5728 research outputs found
Sort by
Treatment-related adverse events of antibody drug-conjugates in clinical trials.
No full textBACKGROUND: Antibody-drug conjugates (ADCs) aim to enhance the therapeutic index of cytotoxic agents but can cause unexpected toxicities. This study evaluated adverse events (AEs) from phase 1 trials at The Royal Marsden Drug Development Unit (DDU) over a decade and pivotal phase 2 and 3 trials leading to FDA registration, correlating AEs with ADC components such as target, antibody, linker, payload, and Drug-to-Antibody Ratio (DAR). METHODS: We performed a retrospective cohort analysis of patients treated with ADCs in phase 1 trials (January 2014 to January 2024) compared to published phase 2-3 trials of FDA-approved ADCs. Univariate and multivariate logistic regression analyzed ADC components and treatment toxicities. RESULTS: One hundred thirty one phase 1 trial patients and 2666 phase 2-3 trial participants were included. High incidences of any-grade treatment-related AEs were observed (89% in phase 1, 93% in phase 2-3), with 58% experiencing grade 3 or higher toxicities in phase 1 and 46% in later phases. Major AEs included fatigue, hematologic toxicities, nausea/vomiting, ocular toxicities, and peripheral neuropathy. Antibody targets were linked to neuropathy, non-cleavable linkers to ocular, pulmonary, and hematologic toxicities, and tubulin-binding payloads to peripheral neuropathy. ADCs with DAR > 4 were associated with higher pulmonary and hematologic AEs. CONCLUSION: Despite their design to minimize toxicity, ADCs were linked to significant AEs. Specific ADC components may contribute to distinct toxicities, necessitating more robust trial data to inform future ADC design
Five-year trends and baseline predictors of patient-reported adverse events following breast radiotherapy with a boost in the IMPORT HIGH phase III randomised controlled trial.
No full textBACKGROUND AND PURPOSE: IMPORT HIGH demonstrated non-inferiority of simultaneous integrated boost against sequential boost for ipsilateral breast tumour relapse. Patient-reported adverse events (AEs) were similar across treatment groups. In this longitudinal analysis of patient-reported AE data from IMPORT HIGH we describe prevalence and baseline predictors of patient-reported AEs over 5-years. MATERIALS AND METHODS: IMPORT HIGH (ISRCTN47437448) recruited women with early breast cancer and higher-than-average local recurrence risk. All participants received breast radiotherapy and a boost. Patient-reported outcomes (PROs) were recorded using EORTC QLQ-C30, QLQ-BR23, Body Image Scale administered at baseline, 6 months, 1, 3, 5-years. AEs were recorded on a 4-point-scale and dichotomised (none/mild versus moderate/marked) for analysis. Generalised Estimating Equations assessed patterns of moderate/marked AEs and their baseline predictors. RESULTS: 52/76 IMPORT HIGH centres participated in the PRO sub-study. 1078/1338 patients consented. 270/762 (35.4 %) patients reported no moderate/marked AEs at 5-years. Most common moderate/marked AEs at 5-years were overall change in breast appearance (257/762, 33.7 %) and having a smaller breast (222/762, 29.1 %). Arm and breast symptoms peaked at 6-month assessment, with breast symptoms improving but arm symptoms persisting over 5-years. Body image-related AEs improved from baseline. Younger age and anxiety were the commonest baseline predictors of AEs. CONCLUSION: This longitudinal analysis of PROs in a large trial of breast and boost radiotherapy demonstrates an overall decrease in the number of patient-reported moderate/marked AEs up to 5-years following radiotherapy. Baseline factors predicting AE development include younger age and anxiety, informing support strategies for patients receiving whole breast and boost radiotherapy
Open-label, phase Ia study of STING agonist BI 1703880 plus ezabenlimab for patients with advanced solid tumors.
