bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics, pharmacodynamics, and toxicity of a PD-1-targeted IL-15 in cynomolgus monkeys.
Authors: Ji Changhua , Kuang Bing , Buetow Bernard S. , Vitsky Allison , Xu Yuanming , Matsumoto Diane , Kraynov Eugenia , Chaparro-Riggers Javier
Published: June 2024

e14568

Background: Interleukin (IL)-15 is a potent cytokine that enhances the proliferation and effector functions of IL-2Rβ/γ-expressing lymphocytes, such as NK cells and T cell subtypes (CD8+, CD4+, gd, and NKT). PF-07209960 is a novel bispecific fusion protein composed of an anti-PD-1 antibody and engineered IL-15 cytokine mutein with reduced binding affinity to its receptors. PD-1 is expressed on tumor-infiltrating T cells at relatively high levels. PF-07209960 has reduced activity on PD-1-negative NK cells and enhanced activity on PD-1-expressing intratumoral CD8+ T cells, therefore is expected to have improved therapeutic window. Methods: The pharmacokinetics (PK), pharmacodynamics (PD), and toxicity of PF-07209960 were evaluated following once every other week subcutaneous (SC) or intravenous (IV) administration to cynomolgus monkeys in a two-dose PKPD (0.01 – 0.3 mg/kg/dose) study and in a three-dose (SC route) GLP toxicity study (0.1 – 3 mg/kg/dose). Results: PF-07209960 showed dose-dependent pharmacokinetics with a terminal T1/2 of 8 and 13 hours following IV administration at 0.03 and 0.1 mg/kg, respectively. The clearance is faster than a typical IgG1 antibody. Slightly faster clearance was also observed following the second dose, likely due to increased target pool and formation of anti-drug antibodies (ADA). Despite a high incidence rate of ADA (92%) observed in GLP toxicity study, PD-1 receptor occupancy, IL-15 signaling (STAT5 phosphorylation) and T cell expansion were comparable following the first and second doses. Activation and proliferation of T cells were observed with largest increase in cell numbers found in gamma delta T cells, followed by CD4+ and CD8+ T cells, and then NK cells. The expansion of T cells and NK cells in peripheral blood peaked around Day 8 and waned to near baseline levels by Day 15. Release of cytokines IL-6, IFNɣ, and IL-10 were detected, which peaked at 72 hours postdose. All animals at 3 mg/kg/dose were euthanized in a moribund condition on Day 4 of the dosing phase, coincident with the peak of cytokine release. Four out of six monkeys administered 1 mg/kg were euthanized between Day 6 and Day 16 due to thrombocytopenia, bleeding, and poor physical condition. Microscopic evaluations revealed generalized mononuclear infiltration in various tissues. Both the no observed adverse effect level (NOAEL) and the highest non severely toxic dose (HNSTD) were determined to be 0.3 mg/kg/dose, which corresponded to mean Cmax and AUC48 values of 1.15 µg/mL and 37.9 µg*h/mL, respectively. Conclusions: PF-07209960 demonstrated dose-dependent exposure and robust PD (T cell and NK cell subsets expansion and cytokine release) in cynomolgus monkeys, with well-characterized safety profile. In summary, the results of the present study support Phase I clinical evaluation of PF-07209960 in cancer patients.
Hyaluronic acid hydrogel to modulate tumor cell clustering and programmed death ligand 1 signaling in cancer stem cells.
Authors: Basu Kaustuv , Mongeau Luc
Published: June 2024

e14584

Background: The root of malignancy lies in the extracellular matrix (ECM) surrounding the stromal cells. Thus, current therapeutic targets manipulate abnormal tumor microenvironments (TME), which nourish cancer stem cells (CSC) and induce tumor cell clustering (TCC). Notably, despite the first line of clinical therapy with surgery and chemotherapy, uncontrolled self-renewal of CSCs, conversion of non-CSCs to CSCs, and TCC trigger cancer recurrence. The transmembrane glycoprotein CD44 is thought to be a potential master regulator in cancer recurrence as it interacts with hyaluronic acid (HA) in TME, expresses aberrantly on CSCs, induces TCC by homophilic interactions like Plakoglobin despite less understanding on their crosstalk, and promotes expression of pro-tumorigenic factor programmed death ligand 1 (PD-L1). Notably, CD44 is expressed in multiple isoforms, and splice isoform switching of CD44 dictates the properties of CSC, which still needs to be clarified. Hence, we aimed to characterize CSCs based on CD44 isoform expression, investigate the crosstalk between CD44 and Plakoglobin, and then design a novel injectable HA hydrogel that can disguise TME and suppress PD-L1 to combat cancer recurrence. Methods: To characterize CSCs, we prepared different scaffolds of HA of varied molecular weights and other ECM proteins, cultured cancer cells (MDA-MB-231, HeLa), and determined the expression of CD44 isoforms. We sorted CD44+/CD24- expressing CSC by flow cytometry. We implemented immunoprecipitation to detect the interaction between CD44 and Plakoglobin. We created a novel HA hydrogel composed of low and very high molecular weight HA, thiolated gelatin, and other components crosslinked with PEGDA. Using a torsional rheometer, we measured matrix stiffness. We assessed the cell proliferation efficiency of CSC by a colony-forming assay. Results: The study disclosed that CD44 isoforms expressed differently based on ECM properties. Matrix stiffness dictated CD44 isoform expression. We observed that CD44 interacted with Plakoglobin. CD44 ablation upregulated Plakoglobin significantly. Tumor suppressor p53 played a significant role in CD44-Plakoglobin crosstalk. We observed that the injectable hydrogel modulated CD44-Plakoglobin signaling and inhibited TCC, likely promoting anoikis. The hydrogel affected CD44 splicing and modified the activity of the CD44 intracellular domain, which interacts with PD-L1 and thus suppressed PD-L1 expression significantly in CSC. Conclusions: Currently, antibodies targeting PD-1/PD-L1 signaling have been clinically approved for various cancers. However, this regimen of treatment is expensive. We report a novel injectable hydrogel that can disguise TME, modulate CSCs and PD-L1, and may advance an alternative cost-effective avenue for cancer immunotherapy.
Expression of alternatively spliced PD-L1 RNA with skipping of transmembrane domain.
Authors: Charifa Ahmad , Lam Alfonso , Zhang Hong , Estella Jeffrey , Agersborg Sally , Mohtashamian Arash , Albitar Maher
Published: June 2024

