICIs were managed to block PD-1/PD-L1 interaction trough all cell lines and mutants, the inhibitory capacity of anti-PD1 ICIs was impaired by glycosylation, especially on N35. Conclusions: Aberrant glycosylation of PD-L1 impair the potency of anti-PD-1 treatment in cancer cell lines. These results might explain why patients with negative PD-L1 staining (Nx4), might respond to ICIs, and suggest an explanation of mechanism in which patients with high PD-L1 staining (i.e. N35), might not respond to anti-PD-1 treatments. Our results shed a light on the mechanism of ICI resistance and response – using this knowledge patient will be stratify better into treatment groups, getting oncology a step closer to precision immunology.
Risk factors for thrombotic events among patients taking immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Song Junmin , Caceres Lessa Ana Yasmin , Lee Pei-Lun , Chowdhury Ishmum , Chang Yu , Chang Yu-Cheng , Schwartz Rachel , Chi Kuan-Yu , Kumar Abhishek
Published: June 2024

e14610

Background: Cancer is well known to be a hypercoagulable state, and several studies suggest that targeted therapies, including immune checkpoint inhibitors (ICIs), may also cause thrombotic events. Despite the identification of multiple risk factors associated with ICI administration, no studies have definitively clarified these factors. This study aims to comprehensively investigate the risk factors of thrombotic events upon ICI use. Methods: We conducted a systematic review and meta-analysis. Search terms included immune checkpoint inhibitors (PD-1, PD-L1, and CTLA-4 inhibitors) and thrombotic events (venous, arterial thrombosis, and immune-related adverse events). The primary endpoint was calculating each risk factor's aggregated odds ratio (OR) for any kind of thrombotic event, including venous and arterial thrombosis. The secondary endpoint was to combine the hazard ratio (HR) for each risk factor on thrombosis formation. Results: Out of 8718 studies found, a total of 13 studies with 10608 patients were included. Most patients had non-small cell lung cancer (37.2%) or melanoma (24.8%) and had advanced disease (stage IV being 84.9%). All possible risk factors included in the studies were extracted, and their OR and HR were aggregated. Notably, previous history of thrombus (OR: 3.01; 95% CI: 1.53-5.92), history of COPD (OR: 1.87; 95% CI: 1.00-3.51), smoking history (OR: 1.69; 95% CI: 1.15-2.48), and BMI higher than 30 (OR: 1.68, 1.37-2.07) were associated with a higher risk of thrombotic events. In multivariate analysis, poor performance status of ECOG PS ≥ 2 (HR: 1.55, 95% CI: 1.02-2.36, I2: 35%) and Khorana risk score ≥ 2 (HR: 1.5, 95% CI: 1.23-1.84, I2: 0%) showed higher thrombotic risk. Conclusions: Similar to the known risk factors for thrombosis, previous history of thrombus, smoking history, and obesity are predictors of future thrombus in patients on ICI treatment. Further studies are needed to know if arterial and venous events happen at different rates and/or are associated with different risk factors. [Table: see text]
Relationship of angiotensin II receptor blocker (ARB) to the effectiveness of immune checkpoint blockade (ICB) in non-small-cell lung cancer (NSCLC) and inhibition of angiotensin II/AGTR1 signaling in fibroblasts to reduce collagen deposition in the tumor microenvironment (TME).
Authors: Yang Kai , Chu Jiahui , Mei Jie , Yin Yongmei
Published: June 2024

e14618

Background: Immune checkpoint blockade (ICB) has achieved remarkable success. However, not all patients with advanced tumors respond to ICB. Remodeling of the tumor microenvironment (TME) has emerged as a strategy to facilitate the development of cancer therapies. As the most notable features of TME, immune cells and collagens play a significant role in influencing anti-tumor immunity, with collagen deposition is the most significant physical barrier that hinders immune cell infiltration. Cancer patients are often prescribed multiple medications to address pre-existing comorbidities or side effects from anti-tumor therapy. Given the high prevalence of concurrent medications and the potential for interactions between them and ICB, we identified that the angiotensin II receptor 1 (AGTR1) was positively expressed in CAFs and AGTR1 inhibitor angiotensin receptor blocker (ARB) suppressed the expression of type I collagen and promote immune infiltration. Methods: Retrospective clinical study: An in-house cohort was a multi-center cohort and included 270 patients with non-small-cell lung cancer (NSCLC) receiving ICB therapy from 2020 to 2021 from The Affiliated Wuxi People's Hospital of Nanjing Medical University and The First Affiliated Hospital of Nanjing Medical University. Meta-analysis: 4 studies involving 1,268 participants in total and an in-house cohort with 270 participants were included. We performed an additional meta-analysis on the association between the use of ARBs in cancer patients receiving ICB therapy. Animal models: Xenograft tumor models were randomly divided into two groups, including control and Losartan-treated groups, and mouse cancer models were randomly divided into three groups at the first round and four groups at the second round. Three groups included control, Losartan-treated, and Losartan-treated & CD8-deleted groups, and four groups included control, Losartan-treated, anti-PD-1-treated, and Losartan & anti-PD-1-treated groups. Results: Patients with NSCLC who received ARBs showed improved overall survival and response to immunotherapy compared to those who did not receive ARBs. Losartan, a representative drug of the ARB class, significantly increased collagen deposition in mice tumors, elevated levels of immune cell infiltration, and sensitized anti-PD-1 therapy. Conclusions: We reported that Losartan shaped an inflamed TME by inhibiting collagen I expression of CAFs and enhanced anti-PD-1 immunotherapy in the mouse tumor model. We recommend that ARB should be selected as much as possible for patients receiving ICB therapy and requiring antihypertensive treatment.