Early Stage Clinical Trials Research Articles

Clinical trial design for novel targeted agents in neuro-oncology.

Biomarker-based clinical trials investigating targeted treatments for brain tumors have surged due to better access to biomarker testing and a deeper grasp of the molecular basis of tumor development. The design of clinical trials is crucial for evaluating safety, confirming effectiveness, and affirming the clinical advantage of novel agents, with the goal of approval by regulatory authorities to expand patient treatment options. Given some challenges unique to brain tumors, early-stage clinical trials for novel targeted agents must integrate pharmacokinetics and tissue-based pharmacodynamic assessments to establish timely go-no-go decisions for larger studies. Surgical window-of-opportunity trials can allow for the comparison of treated and untreated tumor samples, verifying target engagement and its modulatory effects for evidence of biological activity. Due to the challenges of achieving the required sample sizes to power efficacy analyses, later-stage trials of targeted therapies can include basket trials which test one drug on multiple tumor types, while umbrella trials evaluate several biomarkers within a single histology. Platform trials can also be leveraged to investigate multiple biomarker-driven hypotheses within a unified protocol and can incorporate Bayesian algorithms for adaptive randomization. Selecting appropriate endpoints, such as progression-free survival or overall response rate, is crucial and novel response assessment criteria need to be considered in the context of the tumor and therapy being investigated. Lastly, inclusivity in trials is essential to address health disparities and engage diverse patient populations to ensure real-world impact. Future trials should build upon the knowledge gained from both initial achievements and past setbacks in the field.

A Novel Recombinant Vitronectin Variant Supports the Expansion and Differentiation of Pluripotent Stem Cells in Defined Animal-Free Workflows.

An essential aspect of harnessing the potential of pluripotent stem cells (PSCs) and their derivatives for regenerative medicine is the development of animal-free and chemically defined conditions for ex vivo cultivation. PSCs, including embryonic and induced PSCs (iPSCs), are in the early stages of clinical trials for various indications, including degenerative diseases and traumatic injury. A key step in the workflows generating these cells for more widespread clinical use is their safe and robust ex vivo cultivation. This entails optimization of cell culture media and substrates that are safe and consistent while maintaining robust functionality. Here, we describe the design of a human vitronectin (hVTN) variant with improved manufacturability in a bacterial expression system along with improved function in comparison to wild-type VTN and other previously characterized polypeptide fragments. In conjunction with an animal component-free media formulation, our hVTN fragment provides animal-free conditions for the enhanced expansion of iPSCs. This hVTN variant also supports the reprogramming of PBMCs into iPSCs. Furthermore, we show that these iPSCs can be efficiently differentiated into the three major germ layers and cortical neurons, thereby closing the loop on a completely defined animal-free workflow for cell types relevant for regenerative medicine.

Therapeutic Advances in Psoriasis: From Biologics to Emerging Oral Small Molecules.

Psoriasis is a persistent, inflammatory condition affecting millions globally, marked by excessive keratinocyte proliferation, immune cell infiltration, and widespread inflammation. Over the years, therapeutic approaches have developed significantly, shifting from conventional topical treatments and phototherapy to more sophisticated systemic interventions such as biologics and, recently, oral small-molecule drugs. This review seeks to present a comprehensive investigation of the existing psoriasis treatment options, focusing on biologic agents, oral small molecules, and emerging treatments. Several categories of biologic treatments have received regulatory approval for psoriasis, including TNF-α, IL-17, IL-12/23, and IL-23 inhibitors. Biologics have revolutionized the treatment of psoriasis. These targeted therapies offer significant improvement in disease control and quality of life, with acceptable safety profiles. However, limitations such as cost, potential immunogenicity, and administration challenges have driven the exploration of alternative treatment modalities. Oral small molecules, particularly inhibitors of Janus kinase (JAK), have emerged as options due to their convenience and efficacy. These agents represent a paradigm shift in the management of the condition, offering oral administration and targeted action on specific signaling pathways. In addition to existing therapies, the review explores emerging treatments that hold promise for the future of psoriasis care. These include innovative small-molecule inhibitors. Early-stage clinical trials suggest these agents may enhance outcomes for psoriasis patients. In conclusion, the therapeutic landscape of psoriasis is rapidly evolving, emphasizing targeted, patient-centered treatments. Ongoing research and development are expected to lead to more personalized and effective management strategies for this complex condition.