e14596

Background: Programmed death-ligand 1 (PD-L1) is a transmembrane ligand for the programmed cell death protein 1 (PD-1), a receptor that inhibits T-cell activity. The PD-L1/PD-1 immune checkpoint axis has been successfully targeted to enhance antitumor immune responses. This gene is composed of seven exons. Exons 1-4 are responsible for the extracellular domain, exon 5 for the transmembrane domain, and exons 6-7 for the intracellular domain. Emerging data indicates that alternative splicing in genes is an important mechanism for expression of different isoforms that may influence antibody-based therapies. We explored the potential of the presence of alternative splicing in PD-L1 transcripts via sequencing of PD-L1 RNA in patients with various type of solid tumor cancers. Methods: RNA was extracted from 3443 FFPE solid tumor samples including lung, colon, pancreas, breast, and other cancer types. In addition, cfRNA was extracted from 532 peripheral blood plasma samples from patients with solid tumor cancers. RNA was sequenced using a hybrid capture targeted RNA panel on FFPE samples and peripheral blood with analysis focused on PD-L1 gene transcript. Quantification of RNA transcript was done using Salmon algorithm. Results: Of the 3443 FFPE samples, 38 (1.2%) samples showed alternative splicing involving deletion of exon 5 (PD-L1∆Ex5). The alternative splicing was in 2.10% of lung cancer, 2% of colon cancer, 0.70% of pancreatic cancer, 1.40% of gastric cancer, 0.38% of breast cancer, 0.30% of ovarian cancer, 1.10% of sarcoma cases, 1.50% of glioblastomas, 3.30% of thyroid cancer and 2% of urothelial cancer. Of the 532 cfRNA samples, 20 (3.7%) showed PD-L1∆Ex5. The median percentage of PD-L1∆Ex5 transcripts was 2.2% of total PD-L1 transcripts in tissue samples as compared with 6.6% in cfDNA samples. In tissue samples, there was a correlation between levels of PD-L1 and PD-L1∆Ex5 (r = .567, p < .001). In contrast, cfRNA showed no significant correlation between levels of PD-L1 and levels of PD-L1∆Ex5 (r = .268). Conclusions: PD-L1 exon 5 skipping was detected in a number of patients with different types of solid tumor cancers. The percentage of skipping transcripts is low in cells and relatively higher in cfRNA. Since exon 5 skipping deletes the transmembrane domain, the PD-L1 protein may remain in the cytoplasm or perhaps is secreted as cell-free PD-L1 protein. The demonstration of relatively higher levels of PD-L1∆Ex5 in cfRNA is likely reflecting higher turnover of cells and raises the possibility that cells with this isoform of PD-L1 are more aggressive than cells without the expression of this isoform. Further studies are needed to explore the clinical relevance of the expression of such abnormal PD-L1 protein on treatment with immune checkpoint inhibitors.
Treatment-related adverse events of PD-1 versus PD-L1 inhibitors commonly used in lung cancer therapy: Analysis of real-world FAERS data.
Authors: Findakly Dawood , Beedupalli Kavitha
Published: June 2024

e14598

Background: With the increasing utilization of immune checkpoint inhibitors (ICIs) in the dynamic landscape of cancer treatment, understanding immune-related adverse events (AEs) has become crucial for optimizing patient outcomes and therapeutic selection. In this study, we utilized the FDA Adverse Event Reporting System (FAERS) database to assess AEs reported with commonly used PD-1 and PD-L1 inhibitors in lung cancer therapy. Methods: We conducted a retrospective FAERS public database review to assess anti-PD-1 inhibitors (Pembrolizumab and Nivolumab) and anti-PD-L1 inhibitors (Atezolizumab and Durvalumab) reported AEs from January 2017 through September 30, 2023. We assessed disproportionality signals by calculating the reporting odds ratio (ROR) with a 95% confidence interval (CI). Significance was determined when the lower limit of the 95% CI exceeded 1. Results: In our analysis of 134,184 reported AEs, anti-PD-1 therapies had higher rates of cardiac AEs (ROR = 1.08; 95% CI: 1.03-1.14; P = 0.0015), vascular AEs (ROR = 1.23; 95% CI: 1.17-1.30; P < 0.0001), respiratory AEs (ROR = 1.30; 95% CI: 1.25-1.34; P < 0.0001), gastrointestinal AEs (ROR = 1.04; 95% CI: 1.01-1.08; P = 0.0117), hepatobiliary AEs (ROR = 1.12; 95% CI: 1.07-1.17; P < 0.0001), and renal and urinary AEs (ROR = 1.06; 95% CI: 1.01-1.11; P = 0.0195) compared to anti-PD-L1 therapies. Conversely, anti-PD-L1 therapies had higher rates of endocrine AEs (ROR = 1.31; 95% CI: 1.25-1.38; P < 0.0001), skin and subcutaneous tissue AEs (ROR = 1.43; 95% CI: 1.37-1.49; P < 0.0001), and musculoskeletal and connective tissue AEs (ROR = 1.33; 95% CI: 1.26-1.39; P < 0.0001) compared to anti-PD-1 therapies. Conclusions: Our study provides insights into the adverse event profiles of selected anti-PD-1 and anti-PD-L1 therapies in a real-world clinical setting. Further prospective studies are essential to enhance our understanding of the comparative safety profiles of these agents, guiding personalized treatment decisions and, ultimately, advancing patient outcomes.
Arthralgia in patients with cancer receiving immune checkpoint inhibitor: A systematic review and meta-analysis.
Authors: Nishimura Yoshito , Estaris Jonathan , Koseki Mako , Elias Evelyn , Chesta Fnu , Takaoka Kensuke , Shao Theresa , Fujiwara Yu
Published: June 2024