No full textBI 1703880, a novel STimulator of INterferon Genes (STING) agonist, has demonstrated preclinical antitumor activity. As STING activation can upregulate programmed death ligand 1 and human leukocyte antigen in tumor cells, a combination of BI 1703880 and an anti-programmed cell death protein 1-antibody, such as ezabenlimab, may improve efficacy. This first-in-human phase Ia study (NCT05471856) is evaluating BI 1703880 plus ezabenlimab in patients with advanced solid tumors. The study utilizes an innovative lead-in design; all patients receive BI 1703880 monotherapy in Cycle 1 and combination therapy from Cycle 2. The primary endpoint is dose-limiting toxicities during the maximum tolerated dose evaluation period. Results will inform the future development of BI 1703880 for treatment of metastatic or recurrent malignancies.Clinical Trial number: NCT05471856
CXCL12-Targeted Immunomodulatory Gene Therapy Reduces Radiation-Induced Fibrosis in Healthy Tissues.
No full textRadiation-induced fibrosis (RIF) is a progressive pathology deleteriously impacting cancer survivorship. CXCL12 is an immune-stromal signal implicated in fibrosis and innate response. We hypothesized that modulation of CXCL12 would phenotypically mitigate RIF. CXCL12 expression was characterized in a rodent model of RIF and its expression modulated by the intravascular delivery of lentiviral vectors encoding small hairpin RNA to silence (LVShCXCL12) or overexpress (LVOeCXCL12) CXCL12. Multimodal fibrotic outcomes were quantified, and flow cytometry and Y-chromosome lineage-tracking studies performed to examine cellular recruitment and activation after radiotherapy. Whole-tissue RNA sequencing was used to examine matrisomal response. MATBIII tumors were engrafted within tissues with differing levels of CXCL12 expression, and tumoral response to RT was evaluated. CXCL12 was upregulated in irradiated fibroblasts demonstrating DNA damage after radiotherapy, which led to the recruitment of CD68+ macrophages. Silencing CXCL12 with LVShCXCL12 demonstrated reduced RIF phenotype as a result of decreased macrophage recruitment. Transcriptomic profiling identified osteopontin (OPN; SPP1) as being highly differentially expressed in LVShCXCL12-treated tissues. Tumors growing in tissues devoid of CXCL12 expression responded better after RT because of reductions in peritumoral fibrosis as a result of decreased CXCL12 and OPN expression at the tumor/normal tissue interface. This was also associated with greater CD8+ T-cell infiltration in tumors with less fibrosis. Antibody-mediated OPN blockade slowed tumor growth by increased intratumoral CD8+ T-cell activation. The CXCL12/OPN axis is an important node of immune/matrisomal cross-talk in the development of fibrosis. Therapeutic manipulation of this axis may offer greater antitumor efficacy while also reducing adverse effects
Augmented FAP CAR T cell Therapy for the Treatment of Malignant Pleural Mesothelioma
No full textMalignant pleural mesothelioma (MPM) is an aggressive and incurable cancer mainly caused by asbestos exposure. Chimeric antigen receptor (CAR) T-cell therapies are targeted immunotherapies currently being trialled for solid cancers, including MPM. However, despite their success in haematological malignancies, their efficacy in solid malignancies has been limited so far partly due to the hostile solid tumour microenvironment (TME). Two elements in MPM’s TME that pose significant barriers to CAR T-cells are cancer associated fibroblasts (CAFs) in the tumour stroma, and TGF-β, a highly
This project aims to augment FAP CAR T-cells by utilizing TGF-β via two methodologies. First, via re-engineering of FAP CAR T-cells to secrete TGF-β inhibiting peptides that reduce TME immunosuppression. Second, via FAP CAR T-cell differentiation, with the use of exogenous TGF-β, into a “tissue resident”. Phenotype.