New therapeutic target molecules for gastric and gastroesophageal junction cancer.

Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody-drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody-drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors.

The most remarkable finding in synthetic lethality (SL) is the hypersensitivity to PARP inhibitors (PARPis) of the tumors harboring defects in genes involved in homologous repair (HR) such as BRCA1/2. Despite initial responsiveness to PARPi, the penetrance of the synthetic lethal interactions between BRCA1/2 genes and PARPi is incomplete. Thus, a significant proportion of HR-defective tumors experience intrinsic or acquired resistance, representing a key challenge of clinical research. An expanded concept of SL is opening new ways and includes novel forms of genetic interactions, investigating not only traditional SL of pairs genes but also SL between biological pathways that regulate the same essential survival cell function. In this context, recent research showed that HR and theta-mediated end-joining (TMEJ) pathways exhibit SL. DNA polymerase theta (Polθ) is encoded by the POLQ gene and is a key component of the TMEJ, an essential backup pathway, intrinsically mutagenic, to repair resected double-strand breaks (DSBs) when the non-homologous end joining (NHEJ) and HR are impaired. Polθ is broadly expressed in normal tissues, overexpressed in several cancers, and typically associated with poor outcomes and shorter relapse-free survival. Notably, HR-deficient tumor cells present the characteristic mutational signatures of the error-prone TMEJ pathway. According to this observation, the loss of HR proteins, such as BRCA1 or BRCA2, contributes to increasing the TMEJ-specific genomic profile, suggesting synthetic lethal interactions between loss of the POLQ and HR genes, and resulting in the emerging interest for Polθ as a potential therapeutic target in BRCA1/2-associated tumors.This review summarizes the converging roles of the POLQ and HR genes in DNA DSB repair, the early-stage clinical trials using Polθ inhibitor to treat HR-defective tumors and to overcome BRCA-reversion mutations responsible for therapeutic resistance, and the novel pleiotropic effects of Polθ, paving the way for the development of unexplored synthetic lethality strategies.

Immunogenicity of Extracellular Vesicles.

Extracellular vesicles (EVs) are promising next-generation therapeutics and drug delivery systems due to demonstrated safety and efficacy in preclinical models and early-stage clinical trials. There is an urgent need to address the immunogenicity of EVs (beyond the apparent lack of immunotoxicity) to advance clinical development. To date, few studies have assessed unintended immunological recognition of EVs. An in-depth understanding of EV-induced immunogenicity and clearance is necessary to develop effective therapeutic strategies, including approaches to mitigate immunological recognition when undesired. This article summarizes various factors involved in the potential immunogenicity of EVs and strategies to reduce immunological recognition for improved therapeutic benefit.

Evolving Role of Exosomes in Plastic and Reconstructive Surgery and Dermatology.

Exosomes, or extracellular vesicles, represent the latest cell-free addition to the regenerative medicine toolkit. In vitro preclinical studies have demonstrated the safety and efficacy of exosomes, which vary based on source and biomanufacturing, for a myriad of potential therapeutic applications relevant to skin and soft tissue reconstruction. Primary search was performed in September 2021 on the MEDLINE database via PubMed and Ovid, with focus on articles about therapeutic application of exosomes or extracellular vesicles. In total, 130 articles met criteria for applicability, including early-stage clinical trials, preclinical research studies with in vivo application, and articles applicable to plastic and reconstructive surgery and dermatology. Most studies used animal models of human disease processes, using either animal donor cells to isolate exosomes, or human donor cells in animal models. Exosome technology has catapulted as an acellular therapeutic vehicle with off-the-shelf accessibility. These features eliminate prior threshold for broad adoption of regenerative cell-based therapies into surgical and medical practice. To date, there are no exosome products approved by the US Food and Drug Administration. This review highlights exosomes as the new frontier in regenerative medicine and outlines its preclinical therapeutic applications for cutaneous repair and restoration.