e14601

Background: Immune checkpoint inhibitors (ICIs) have become an integral part of the standard therapeutic approaches for patients with cancer. However, the occurrence of immune-related adverse events (irAEs) occasionally poses challenges to quality of life (QoL). Despite the utility of ICIs in a daily practice, evidence about the frequency of arthralgia associated with ICIs, which severely affects QoL of patients with cancer, is limited. The study aimed to evaluate the incidence and treatment outcomes of arthralgia associated with ICIs. Methods: We performed a database search in PubMed/Medline, Embase, and Web of Science for phase 3 randomized control trials (RCTs) evaluating ICI therapy and reporting the incidence of arthralgia. The incidence of arthralgia was calculated in patients with solid tumors treated with ICIs. We performed a random-effect model meta-analysis to pooled odds ratios (ORs) of these outcomes using RCTs evaluating 1) the combination of ICIs with systemic therapy versus systemic therapy alone, 2) ICI vs chemotherapy (taxanes, non-taxanes, and mixed chemotherapeutic regimens) to assess the effect of ICIs on the incidence of arthralgia. I2 statistics was used to assess heterogeneity among the included studies and subgroups with I2 higher than 50% being considered high heterogeneity. Results: A systematic review identified 40 RCTs to analyze the incidence of arthralgia. The incidence of any-grade treatment-related arthralgia was 12.0% (n=1125/9395), and that of grade 3–5 treatment-related arthralgia was 0.54% (n = 47/8723). The addition of ICIs was associated with an increase in both any-grade (OR 1.32, 95% CI: 1.13–1.54, p = 0.001) and grade 3-5 arthralgia (OR 1.78, 95% CI: 1.08-2.94, p = 0.02: subgroup differences by ICB subtype: I2 = 0%). Subgroup analysis revealed that the addition of ICIs to cytotoxic chemotherapy was associated with an increase in the incidence of any-grade arthralgia (OR 1.35, 95% CI: 1.05–1.73, p = 0.02. The meta-analysis of ICI versus chemotherapy found that the incidence of arthralgia remained significantly increased when ICIs were compared with non-taxane chemotherapy (OR 6.83, 95% CI: 3.05–15.30, p < 0.00001), but not with taxanes (OR 0.74, 95% CI: 0.44–1.24, p = 0.25, I2 = 67%). Conclusions: Although the incidence of grade 3–5 arthralgia seems low, we revealed that the addition of ICIs to systemic therapy increased both any-grade and grade 3-5 arthralgia. Additionally, the incidence of any-grade arthralgia was more observed with ICIs than with non-taxane chemotherapy. In contrast, the incidence of arthralgia was not significantly different between ICIs and taxanes or mixed chemotherapy. The findings may be useful for patient education receiving ICIs for solid tumors. Future prospective studies are warranted to evaluate the therapeutic approach to grade 3–5 arthralgia and the need for ICI discontinuation.
Association between antibiotic use and mortality among older persons receiving first-line immune checkpoint inhibitors for non-small cell lung cancer (NSCLC).
Authors: Goldberg Chaya , Nelson Julia , Rua Melanie , Bannerji Rajat , Setoguchi Soko , Bates Benjamin
Published: June 2024

e14607

Background: There is biologic plausibility that antibiotics (ABX) may reduce the effectiveness of cancer therapy, most notably immune checkpoint inhibitors (ICI). As ABX are commonly prescribed to older persons and more than a third of US persons with cancer are eligible for ICIs, use of ABX has important population health implications. We assess the association between ABX use and mortality among persons with NSCLC who receive first-line (1L) treatment. Methods: Using SEER-Medicare, we assembled a cohort of persons ≥66 years with NSCLC who received 1L treatment with platinum-based chemotherapy (PLT) or ICI (PLT without ICI, PLT with ICI, and ICI monotherapy) within one year of cancer diagnosis between 2017-2019. We assessed overall ABX exposure from 1 month to 1 year prior to treatment initiation and by ABX class. Primary outcome was all cause deaths within three years of treatment initiation or until 12/31/2020. Multivariable Cox proportional hazard models adjusting for individual-level characteristics (demographics, time-to-treatment, comorbidities, healthcare use, SEER registry, and neighborhood socioeconomic status) and landmark analyses of 1-6 months after cancer treatment were used to assess the association between ABX exposure and mortality. Results: Among 4,182 persons (mean age 75 years, 85% white, 68% chemo-immunotherapy within 2 months of NSCLC diagnosis), 63%, 18%, and 18% received PLT, PLT+ICI, and ICI, respectively. ICI+/-PLT increased in prevalence from 20% of treatments (2017) to 55% (2019). The mean age of persons who received ICI alone (78 years old) was higher than PLT or PLT+ICI. Prior to 1L treatment, 22% and 72% of persons received ABX within 30 days and 1 year prior to cancer treatment, respectively. The three most common ABX classes were fluoroquinolones (48%), penicillins (21%), and macrolides (18%). The cohort was followed for 3,274 person-years and included 2,958 deaths within 1 year and 4,144 deaths within 3 years of follow-up. Compared with persons who did not receive ABX within 3 months of cancer treatment, ABX use was associated with higher risk of death within 3 years for ICI alone [HR 1.24 (1.05-1.46) but not for PLT alone or PLT+ICI. Fluoroquinolones were associated with an elevated risk of mortality among persons who received ICI alone HR 1.41(95%CI: 1.1-1.8) and PLT alone HR 1.18 (95%CI: 1.05-1.32) but not PLT+ICI. Our findings were similar across definitions of ABX exposure (30 days to 1 year prior to treatment) and analytic landmarks after treatment initiation. Conclusions: Among patients with NSCLC who received 1L treatment, we identified an association between ABX exposure prior to treatment and increased mortality among persons who received ICI monotherapy but not PLT+ICI. As ICIs expand to more cancer types and earlier stages, ABX use may have a significant impact on outcomes and population health.
Effect of targeting DDR pathway on the late-phase autophagy and the killing effect of CD8+ T cells.
Authors: Li Guo , Xuan Chenghao , Zhong Diansheng , Zhang Linlin
Published: June 2024

