Face Hurdles Research Articles

Abstract 3611: A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid tumors

Abstract Recent advances in cancer immunotherapy have positively impacted the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when embedded into the extracellular matrix. Patient-derived organoids are generated from healthy and malignant tissues, and they recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. Cell therapies have achieved positive results in treating haematological cancers. Recently, the unique tumour-targeting properties of γδ T cell receptors have been leveraged to develop safer and more effective strategies. HUB and Gadeta joined efforts to explore the therapeutic potential of GDT002 - i.e. αβ T cells engineered with a Gadeta proprietary new γδTCR - to target solid cancers. A preclinical basket trial was performed using patient-derived organoids from several tumour types (colorectal, breast, head and neck, ovarian cancers) cocultured with GDT002. The results showed broad reactivity of GDT002 against solid tumor PDOs. Interestingly, GDT002 was particularly efficient at killing ovarian cancer-derived PDOs, allowing Gadeta to move GDT002 to clinical trials for this indication confidently. This study reveals that our tumor organoid co-culture with engineered T cells platform holds significant value for the preclinical development of cellular therapies. Citation Format: Andrea Bisso, Rene Overmeer, Sjoerd Baardman, Chris Coomans, Cesar Oyarce, Sylvia F. Boj. A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid tumors [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 3611.

Abstract 2696: Tumor organoid and immune cells co-cultures to study myeloid cells-targeting immunotherapy

Abstract Cancer immunotherapy is one of the main pillars of oncology treatment due to the clinical success of approaches that enhance anti-tumoral T cell responses. Nonetheless, many patients do not benefit from these approaches, highlighting the need to develop novel immunomodulatory strategies. Exploiting the anti-tumor capacity of innate immune cells is a promising approach that can overcome specific limitations of T cell-targeting therapies and complement existing immunotherapies. Still, promising therapeutic developments face hurdles in translating preclinical findings into treatment since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures. Patient-specific organoids are generated from healthy and disease tissues and recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. To assess the efficacy of therapies that engage innate immune cells, we developed an assay in which organoids derived from colorectal (CRC) or breast cancer patients are co-cultured with PBMC-derived macrophages or monocytes to evaluate the cytotoxic potential of exogenously activated myeloid cells. We tested the ability of macrophages to phagocyte human CRC organoid cells in response to anti-CD47 antibody. The pro-phagocytic function of anti-CD47 was detected by several methods (i.e., flow cytometry, imaging), indicating the platform's suitability to evaluate ADCP-modulating compounds. Moreover, to assess whether our PBMC-organoids co-culture platform is suited to detect monocyte-mediated effects, Lipopolysaccharide (LPS) plus IFN-γ were used to activate monocytes in the co-culture assays. We observed an increase in cytokines secretion (i.e., CXCL10), immune cell activation and organoid killing, indicating that our assay allows the detection of monocyte activation through different types of readouts. In summary, our organoid-immune cell co-culture platform allows to study the response of tumor organoids to innate immune cells, holding significant value for the preclinical development of immunotherapies based on innate immune cells. Citation Format: Lorenzo Spagnuolo, Francisco Morales-Rodriguez, Alessandra Merenda, Cesar Oyarce, Farzin Pourfarzad, Robert G. Vries, Sylvia F. Boj. Tumor organoid and immune cells co-cultures to study myeloid cells-targeting immunotherapy [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 2696.

Systemic Barriers to Optimal Cancer Care in Resource-Limited Countries: Jordanian Healthcare as an Example.

This narrative review explores the multifaceted barriers hindering access to quality cancer care in Jordan. A literature-based narrative review was undertaken to explore the current identified barriers to cancer care in Jordan. Four databases were searched using relevant keywords to identify key insights on barriers and proposed solutions. Key challenges and potential solutions were identified based on evidence from studies, reports, and initiatives. Medical services and infrastructure exhibit centralized disparities, impacting rural and underserved areas. Human resources shortages, geopolitical instability, and quality management issues pose significant challenges. Public awareness campaigns face hurdles in addressing the tobacco epidemic and late-stage diagnosis. Socioeconomic disparities, particularly in health insurance and urban-rural divides, further compound barriers. Refugees encounter distinct challenges, including late-stage diagnosis, financial barriers, and psychological distress. Despite multiple challenges, Jordan presents a model for regional development and health equity. This study not only contributes to improving cancer care in Jordan but also offers a roadmap for policymakers, healthcare practitioners, and researchers in similar contexts globally. Government initiatives, financial aspects, and proposed policy measures are examined as potential solutions. Recommendations include coordinated prevention strategies, enhanced screening uptake, training programs, the equitable distribution of facilities, and policy directives aligned with global commitments. The role of digital technologies, telemedicine, and community engagement models is emphasized.