Deep Learning-based Modeling for Preclinical Drug Safety Assessment.

In drug development, assessing the toxicity of candidate compounds is crucial for successfully transitioning from preclinical research to early-stage clinical trials. Drug safety is typically assessed using animal models with a manual histopathological examination of tissue sections to characterize the dose-response relationship of the compound - a time-intensive process prone to inter-observer variability and predominantly involving tedious review of cases without abnormalities. Artificial intelligence (AI) methods in pathology hold promise to accelerate this assessment and enhance reproducibility and objectivity. Here, we introduce TRACE, a model designed for toxicologic liver histopathology assessment capable of tackling a range of diagnostic tasks across multiple scales, including situations where labeled data is limited. TRACE was trained on 15 million histopathology images extracted from 46,734 digitized tissue sections from 157 preclinical studies conducted on Rattus norvegicus. We show that TRACE can perform various downstream toxicology tasks spanning histopathological response assessment, lesion severity scoring, morphological retrieval, and automatic dose-response characterization. In an independent reader study, TRACE was evaluated alongside ten board-certified veterinary pathologists and achieved higher concordance with the consensus opinion than the average of the pathologists. Our study represents a substantial leap over existing computational models in toxicology by offering the first framework for accelerating and automating toxicological pathology assessment, promoting significant progress with faster, more consistent, and reliable diagnostic processes.

Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1–7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK–AMPK–mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.

Novel measures of cognition and function for the AD spectrum in the Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD) project: Psychometric properties, convergent validation, and contrasts with established measures.

This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early-stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well-established measures. For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test-retest reliability) and stronger associations with AD-related demographic, genetic, and brain risk markers than well-established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early-stage AD clinical trials. Well-established cognitive tests may not accurately detect subtle cognitive changes. No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties. NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains. Novel measures had better psychometric properties compared to established measures. Significant associations with Alzheimer's disease biomarkers were found with novel measures.

Limbal stem cell therapy.

To highlight the progress and future direction of limbal stem cell (LSC) therapies for the treatment of limbal stem cell deficiency (LSCD). Direct LSC transplantation have demonstrated good long-term outcomes. Cultivated limbal epithelial transplantation (CLET) has been an alternative to treat severe to total LSCD aiming to improve the safety and efficacy of the LSC transplant. A prospective early-stage uncontrolled clinical trial shows the feasibility and safety of CLET manufactured under xenobiotic free conditions. Other cell sources for repopulating of the corneal epithelium such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells are being investigated. The first clinical trials of using MSCs showed short-term results, but long-term efficacy seems to be disappointing. A better understanding of the niche function and regulation of LSC survival and proliferation will lead to the development of medical therapies to rejuvenate the residual LSCs found in a majority of eyes with LSCD in vivo. Prior efforts have been largely focused on improving LSC transplantation. Additional effort should be placed on improving the accuracy of diagnosis and staging of LSCD, and implementing standardized outcome measures which enable comparison of efficacy of different LSCD treatments for different severity of LSCD. The choice of LSCD treatment will be customized based on the severity of LSCD in the future. New approaches for managing different stages of LSCD are being developed. This concise review summarizes the progresses in LSC therapies for LSCD, underlying mechanisms, limitations, and future areas of development.

Nutrition Interventions as Geroprotectors: Design and Interpretation of Early-Stage Clinical Trial of Strawberries

Nutrition Interventions as Geroprotectors: Design and Interpretation of Early-Stage Clinical Trial of Strawberries