e14646

Background: Deficiency in DDR signaling pathways has been reported to be associated with better response to immunotherapy. This study aims to investigate whether inhibition of the key mediator of DDR pathways ATR could enhance the function of CD8+ T cells and its underlying mechanism. Methods: The CD8+ T cell-killing experiment was conducted in vitro to demonstrate the efficiency in the presence of ATR inhibitors. To investigate the regulatory mechanism, RNA Sequencing analysis was performed to identify gene changes after ATR inhibition. Subsequently, Western blotting and immunofluorescence assays were performed to access the autophagy flux based on the results of the RNA sequencing analysis. Flow cytometry was used to detect the surface MHC-I expression to validate our speculation with the change of autophagy activity. Results: ATR inhibitor (VX970) had been shown to enhance the cytotoxic effect of CD8+ T cells on tumor cells. RNA-seq analysis revealed the enrichment of pathways related to autophagy and its regulation, as well as inflammatory factor pathways. Accumulation of p62/SQSTM1 and an increased LC3II/I ratio had been found, indicating the involvement of autophagy after the inhibition of ATR. No further increase in autophagy proteins was observed upon treatment with autophagy inhibitors, suggesting the late stage of autophagy inhibition was affected. In addition, increased MHC-I molecular expression has been found in accordance with autophagy inhibition, which could further explain the reason ATR inhibition could induce the accumulation of CD8+ T cells. Conclusions: Targeting DDR pathway leads to stimulated CD8+ T cells accumulation probably by increased MHC-I surface expression through inhibition of late-phase autophagy, which may in turn enhance the efficiency of immunotherapy.
Preclinical studies of an innovative 5T4-ADC ACR246 with the potential to better treat 5T4-positive solid tumors.
Authors: Miao Zhenwei , Huang Yunsheng , Li Deliang , Wang Xiaobei , Sheng Guorong , Wang Feng , Wu Kai , Huang Xiuying , Yang Li , Li Yaowu , Weng Shanhui , Manchukonda Naresh kumar , LU Yao
Published: June 2024

e15005

Background: 5T4 oncofetal antigen shows limited expression in normal adult tissues but highly expressed by many different cancers. It drives spread of cancer cells through epithelial mesenchymal transition (EMT), potentiation of CXCL12/CXCR4 chemotaxis and favoring non-canonical Wnt pathway, leading to poor prognosis of cancer patients. Besides, 5T4 has a highly efficient endocytosis ability which enables it to be an ideal target for the development of ADC drugs. A handful of 5T4-targeted ADCs have been evaluated in early phase clinical trials for several years showing only preliminary anti-tumor activity. However, uncertainty of their safety profiles has also raised concerns due to high toxic payloads, MMAF and duocarmycin, being used. Thus, additional approaches to this target with the potential of improved efficacy and reduced toxicity are needed urgently. ACR246, an innovative 5T4-targeted ADC consisting of specific humanized monoclonal antibody site-specifically conjugated with a cell penetrating and moderate toxic payload (DNA topoisomerase I inhibitor, D2102) that has a robust bystander effect through a stable and cleavable linker, with a drug-to-antibody ratio (DAR) of 8, was designed to improve the safety and efficacy in treating tumor patients. Methods: The pharmacologic profiles of ACR246 were assessed in vitro and in vivo including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, in 5T4-positive cell lines, cell-derived xenograft (CDX) models and cynomolgus monkeys. Results: ACR246 bound specifically to 5T4 and was internalized into tumor cells followed by D2102 release, which induced DNA damage, cell cycle arrest and apoptosis in 5T4 positive tumor cells in vitro. In vivo low systemic exposure and tumor-specific accumulation of D2102 rendered ACR246 superior efficacy and safety property. Accordingly, ACR246 exhibited robust in vivo anti-tumor activity across various types of 5T4 positive CDX models in a dose-dependent manner, with DNA damage induced by the accumulated D2102 in tumor tissue. GLP toxicity studies indicated that ACR246 was well tolerated in cynomolgus monkeys. The estimated therapeutic index was 24. Conclusions: The overall preclinical profile marks ACR246 has the potential to become the best in class (BIC) 5T4-ADC, showing more favorable benefit-risk ratio in clinic.
Hemay181: A novel SDC (sugar linked drug conjugate) for solid tumors targeting tumor microenvironment.
Authors: Jones Richard , Lv Jingjing , Fu Wei , Zeng Guanghuai , Zhang Hesheng
Published: June 2024