Preliminary Study of Novel Bio-Crypto Key Generation Using Clustering-Based Binarization of ECG Features.

In modern society, the popularity of wearable devices has highlighted the need for data security. Bio-crypto keys (bio-keys), especially in the context of wearable devices, are gaining attention as a next-generation security method. Despite the theoretical advantages of bio-keys, implementing such systems poses practical challenges due to their need for flexibility and convenience. Electrocardiograms (ECGs) have emerged as a potential solution to these issues but face hurdles due to intra-individual variability. This study aims to evaluate the possibility of a stable, flexible, and convenient-to-use bio-key using ECGs. We propose an approach that minimizes biosignal variability using normalization, clustering-based binarization, and the fuzzy extractor, enabling the generation of personalized seeds and offering ease of use. The proposed method achieved a maximum entropy of 0.99 and an authentication accuracy of 95%. This study evaluated various parameter combinations for generating effective bio-keys for personal authentication and proposed the optimal combination. Our research holds potential for security technologies applicable to wearable devices and healthcare systems.

Ratification of the UN Anti-Corruption Convention: Legal and Political Implications in Indonesia and its Context within Southeast Asian International Law Discourse

This paper scrutinizes Indonesia's ratification of the UN Anti-Corruption Convention, examining its legal and political implications within Southeast Asia's international law discourse. Analyzing treaty provisions alongside Indonesia's legal framework, it assesses challenges and opportunities in combating corruption. The study emphasizes several key findings. Firstly, domestically, ratification showcases Indonesia's commitment to combat corruption, addressing a long-standing governance and economic development issue. Aligning with international standards signals intent to fortify anti-corruption efforts, bolster transparency, and augment accountability mechanisms. This aligns with fostering good governance practices vital for sustainable development and attracting foreign investment. Secondly, ratification holds political significance, affirming the government's dedication to tackling corruption, potentially enhancing its legitimacy. However, effective implementation may face hurdles due to entrenched political interests and bureaucratic challenges. In the Southeast Asian context, Indonesia's ratification serves as a model for regional cooperation against corruption. As a major economy and populous nation, Indonesia's commitment sets a precedent for collective action. It underscores the importance of regional collaboration in combating corruption, opening avenues for dialogue, collaboration, and capacity-building initiatives. This offers prospects for strengthening anti-corruption frameworks and mechanisms both nationally and regionally. In conclusion, Indonesia's ratification of the UN Anti-Corruption Convention signifies a pivotal step in combating corruption domestically and regionally. While it showcases political will and potential for regional cooperation, effective implementation remains contingent on overcoming internal challenges and fostering collaboration across Southeast Asia. This study illuminates the complex interplay between national and international efforts to combat corruption, contributing to a deeper understanding of the regional dynamics at play.

PromotingLGBTQ+ for financial aid: (Mis)Construing sexuality education for early childhood development in Ghana

One of the primary goals of a curriculum change is to address the needs of a society. Nonetheless, its implementation may face hurdles if the cultural heritage, worldview, and philosophy of society are not well represented in the curriculum. Thus, this study was an attempt to discover the sociocultural and curriculum-related concerns that led to Ghanaians’ opposition to the introduction of comprehensive sex education (CSE) in the basic school curriculum. Data were gathered from the online social media platforms: Facebook and Twitter. The analysis show that CSE, as an educational initiative for early childhood learners in Ghana, conflicts with the culturally accepted means of bringing up children in the sociocultural context of Ghana. Consequently, the idea of CSE was strongly opposed by Ghanaians because they misconstrued the initiative as a concealed attempt by the Westerners to promote LGBTQ+. Nonetheless, some consider it a crucial means of preventing STIs and unintended pregnancies. We, thus, argue in this paper that Ghanaians misconstrued this initiative because major stakeholders in the curriculum were not engaged in the curriculum development process. We, therefore, recommend that effective situational analysis and needs assessment precede the introduction of any culturally sensitive educational initiative in Ghana.