RNA Sequencing Reveals Candidate Genes and Pathways Associated with Resistance to MDM2 Antagonist Idasanutlin in TP53 Wild-Type Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a genetically and clinically diverse hematological cancer affecting middle-aged and elderly individuals. Novel targeted therapy options are needed for patients who relapse following initial responses or who are intrinsically resistant to current treatments. There is a growing body of investigation currently underway on MDM2 inhibitors in clinical trials, reflecting the increasing interest in including these drugs in cancer treatment regimens. One of the developed compounds, idasanutlin (RG7388), has shown promise in early-stage clinical trials. It is a second-generation MDM2-p53-binding antagonist with enhanced potency, selectivity, and bioavailability. In addition to the TP53 status, which is an important determinant of the response, we have shown in our previous studies that the SF3B1 mutational status is also an independent predictive biomarker of the ex vivo CLL patient sample treatment response to RG7388. The objective of this study was to identify novel biomarkers associated with resistance to RG7388. Gene set enrichment analysis of differentially expressed genes (DEGs) between RG7388-sensitive and -resistant CLL samples showed that the increased p53 activity led to upregulation of pro-apoptosis pathway genes while DNA damage response pathway genes were additionally upregulated in resistant samples. Furthermore, differential expression of certain genes was detected, which could serve as the backbone for novel combination treatment approaches. This research provides preclinical data to guide the exploration of drug combination strategies with MDM2 inhibitors, leading to future clinical trials and associated biomarkers that may improve outcomes for CLL patients.

TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons

Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival invivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.

Quantitative systems pharmacology modeling of macrophage-targeted therapy combined with PD-L1 inhibition in advanced NSCLC.

Immune checkpoint inhibitors remained the standard-of-care treatment for advanced non-small cell lung cancer (NSCLC) for the past decade. In unselected patients, anti-PD-(L)1 monotherapy achieved an overall response rate of about 20%. In this analysis, we developed a pharmacokinetic and pharmacodynamic module for our previously calibrated quantitative systems pharmacology model (QSP) to simulate the effectiveness of macrophage-targeted therapies in combination with PD-L1 inhibition in advanced NSCLC. By conducting in silico clinical trials, the model confirmed that anti-CD47 treatment is not an optimal option of second- and later-line treatment for advanced NSCLC resistant to PD-(L)1 blockade. Furthermore, the model predicted that inhibition of macrophage recruitment, such as using CCR2 inhibitors, can potentially improve tumor size reduction when combined with anti-PD-(L)1 therapy, especially in patients who are likely to respond to anti-PD-(L)1 monotherapy and those with a high level of tumor-associated macrophages. Here, we demonstrate the application of the QSP platform on predicting the effectiveness of novel drug combinations involving immune checkpoint inhibitors based on preclinical or early-stage clinical trial data.

Beyond Immune Checkpoint Inhibitors: Emerging Targets in Melanoma Therapy.

This review provides a comprehensive update on recent advancements in melanoma treatment by highlighting promising therapeutics with an aim to increase awareness of novel interventions currently in development. Over the last decade there has been considerable expansion of the previously available treatment options for patients with melanoma. In particular, novel immunotherapeutics have been developed to expand on the clinical advancements brought by BRAF targeting and immune checkpoint inhibitors. Despite the success of checkpoint inhibitors there remains an unmet need for patients that do not respond to treatment. This review delves into the latest advancements in novel checkpoint inhibitors, cytokines, oncolytic viruses, vaccines, bispecific antibodies, and adoptive cell therapy. Preclinical experiments and early-stage clinical trials studies have demonstrated promising results for these therapies, many of which have moved into pivotal, phase 3 studies.

Abstract P65: Single Cell Profiling Reveals Unique TCR Repertoire and Transcriptomic Signatures of Epstein-Barr Virus-Specific T cells (EBVSTs) Armoured with Chimeric Antigen Receptors (CARs)