e15006

Background: Hemay181 is a novel broad-spectrum conjugated cytotoxic drug for treating advanced solid tumours. The drug exerts its inhibitory effect on tumour growth by releasing cytotoxic drug SN-38 in tumour tissues via β-glucuronidase (βGU) metabolism to inhibit the activity of topoisomerase I (TOP1). The water solubility of Hemay181 is increased > 5000-fold compared to SN-38. Hemay181 also binds to plasma albumin to form a macromolecular drug transporter, significantly improving the drug's pharmacokinetics. In addition, βGU has low activity in normal tissues, localised to the lysosomes, but is highly expressed in the hypoxic tumour microenvironment. Methods: In vitro and In Vivo studies showed Hemay181 inhibited growth in 29 human tumour cell lines and 16 human tumor Xenograft models, including colorectal cancer, gastric cancer, triple-negative breast cancer, head and neck cancer, pancreatic cancer, lung cancer, prostate cancer and melanoma. Results: In the absence of βGU, Hemay181 showed significantly weaker inhibitory activity than Hemay181+βGU or no significant inhibitory activity. In these In vitro studies with the addition of βGU, the activity was similar to SN-38, ranging from 3.9 nM to 159 nM. Hemay181 showed tumor selectivity with low activity against two normal human cell lines. The IC50 values of Hemay181 against Chang liver (normal liver cells) and MRC 5 (embryonic lung cells) were 318 nM and 14566 nM under non-enzymatic digestion conditions. In vivo, Hemay181 had significant inhibitory effects on the growth of human colorectal cancer, pancreatic cancer, head and neck cancer, triple-negative breast cancer, lung cancer, liver cancer, ovarian cancer and gastric cancer tumour models. The lowest effective dose of Hemay181 was 1.875mg/kg in the human colon cancer HCT116 model. Within the dose range of 3.75~60 mg/kg, the highest inhibitory rate of the above different tumour models could reach more than 90%. Hemay181 significantly reduced tumour volume compared to irinotecan, which only slowed the tumour growth rates. There was no significant decrease in the body weight of Hemay181 in these studies. In the colon cancer PDX model (CR0029) (30mg/kg), the tumour inhibition rate (TGI) was 78%. At 60mg/kg, in triple-negative breast cancer (BR1458) and non-small cell lung cancer (LU3075) PDX models, a TGI was 97% and 98%, respectively. At 60mg/kg, there was a significant tumour suppressive effect on larger tumours treated with irinotecan, with a reduction of tumour volume. In vitro , 1 μM Hemay181 is stable in CD1 mouse and SD rat plasma, with a minor degree of metabolism in beagle dog, cynomolgus monkey and human plasma. Conclusions: In summary, the novel broad-spectrum anti-tumour drug Hemay181 has the characteristics of high water solubility, tumour-targeting ability, low toxicity and side effects on normal tissues. It is under evaluation in ongoing clinical studies.
HER2 expression-independent antitumor effect of trastuzumab deruxtecan (T-DXd) on pediatric solid tumors.
Authors: Takasugi Nao , Deguchi Takao , Kato Motohiro
Published: June 2024

e15016

Background: Treatment of pediatric solid tumors shows limited improvement even with intensification of conventional chemotherapy, suggesting novel approaches such as targeted therapies are needed. Trastuzumab Deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate, exhibits significant anti-cancer activity in breast cancers with a broad range of HER2 expression. T-DXd might be a promising agent for refractory or relapsed pediatric solid tumors, but its efficacy in pediatric tumors needs to be studied. Methods: Anti-cancer efficacy of T-DXd and its payload DXd were assessed in vitro by utilizing our in-house cancer cell line models. Cytotoxicity assays were performed for 60 pediatric cancer cell lines, including Neuroblastoma (NB) = 25, Ewing sarcoma / Ewing sarcoma family of tumors (EWS / EWSFT) = 17, Rhabdomyosarcoma (RMS) = 10, Others (Osteosarcoma, Brain tumor, Wilms tumor, Hepatoblastoma, and Malignant rhabdoid tumor (MRT) = 8, and 2 breast cancer cell lines expressing HER2 high or low (IHC score 2+ or 0) as positive or low control, respectively. We analyzed HER2 expression on the cell surface by flow cytometry and evaluated relative mean fluorescence intensity (MFI) values. Results: In the flow cytometric assessment, pediatric cancer cell lines showed smaller median MFI of 1.40 (0.67 - 2.71) compared with breast cancer control with HER2 high expression (33.77). The median MFI of each cell lines were 0.94 in NB, 1.76 in EWS / EWSFT, 1.42 in RMS, 1.52 in other pediatric cancers. Although low or no expression of HER2, certain inhibitory activities to the cell growth were observed for T-DXd against a part of NB, EWS, RMS and MRT cell lines, with the minimum IC50 values of 14.5 nM, 6.5 nM, 10.2 nM, 8.1 nM, respectively. In NB, EWS and RMS, a wide range of sensitivity to T-DXd were seen among different cell lines in the same disease. Most of cell lines showed high sensitivity to DXd (Median IC50 value: 0.90 nM [0.08 - 6.46 nM]), but, among them, cell lines with lower sensitivity to DXd tend to show less sensitivity to T-DXd. There was no clear correlation between sensitivity to T-DXd and HER2 expression among pediatric cancer cell lines, indicating that other mechanism such as intrinsic sensitivity to payload might affect antitumor activity of T-DXd. Conclusions: T-DXd exhibited antitumor efficacy against pediatric solid tumors in vitro irrespective of HER2 expression. Our results suggest that T-DXd might be an alternative therapy for pediatric solid tumor cases for whom conventional chemotherapies and other targeting therapies are ineffective. This study supports further investigation for T-DXd in this population.
Adverse events of patients treated with antibody-drug conjugates in phase 1 clinical trials at the Royal Marsden Drug Development Unit from 2014 to 2024.
Authors: Tan Harold Nathan , Ascanio Morcillo Marta , De Bono Johann S. , Lopez Juanita Suzanne , Minchom Anna Rachel , Sharp Adam , Paschalis Alec , Banerji Udai
Published: June 2024