Proof principal studies showed that peptides P17 and P144 inhibit TGF-β activity in vitro and in vivo. Attempts to incorporate the peptides into the lentiviral backbone of the human FAP CAR have been unsuccessful; however the peptides were incorporated into the retroviral murine FAP CAR, whose efficacy and toxicity was assessed in vitro and in vivo. FAP CAR T-cells with tissue resident phenotype were also successfully generated and were tested in vitro 2D and 3D MPM cultures. Ultimately, this project explored how the inhibition of TGF-β in the MPM TME contributes to TME differentiation into a more immunogenic phenotype
Reshaping the T-cell landscape and Nr4a3 transcriptional dynamics with oncolytic virotherapy
No full textOncolytic viruses (OV) are naturally occurring or genetically modified viruses that
selectively infect and replicate within cancer cells, with the potential to induce
oncolysis, immunogenic cell death (ICD) and systemic anti-cancer immunity. Often
described as a “novel therapeutic class”, oncolytic viruses are now decades old, and
while milestone moments for the field include the worldwide approval of oncolytic
herpes simplex virus-1 (HSV-1) Talimogene Laherparepvec in 2015 for the treatment
of advanced melanoma, there have also been notable recent failures of OV in latestage
clinical trials, including in combination with immune checkpoint blockade
despite pre-clinical and early-phase promise.
One advantage of OV is their unmatched flexibility to evolve with the immuneoncology
(IO) landscape. From the ability to encode diverse immune-modulatory
transgenes for expression within tumour tissue, to synergy within complex
combinations, including with immune checkpoint inhibitors (ICI) and adoptive cell
transfer (ACT) therapy. As a result, the number of agents and combinations
undergoing pre-clinical and clinical testing is burgeoning, and the field is challenging
sceptics with persistent, justified optimism. The vast majority of these modifications
and combination strategies target T-cells, as the key effector cells of the immune
system. However, the rate of development has far outstripped our knowledge of Tcell
effects of the viruses themselves, which face a complex juxtaposition of anti-viral
and anti-tumour immunity.
This thesis aims to take a step back, to deeply evaluate the T-cell effects of one of
the lead clinical agents, HSV-1 RP1, to understand what T-cell populations are
induced, and how thes
Assessment of a Polygenic Risk Score in Screening for Prostate Cancer.
No full textBACKGROUND: The incidence of prostate cancer is increasing. Screening with an assay of prostate-specific antigen (PSA) has a high rate for false positive results. Genomewide association studies have identified common germline variants in persons with prostate cancer, which can be used to calculate a polygenic risk score associated with risk of prostate cancer. METHODS: We recruited persons 55 to 69 years of age from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, we derived polygenic risk scores from 130 variants known to be associated with an increased risk of prostate cancer. Participants with a polygenic risk score in the 90th percentile or higher were invited to undergo prostate cancer screening with multiparametric magnetic resonance imaging (MRI) and transperineal biopsy, irrespective of PSA level. RESULTS: Among 40,292 persons invited to participate, 8953 (22.2%) expressed interest in participating and 6393 had their polygenic risk score calculated; 745 (11.7%) had a polygenic risk score in the 90th percentile or higher and were invited to undergo screening. Of these 745 participants, 468 (62.8%) underwent MRI and prostate biopsy; prostate cancer was detected in 187 participants (40.0%). The median age at diagnosis was 64 years (range, 57 to 73). Of the 187 participants with cancer, 103 (55.1%) had prostate cancer classified as intermediate or higher risk according to the 2024 National Comprehensive Cancer Network (NCCN) criteria, so treatment was indicated; cancer would not have been detected in 74 (71.8%) of these participants according to the prostate cancer diagnostic pathway currently used in the United Kingdom (high PSA level and positive MRI results). In addition, 40 of the participants with cancer (21.4%) had disease classified as unfavorable intermediate risk or as high or very high risk according to NCCN criteria. CONCLUSIONS: In a prostate cancer screening program involving participants in the top decile of risk as determined by a polygenic risk score, the percentage found to have clinically significant disease was higher than the percentage that would have been identified with the use of PSA or MRI. (Funded by the European Research Council Seventh Framework Program and others; BARCODE1 ClinicalTrials.gov number, NCT03857477.)