Abstract Allogeneic Epstein-Barr Virus-specific T cells (EBVSTs) have thus far been a safe immunotherapy product in the clinic, with little graft-versus-host-disease reported in over 300 recipients to date. Consequently, EBVSTs armoured with chimeric antigen receptors (CARs) have emerged as a promising platform for allogeneic T cell therapies. Believing that a deep characterisation of CAR EBVST cell products can enhance insights into their clinical safety, we performed single cell T cell receptor (TCR) sequencing on CAR EBVSTs, taking CD30.CAR EBVSTs as a prototype. Non-transduced (NT) EBVSTs and CD30.CAR EBVSTs generated from three healthy donors exhibited a narrower, more focused TCR repertoire by diversity indices, compared to resting T cells and CD30.CAR-transduced activated T cells (ATCs) from the same donors. EBVSTs harboured a lower frequency of unique TCR clonotypes and a higher proportion of expanded clones, indicating a tendency toward clonal dominance. Narrower TCR repertoires corresponded to greater IFNγ and TNFα secretion in response to stimulation with EBV peptides, with no cross-reactivity toward other common viruses, and were associated with lower allogeneic reactivity in mixed lymphocyte reactions. To investigate whether the EBVST nature of the product might contribute to better CAR activity, we concurrently performed single cell transcriptomic sequencing on NT EBVSTs, CD30.CAR EBVSTs, and CD30.CAR ATCs. Transcriptomic signatures revealed that each sample type contained two major, distinct populations of CD4+ T cells: proliferative and activated. While the proliferative subsets appeared to be closely related, the activated populations had distinct transcriptional profiles. In particular, CD30.CAR EBVSTs appeared to be more polyfunctional and metabolically poised than CD30.CAR ATCs. The restricted TCR repertoire and apparent functional superiority of CD30.CAR EBVSTs may underlie their safety and efficacy observed in early-stage clinical trials and preclinical models, with the larger implication that these qualities extend to CAR EBVSTs targeting antigens beyond CD30. Citation Format: Lindsay Kua, Ting Wei Lim, Fiona Wong, Pei Yun Teo, Lionel Low, Ivan Horak, Jinmiao Chen, Kar Wai Tan. Single Cell Profiling Reveals Unique TCR Repertoire and Transcriptomic Signatures of Epstein-Barr Virus-Specific T cells (EBVSTs) Armoured with Chimeric Antigen Receptors (CARs) [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P65.

Abstract 3560: Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials

Abstract Background: Serious adverse events (SAEs) are a critical determinant of drug toxicity in clinical trials. However the drivers of toxicity may be related to patient factors as much or more than drug related factors. Prior studies have shown that time in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. SAEs are a critical determinant of drug toxicity in clinical trials. However, predicting SAEs using conventional PS scales measurements, such as ECOG is challenging because measurements can vary among observers. Prior studies have used activity trackers to measure physical activity and showed that time spent in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. Here, we sought to extend these findings to early phase clinical trial participants by examining data collected in two single-arm, observational, prospective studies at USC Keck and MD Anderson centers. We explored the use of out-of-clinic wearable sensors as an objective metric of frailty so as to identify patients at risk for therapy complications. Methods: Adult patients diagnosed with cancer and enrolled in early stage clinical trials across USC Keck and MD Anderson centers were included in parallel single-arm, observational, prospective studies. Patients used a consumer grade wearable activity tracker (Fitbit) and the study examined associations between the number of severe adverse events to activity levels measured by metabolic equivalents (METs) and get-up-go times across the first 30 days. Trends were assessed using t-tests. Results: 36 eligible patients were included in METs activity analysis. There was a total of 16 recorded incidences of SAEs within the first 30 study days, with 10 patients experiencing at least one SAE. The median non-sedentary time for patients with no SAEs was 27.5 hours above 1.5 METs per week, compared to 21.5 hours for those with at least one SAE occurrence (p-value=0.0146, r2=0.1629). The median get-up-go times for those without SAEs was 10.0 seconds (n=26) and with SAEs was 9.8 seconds (n=10), (p-value=0.828, r2=0.0014). Conclusions: Non-sedentary time, as an objective measure of activity, can be used to identify those patients who are at greatest risk for SAEs in clinical trials. Widely available and inexpensive consumer grade sensors can be used as a stratification tool. Findings should be confirmed in larger patient cohorts across a wider variety of trial settings. Figure 1: Weekly non-sedentary hours vs. presence of SAE in first 30 days of trial enrollment Citation Format: Eli Tran, Luciano Nocera, Anand Kolatkar, Anthony El-Khoueiry, Jacob Thomas, Peter Kuhn, Andrew Zeng, Megumi Kai, Meghan Karuturi, Jorge Nieva. Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3560.