e15020

Background: Antibody-drug conjugates (ADCs) are designed to improve therapeutic indices of cytotoxic agents. Nevertheless, they may induce unexpected toxicities not observed with parent payloads. This study aimed to characterize the adverse events (AEs) seen in patients treated with ADCs in Phase 1 trials at The Royal Marsden Drug Development Unit (DDU). Methods: This is a retrospective cohort analysis of consecutive patients who received at least one dose of an ADC in a phase I trial from January 2014 to January 2024 at The Royal Marsden DDU. Descriptive statistics of patient characteristics, ADCs, and treatment-related AEs were performed. Univariate and multivariate logistic regression will be utilized to assess correlations among patient and ADC characteristics and adverse events. P values of < 0.05 will be considered significant. Results: A total of 131 patients who participated in twelve ADC trials were included. The median age of participants was 63 years (range: 31-84) and 61% were females. Patients received a median of three prior lines of systemic treatment. The most common type of ADC target, antibody, linker and payload were receptor tyrosine kinase (51%), humanized IgG monoclonal antibody (69%), valine-citrulline (VC) cleavable linker (85%), and a tubulin-binding payload (59%), respectively. Most patients received an ADC dose of 1-3 mg/kg (76%) with each cycle given once every 3 weeks (64%). The median number of cycles was 3 with an average treatment duration of 63 days. Within the cohort, 89% of patients developed any grade AE and 17% experienced grade 3 or higher AEs. The major treatment-related AEs were fatigue (48%), nausea/vomiting (27%), ocular toxicity (26%), neuropathy (26%), skin rash (20%) and pneumonitis (8%). The median time to first onset of treatment-related adverse events were 37 days for ocular toxicity, 46 days for pneumonitis, and 54 days for neuropathy. ADC-related AEs led to treatment interruptions (51%), dose reductions (13%), and treatment discontinuations (28%). Two treatment-related grade 5 events occurred. The objective response rate was 18%, with 1 complete response and 22 partial responses. Conclusions: Despite being designed to minimize side effects, ADCs were associated with significant toxicities, including unexpected adverse events unrelated to target, antibodies or the payloads, limiting their therapeutic indices. Further analysis of the relationship between different components of the wide range of ADCs and AEs are warranted to better understand the potential mechanisms of ADC toxicity.
Evaluation of lipopolymer as therapeutic siRNA delivery agents in non-malignant and malignant primary cells.
Authors: Ansari Aysha , Kucharski Cezary , Mohseni Mahsa , Sundaram Daniel NM , Brandwein Joseph M. , Jiang Xiaoyan , Uludag Hasan
Published: June 2024

e15189

Background: Targeting leukemia-driving oncogenes via short interfering RNA (siRNA) offers an alternative approach to leukemia treatment that can overcome the limitations of current therapies. Low molecular weight polyethyleneimine grafted with lipids (lipopolymers) have emerged as promising carriers for siRNA delivery to leukemia cells. Lipopolymers harboring select lipids were recently shown to downregulate target oncogene leading to significant anti-leukemic activity in both in vitro and in vivo cell line-based leukemia models. The goal of this study was to evaluate these lipopolymers in (i) PBMCs obtained from healthy donors to determine the potential impact on non-malignant cells, and (ii) primary leukemia patient cells to assess therapeutic efficacy. Methods: Target gene levels were determined by RT-qPCR and the effect of treatment on progenitor cells was assessed by measuring changes in colony forming ability. Results: At day 1 post-treatment, no changes in FLT3 mRNA levels were observed in all 6 PBMC samples with the 2 candidate lipopolymers (LeuFectB and LeuFectC) tested. Among 11 PBMC samples evaluated at day 2, only one sample showed a significant reduction in oncogene transcript levels on treatment with LeuFectB. The impact of lipopolymer/siRNA complex treatment on progenitor cells in the PBMC population was then assessed. Of the 7 PBMC samples tested, significant reduction in colony numbers was observed in one sample with LeuFectB and two samples with LeuFectC. On an average, the lipopolymer/siRNA complexes were well tolerated by normal healthy cells as changes observed in oncogene expression and colony forming ability were not consistent across the whole pool. Primary acute lymphoblastic leukemia (ALL) patient cells treated with complexes targeting STAT5A showed marked reduction in STAT5A transcript levels in 4 out of 7 samples with both the lipopolymers tested. The subsequent impact of STAT5A downregulation on the clonogenicity of leukemia stem cells was observed in the significant decrease in colony numbers seen in 3 samples (out of 8) with LeuFects. Additionally, combined downregulation of STAT5A and BCR-ABL genes in BCR-ABL+ ALL patient samples led to a notable decrease in cell proliferation and viability. Moreover,2 out of 3 acute myeloid leukemia (AML) patient samples harboring the FLT3-ITD mutation showed significant retardation in their colony forming ability on treatment with FLT3-targeting siRNA complexes. Collectively, the ALL and AML primary samples demonstrated promising preliminary results, suggesting a therapeutic effect on the stem cell population which is critical for mitigating relapse or prolonging remission. Conclusions: These findings provide further proof-of-concept for clinical translation of lipopolymer mediated siRNA therapy of leukemia, showing relative safety and selectivity of these lipopolymer/siRNA complexes.
Updated efficacy and safety results from the phase Ib/II study of surufatinib combined with camrelizumab and chemotherapy in patients with advanced colorectal cancer.
Authors: Li Sheng , Zhu Liangjun , Li Xiaoyou , Huang Jiayuan , Bao Jun
Published: June 2024

e15547

Background: Preclinical and clinical data have demonstrated the synergistic anti-tumor effects of surufatinib, a novel VEGFR1-3, FGFR and CSF-1R inhibitor, in combination with immune checkpoint inhibitors (ICIs)/chemotherapy. A phase Ib/II, open-label study (NCT04929652) was conducted to evaluate the efficacy and safety of surufatinib plus camrelizumab (anti-PD-1), irinotecan and GM-CSF as second-line treatment in advanced colorectal cancer (CRC). In the phase Ib part, this combination showed favorable safety and efficacy profile, which was presented at ASCO 2023 in poster format (#255). Here, we reported the updated results from the phase Ib and phase II dose escalation part together. Methods: In the phase Ib, pts with CRC received surufatinib at 250mg once daily (QD) as starting dose, in combination with fixed dose of camrelizumab (200 mg, d1), irinotecan (200 mg/m2, d1) and GM-CSF (5ug/kg, d2-d7), every 3 weeks (Q3W). It had been reported in phase Ib that surufatinib 300 mg QD was defined as the recommended phase 2 dose (RP2D). In phase II dose expansion part, a further 36 pts were treated with the same regimen. The primary endpoint of phase II was ORR as per RECIST 1.1. Secondary endpoints included PFS, DCR, OS and safety. Results: As of Jan 18, 2024, 30 CRC pts (median age 57) were enrolled in the study with 12 pts in the phase Ib part and 18 pts in the phase II part. 70% were male and 23% had ECOG PS 1. 24/30 (80%) pts were positive for KRAS, NRAS or BRAF mutations. Among the 30 efficacy evaluable pts, the ORR was 30.0% (95% CI 14.7–49.4; 9 PR) and DCR was 93.3% (95% CI 77.9–99.2; 28 PR+SD). Pts with RAS/BRAF mutations were more likely to achieve better responses (9 PR in 24 pts, ORR-37.5%). After a median follow-up time of 11.1 months, the median PFS was 6.34 months (95% CI 4.57-9.23) and median OS was not mature. The most common grade 1-2 treatment related adverse events (TRAEs) (≥35%) were diarrhea (70%), fatigue (40%), anemia (36.7%), proteinuria (36.7%) and nausea (36.7%). Eleven pts experienced at least one grade 3 or 4 TRAEs. Grade 3 or 4 TRAEs occurred in > 1 pt included diarrhea (n = 3, 10%) and neutrophil count decreased (n = 2, 6.7%). Conclusions: Surufatinib plus camrelizumab, irinotecan and GM-CSF demonstrated promising anti-tumor activity in pts with advanced CRC, with a manageable safety profile. Expansion enrollment is ongoing and updated information will be presented. Clinical trial information: NCT04929652 .
Treatment of colon cancer using a novel approach comprising cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy and intraoperative radiation therapy.
Authors: Alaswad Marwan , Arabi Tarek , Sabbah Belal Nedal , Al Otry Abdullah , Hejazi Alwalid , Ismail Aya , Jaamour Heba , Alhosainy Ziad , Al Homoud Samar , Azzam Ayman , Amin Tarek
Published: June 2024