The Quest for Fluency: English Language Challenges for Non-Native Learners

English language acquisition presents challenges for non-native speakers worldwide. Despite its global significance, many encounter difficulties in mastering it. The colonial legacy has entrenched English as an international language, leading to its widespread use across various domains. However, in nations with diverse linguistic landscapes, attempts to promote English learning face hurdles. In the Indian education system, for instance, reforms aiming to enhance English proficiency have yielded limited success due to multifaceted reasons, including societal attitudes and educational priorities. The prevailing mindset often prioritizes core subjects over language learning, hindering students' progress. Moreover, learners grapple with fear, lack of confidence, grammatical complexities, pronunciation issues, and native language interference. Environmental factors, peer pressure, and inadequate teaching further exacerbate these challenges. Overcoming these obstacles requires a shift in attitudes, with recognition of the value of language subjects and concerted efforts to provide supportive learning environments. Emphasizing foundational grammar concepts and fostering holistic language skills development through listening, speaking, reading, and writing activities are crucial. Addressing these issues can enhance the efficacy of English language education and empower non-native speakers to navigate the linguistic demands of the modern world effectively.

Exploring the Conceptual Realm of Machine Learning in Small and Medium-sized Industries: A Qualitative Study

The pote­ntial of machine learning in small and medium busine­sses remains largely untappe­d. Through a qualitative study, it is e­xplored how the SMEs can practically apply ML to optimize processes and spark innovation. We­ aimed to demystify key conce­pts like supervised le­arning, data preparation, and model evaluation. Re­al-world examples across industries de­monstrate ML's versatility, from enhancing de­cision-making to improving efficiency. Our rese­arch highlights the transformative power of ML, e­specially for resource-constraine­d SMEs. With some guidance, eve­n small teams can implement ML solutions that unlock ne­w opportunities. Though adoption has barriers, from data to skills, ML’s value for SMEs is cle­ar. With a strategic approach, companies of all sizes can tap into its possibilitie­s. Current re­search on implementing machine­ learning in small and medium ente­rprises has gaps. More investigation is re­quired to understand adoption challenge­s fully, highlight successes, and mee­t unique needs. A qualitative­ approach that explores expe­riences and perspe­ctives can provide those rich insights. Some­ small and medium companies use machine­ learning, but many face hurdles adopting it. Re­search case studies showcase­ machine learning success storie­s, though each company's path differs. By understanding individual difficultie­s, researchers can he­lp more small and medium enterprises use machine learning appropriate­ly. This literature revie­w examines machine le­arning models, adoption trends, triumphs, and example­s in small and medium enterprise­s. Moreove­r, it also examines the advantage­s and obstacles SMEs encounter whe­n adopting ML tactics.

Hurdling on home straight in the women 3000m steeplechase

The 3000m steeplechase is an event in which athletes must clear 28 hurdles and 7 water jumps while competing for the fastest time. In this race, women must clear hurdles set at a height of 0.762 meters, whereas men face hurdles set at a height of 0.914 meters. There is a paucity of research on the 3000m steeplechase compared to other long-distance events. This study aimed to clarify the characteristics of hurdle clearance for the 3000m steeplechase. Investigating how to clear the hurdles on the home straight could significantly enhance race strategies and performance. Data were collected from the women’s 3000m steeplechase races at Kanto intercollegiate race. 15 women’s performances were analyzed. The 3000m steeplechase races were recorded by video camera. All jumps from participants were digitized using Kinovea (version 0.9.3). I focused on variables of three steps related to the three steps around hurdles, and comparisons were made among each lap. In terms of total clearance speed, we observed that lap 4 had a lower speed than lap 3, and lap 7 had a higher speed than lap 4. Before the increase in speed at the hurdle, there was an increase in the length of three steps in lap 7. Athletes in the final lap took off from a longer distance and achieved a faster clearance speed. The step frequency before hurdle clearance was higher in lap1 and lap2 than in lap4, lap5, lap6, and lap7. In addition, step frequency after hurdle clearance did not differ among laps and was lower than before hurdle clearance. Fatigue might be a contributing factor to this decline in step frequency before hurdle clearance. It would be advantageous for athletes to consciously increase their step frequency when approaching the next hurdle. The present study provided practical evidence for hurdle clearance of 3000m steeplechase.