Abstract 5300: BH3120, PD-L1 X 4-1BB bispecific antibody, plus PD-1 antagonist results in synergistic anti-tumor efficacy with excellent safety profile

Abstract BH3120 is a clinical stage PD-L1 binding dependent 4-1BB agonist with moderate affinity against 4-1BB. In multiple preclinical evaluations, BH3120 decoupled T cell modulation in TME from that in normal tissues, indicating potential decoupling of efficacy from safety concerns. 4-1BB agonism improves T cell functions in TME, combining BH3120 and PD-1 antagonist shows dose dependent and complete control of established tumor burden with bi-directionally synergistic mechanism: Blockade of PD-1 increases the expression and exposure of surface PD-L1, providing BH3120 more chance to form immune clusters in the tumor environment. In the meantime, increased PD-1 induced by BH3120 can be blocked by PD-1 antagonist. This bi-directional mechanism results in rapid eradication of tumor tissues shortening the time to regression, indicating potentially fast control of tumor burden and associated symptoms. With the characteristics decoupling co-stimulatory activity in TME from that in normal tissues, BH3120 either as a monotherapy or in combination with PD-1 antagonist was not associated with liver toxicity and other concerns in relation to excessive modulation of immune cells systemically. Safety profile and clinical signs with BH3120 are being investigated in early-stage clinical trials as a monotherapy and in combination with a PD-1 antagonist. Citation Format: Jun Wang, Jing Wang, Yang Liu, Jiangcheng Xu, Jiawang Liu, Kyoungwoo Lee. BH3120, PD-L1 X 4-1BB bispecific antibody, plus PD-1 antagonist results in synergistic anti-tumor efficacy with excellent safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5300.

Abstract 2130: Glioblastoma-derived extracellular vesicle cargo as a reporter of drug delivery and effect

Abstract The selectivity of the blood-brain-barrier (BBB) can prevent therapeutics from reaching the brain, and this may contribute to the high failure rate of new drugs for tumors like glioblastoma (GBM) and brain metastasis. The capacity to detect BBB penetrance in real-time in a noninvasive manner would arguably aid the rate of therapeutic development. Extracellular vesicles, which are membrane bound particles secreted by all cell types in the body, have potential as a neuro pharmacodynamic reporter given that their protein and RNA cargo reflect the originating cell population. We hypothesized that the exposure of GBM cells to therapy results in altered EV cargo, and that the detection of this shift can be leveraged as a liquid biopsy from patients during early clinical trials to determine BBB penetrance and tumor engagement. To identify cargo shifts indicative of treatment, we exposed four short-term patient derived glioma cell lines to arsenic trioxide (an idiopathic toxin), MLN4924 (a neddylation inhibitor), and the alkylating agent temozolomide, then harvested EVs for unbiased mass spectrometry and RNA sequencing. Interestingly, we identified conserved upregulated and downregulated protein and RNA species across cell lines and across drug treatments, despite the diverse mechanisms of action. Candidate proteins were further validated by mesoscale immunoassays and exoview evaluation of tetraspanin-captured EVs. RNA species were validated by qRT-PCR. Overall, we demonstrate that GBM-derived EV cargo changes in response to therapy, supporting the development of EVs as a reporter of drug delivery in GBM. Ongoing and future work is focused on identifying enrichment handles in order to selectively evaluate GBM-derived EV cargo from patient biofluids. Thus far, B7H3, PTPRZ1, EGFRvII and IL13Ra2 have been screened as putative handles. Success in this pursuit could substantially enhance findings and accelerate drug testing in early-stage clinical trials in brain tumor patients by reporting drug accessibility to the tumor and engagement with drug targets. Citation Format: Valerie DeLuca, Nanyun Tang, Nathaniel Hansen, Anjali Raju, Charles Shaffer, Yue Hao, Terry C. Burns, Jann N. Sarkaria, Ian Parney, Patrick Pirrotte, Kendall Van Keuren-Jensen, Michael E. Berens. Glioblastoma-derived extracellular vesicle cargo as a reporter of drug delivery and effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2130.