e15573

Background: Approximately 10% of colon cancer (CCa) develop peritoneal carcinomatosis. Studies have found that the administration of hyperthermic intraoperative chemotherapy (HIPEC) during cytoreductive surgery (CRS) can reduce the risk of recurrence and development of peritoneal carcinomatosis (PC). Additionally, intraoperative radiotherapy (IORT) has been shown to effectively treat and blunt neoplasm growth. However, no reports of the impact of concurrent HIPEC and IORT in CRS on CCa are available. Methods: We retrospectively reviewed the medical records of CCa patients with PC who received HIPEC and IORT during CRS. Demographics, treatment details, PC indexes (PCI), completeness of cytoreduction scores (CCS), and operative complications were recorded. Subsequently, overall survival (OS) was defined as the time period from surgery until death or loss of follow-up, and recurrence-free survival (RFS) was defined as the period from surgery until recurrence or loss of follow-up. Univariate hazard ratios (HR) were used to check for prognostic factors. Results: 17 CCa patients were included in our analysis. Patient characteristics are summarized in Table 1. The pT staging was T0 in 1 (5.9%), T3 in 6 (35.3%), T4a in 4 (23.5%), and T4b in 6 (35.3%). The pN staging was N0 8 (47.1%), N1a in 4 (23.5%), N1b in 2 (11.8%), N1c in 2 (11.8%), and N2b in 1 (5.9%). Finally, the pM staging was M0 in 8 (47.1%), M1a in 4 (23.5%), M1b in 2 (11.8%), and M1c in 3 (16.4%). PCI was ≤6 in 13 (76.5%) patients. The CCS was 0-1 in all, but two, patients. 1 patient had a positive resection margin. 8 (47.1%) received cisplatin with mitomycin C during HIPEC, followed by mitomycin alone (29.4%), reduced doses of cisplatin + mitomycin C (17.6%), and a reduced dose of mitomycin C alone (5.9%). Reduced dosage was due to old age in 3 and renal impairment in 1 patient. There were no intraoperative complications or HIPEC-related adverse effects. Two patients received two doses of IORT. 4 (23.5%) patients had postoperative complications, of which two complications were Clavein-Dindo grade 4a. Recurrence occurred in 8 (47.1%) patients, and 4 (23.5%) patients passed away. The median OS was not reached, and the RFS was 19 months. PCI > 6 (HR: 12.6, 95% CI: 1.6-256.8) and postoperative complication of grade 4 (HR: 8.6, 95% CI: 1-73) were associated with poor OS. Only PCI > 6 was associated with poor RFS (HR: 10.4, 95% CI: 1.7-80.8). Conclusions: Postoperative complications in HIPEC+IORT during CRS are comparable to other accepted treatments for CCa. Large, double-arm studies are needed to compare the effectiveness of this treatment. [Table: see text]
Three-year survival data from a phase 2 trial of neoadjuvant short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer.
Authors: Lin Zhenyu , Zhai Menglan , Zhang Peng , Tao Kaixiong , Zhang Tao
Published: June 2024

e15611

Background: For locally advanced rectal cancer (LARC), short-course radiotherapy (SCRT) or long-course chemoradiotherapy combined with chemotherapy have been the established neoadjuvant treatment, but the optimal therapeutic modality is still under exploration. We previously reported the short-term results of neoadjuvant SCRT followed by chemotherapy and camrelizumab (a PD-1 inhibitor), encouragingly noting pathological complete response (pCR) in 48.1% of LARC patients (Lin Z et al. J Immunother Cancer 2021;9:e003554). Here, we report the further 3-year follow-up results. Methods: Adult patients with histologically confirmed T3-4N0M0 or T1-4N+M0 rectal adenocarcinoma were enrolled. Prior to surgery, eligible patients received 5×5 Gy SCRT, and after one week, they were treated with camrelizumab (200 mg, i.v., on day 1) plus CAPOX chemotherapy (oxaliplatin 130 mg/m2, i.v., on day 1 and capecitabine 1000 mg/m2, orally, bid, on days 1-14) in 21-day cycles for 2 cycles. Radical surgery was performed one week after the last neoadjuvant cycle. For this updated analysis, disease-free survival (DFS) and overall survival (OS) at 3 years are reported. Results: Thirty patients were enrolled and received SCRT, and all of these patients were included in this OS analysis. Among them, 27 patients received camrelizumab plus CAPOX chemotherapy, all of whom underwent surgery and were included in this DFS analysis. Of the 27 patients, 21 patients (77.8%) received at least one cycle of postoperative adjuvant chemotherapy with CAPOX regimen. With a median follow-up of 40.8 months (IQR 40.3-44.3), disease recurrence or death occurred in six (22.2%) patients. The median DFS and OS were both not reached, with the 3-year DFS and OS rates of 80.2% (95% CI 58.6-91.3) and 93.3% (95% CI 75.9-98.3), respectively. Subgroup analysis showed that patients with pCR, postoperative pathological node-negative status, PD-L1 combined positive score ≥ 1, and negative circumferential resection margin and negative extramural venous invasion by MRI at baseline had a tendency towards improved 3-year DFS and OS compared to those without these characteristics. No new or long-term safety signals were identified. Conclusions: With 3 years of extended follow-up, a favorable survival benefit was observed with neoadjuvant SCRT combined with subsequent CAPOX plus camrelizumab followed by delayed surgery in LARC patients. A randomized phase 3 trial (NCT04928807) is ongoing to confirm these results. Clinical trial information: NCT04231552 .
Neoadjuvant chemotherapy versus surgery plus adjuvant chemotherapy for locally advanced colon cancer: A meta-analysis of randomized controlled trials.
Authors: Kato Barbara Klyslie , Pompeu Bernardo Fontel , Delgado Lucas Monteiro , Formiga Fernanda Bellotti , Alves Daniele Evaristo Vieira
Published: June 2024