Fitness and transcriptional plasticity of human breast cancer single-cell-derived clones.
No full textClonal fitness and plasticity drive cancer heterogeneity. We used expressed lentiviral-based cellular barcodes combined with single-cell RNA sequencing to associate single-cell profiles with in vivo clonal growth. This generated a significant resource of growth measurements from over 20,000 single-cell-derived clones in 110 xenografts from 26 patient-derived breast cancer xenograft models. 167,375 single-cell RNA profiles were obtained from 5 models and revealed that rare propagating clones display a highly conserved model-specific differentiation program with reproducible regeneration of the entire transcriptomic landscape of the original xenograft. In 2 models of basal breast cancer, propagating clones demonstrated remarkable transcriptional plasticity at single-cell resolution. Dichotomous cell populations with different clonal growth properties, signaling pathways, and metabolic programs were characterized. By directly linking clonal growth with single-cell transcriptomes, these findings provide a profound understanding of clonal fitness and plasticity with implications for cancer biology and therapy
Mechanisms of replication stress: the role of RAD52 in replication and a new vulnerability in mismatch repair deficient cancers
No full textFaithful duplication of chromosomes is critical for maintaining survival and preventing genomic instability.
However, both endogenous and exogenous factors can disrupt the DNA synthesis process, leading to
replication stress (RS). In turn, RS leads to the accumulation of genetic modifications causing genomic
instability, a hallmark of tumorigenesis. Understanding the causes and consequences of replication stress
is critical, not only for furthering the knowledge of the mechanistic landscape of tumorigenesis but also
for the development of better anti-cancer strategies targeting cancer vulnerabilities.
The first part of the thesis explores the consequences of RAD52 knockout in non-cancerous (RPE1) and
cancerous cells (HeLa and HCT116) under conditions of low-dose aphidicolin (APH) treatment and
translesion synthesis inhibition (TLSi). While TLSi alone reduces global DNA synthesis in cancer cells, it
has minimal impact on untransformed cells. Notably, combined TLSi and APH treatment exacerbates the
DNA synthesis defect in all cell lines, highlighting a requirement for TLS in mitigating RS. Interestingly,
RAD52 loss is synergistic with these effects only in HCT116 cells. Treatment with APH leads to underreplicated
regions that complete DNA synthesis in G2. Further, analysis of these G2 DNA synthesis
events reveals that TLS plays a critical role in maintaining replication at these regions. The data also
shows RAD52 to be necessary in HCT116, but dispensable in RPE1 cells. Investigation using chemical
inhibitors and siRNA-mediated depletion of RAD52 indicates that the phenotypes observed in HCT116
are likely due to compensatory mechanisms rather than direct functional loss of RAD52. Additionally, a
potential synthetic lethal interaction between MLH1 loss and TLSi was identified, warranting further
exploration.
The biological complexities in studying the functional role of RAD52 across various cell types and
conditions led to a shift in focus towards exploring novel synthetic lethality relationship between mismatch
repair (MMR) deficiency and TLSi in the second part of the thesis. This lethality was confirmed across
multiple untransformed cell lines (RPE1, RPE1P53KO, 1BR3, MCF10A). Notably, MMR-deficient colon
cancer cell lines exhibit increased sensitivity to TLSi compared to MMR-proficient colorectal cancers. A
proof-of-concept analysis of the TCGA cohort further demonstrates that this interaction could be exploited
in gastrointestinal and endometrial cancers. At a molecular level, it is demonstrated that combined loss
of MMR and TLS leads to ssDNA accumulation, increased p21 levels, heterochromatinization and cell
cycle delays. Furthermore, new insights reveal that loss of MMR genes alone modulates cellular
homeostasis, significantly impacting chromatin compaction, replication speed, and cell cycle progression
DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes.
No full textThe t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with >500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor & Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of FOXC1 and HOX genes that are key leukemia mediators. CUT&RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population