e15631

Background: The primary treatment for colon tumors is surgical resection, but the use of neoadjuvant chemotherapy (NAC) in managing locally advanced cases remains a subject of ongoing debate. We conducted a thorough meta-analysis, including randomized clinical trials (RCTs), to assess the oncological safety of neoadjuvant chemotherapy (NAC) in colorectal tumor patients. Methods: We systematically searched in PubMed, Scopus, Google Academic and Cochrane Library in January 2024 for studies that directly compared NAC versus surgery in patients with T3-4, N0-2, M0 colorectal cancer. We assessed overall survival (OS) and disease-free survival (DFS). We calculated odds ratios (ORs) and hazard ratios (HRs) using generic inverse variance in Review Manger 5.4. Heterogeneity was assessed using I² statistics. Results: We included seven RCTs, involving 4,391 patients. Among them, 53.5% underwent NAC, with a median age of 61.41 years and an average follow-up of 62.35 months. The comprehensive analysis revealed no statistically significant differences in 3-year OS (OR: 1.20, 95% CI: 0.91 to 1.59, p = 0.20), more than 2 years DFS (OR: 0.88, 95% CI: 0.37 to 2.13, p = 0.78) and five-year DFS (OR: 1.09, 95% CI: 0.83 to 1.43, p = 0.55). Employing a time-to-effect modeling approach, there was no significant difference in OS (HR: 1.04, 95% CI: 0.63 to 1.70, p = 0.88) or DFS (HR: 0.86, 95% CI: 0.7 to 1.06, p = 0.16); (Table 1). Conclusions: Our systematic review and meta-analysis of seven RCTs showed that neoadjuvant chemotherapy compared with surgery followed by adjuvant chemotherapy had similar overall survival and disease-free-survival in patients with locally advanced colon cancer. [Table: see text]
Charting heterogeneity and spatial landscape of consensus molecular subtypes in colorectal cancer.
Authors: Zhou Jie , Sheridan Todd B. , Domanskyi Sergii , Cowles Stephanie L. , Park Sunghee , Putra Ilham , Anczukow Olga , Chuang Jeffrey H. , Rubinstein Jill Carol
Published: June 2024

e15647

Background: High inter-patient heterogeneity and spatial diversity within tumors represent significant challenges to improving outcomes in colorectal cancer (CRC). Despite elucidation of consensus molecular subtypes (CMS), little progress has been made in translating this knowledge into clinical gain. Intratumoral CMS heterogeneity remains a relatively unexplored area and understanding of the interplay between subtypes holds promise for improving prognostication. We leverage spatial transcriptomics (ST) to enhance understanding of CMS heterogeneity and spatial distribution, with the goal of advancing personalized therapy through high resolution molecular sub-typing. Methods: ST using the 10x Genomics Visium platform was performed on paraffin-embedded CRC specimens for which comprehensive clinicopathological and long-term clinical outcome data were available. ST data were deconvoluted with respect to CMS single-cell RNA sequencing (scRNA-seq) data, yielding maps of CMS landscapes at a resolution of 55 microns. A pre-trained deep learning model was used to identify distinct CRC tissue classes (tumor epithelium, stroma, etc.) within H&E images, enabling spatial correlation of histomorphology with CMS. Cellular composition within these CMS maps was quantified through deconvolution of six major cell types using reference scRNA-seq data. Pseudo-bulk samples were generated from the ST data to evaluate CMS behaviors and compute pathway activities. Results: 40 CRC patients were assayed using ST and H&E profiling (13, 8, 14, and 5 from stages 1-4, respectively). Median follow-up was 112 months (Range 1–192). Intratumoral CMS heterogeneity was evident in all patients, with diverse CMS compositions. Using Simpson diversity index to quantify this heterogeneity, we observed significant correlation of heterogeneity with disease specific survival (DSS) (p = .03). CMS landscapes displayed spatial patterns that were distinct among tissue categories (average F1-score: testing = .92, validation = .89. Tissue categories based on deep learning from H&E images). Tumors with higher levels of CMS1 or 4 were associated with worse outcome. Stratification by the composite CMS biomarker (CMS1+CMS4)/(CMS2+CMS3) yielded significant separation of the Kaplan-Meier curve for DSS (p = .018). Conclusions: This study demonstrates that CRC tumors contain significant intratumoral CMS heterogeneity that is not detectable using bulk classification methods. Spatial patterns in CMS transcriptional topographies correlate with H&E-derived morphology, suggesting the potential for estimating CMS composition from histopathological features. Importantly, we show that spatially composite CMS-derived biomarkers possess strong prognostic potential. The capacity to decode CMS topographic patterns and associate these with clinical outcome offers great potential to advance personalized therapy for CRC.