A thematic analysis on understanding the mastery of knowledge sharing and outcome expectations on student academic performance in science at Junior High School Level

Learning Science, Knowledge Sharing, Outcome Expectations, and Academic Performance. Participants predominantly express a favorable stance towards learning science, which is enjoyable and challenging, though they face hurdles such as language barriers and stress. Underlining the need for supportive learning conditions, the study reveals that knowledge sharing, driven by intrinsic motivation, aids in addressing gaps and enhances academic performance. Anticipations in science education significantly influence students' motivation and academic success, as seen through the value placed on control, focus, and the functional role of science in daily life. Improved academic performance, attributed to overcoming challenges, motivation, and a positive shift in attitude, underscores the significance of collaborative learning and individualized approaches. These findings emphasize the intricate interplay among positive attitudes, knowledge sharing, expectations, and academic achievement in shaping students' experiences in science education. Teachers and educational institutions can leverage these insights to refine teaching methods and create inclusive environments that foster student success in science education while addressing obstacles like language barriers and stress.

A Programmable Oxygenation Device Facilitates Oxygen Generation and Replenishment to Promote Wound Healing.

Inadequate oxygenation is one of the chief culprits for delayed wound healing. However, current oxygen therapies, such as hyperbaric oxygen therapy and topical oxygen therapy, face hurdles in providing sustained and long-term oxygenation to reverse wound hypoxia. Furthermore, their efficacy in rejuvenating wound injury is restricted by limited penetration of oxygen in the wound bed. Herein, this study proposes a programmable and portable oxygenation device (named GUFO oxydevice) by ingeniously integrating i) a controllable oxygen generation and unidirectional transmission system (COGT-UTS), and ii) a supramolecular assembled perfluorinated hyperbranched polymer/gelatin (GUF) hydrogel in which the perfluorinated hyperbranched polymer (FHBP) acts as an oxygen reservoir to ensure sustained and convenient oxygen replenishment and thus directly regulate the hypoxic wound microenvironment. Accelerating the wound healing process by GUFO oxydeviceis achieved in both a diabetic rat and an acute porcine wound model without any secondary tissue damages. The present study demonstrates that the GUFO oxydevice holds promise as a practically feasible candidate for wound treatment.

Edge-selective covalent passivation of black phosphorus nanosheets by fullerene C70 toward enhanced antimicrobial performance

In the fight against bacterial infection, conventional antibiotic treatment encounters the formidable challenges of drug resistance and sluggish development. Non-metallic two-dimensional (2D) nanomaterials such as black phosphorus (BP) have emerged as promising non-antibiotic antimicrobial candidates due to its peculiar physiochemical properties, but face hurdles including low ambient stability and limited antibacterial activity, hindering its widespread utilization in disinfection. Herein, few-layer BP nanosheets (BPNSs) were covalently passivated by edge-selectively grafting fullerene C70 via a one-step solid-state mechanochemical route, and for the first time the covalently functionalized BPNSs is employed in disinfection. Fullerene edge-selective covalent passivation not only effectively overcomes the obstacles of poor ambient stability, but also substantially enhances the antibacterial activities of BPNSs. The BPNSs-C70 hybrid (denoted as BPNSs-C70) was applied as a novel non-metallic and non-antibiotic nano-antibacterial agent. Under 660 nm visible light irradiation, BPNSs-C70 demonstrates high generation capacity of reactive oxygen species (ROS), resulting in boosted in vitro and in vivo antibacterial efficacies against methicillin-resistant Staphylococcus aureus (MRSA) relative to the pristine BPNSs with exceptional biocompatibility. The significantly enhanced antibacterial performance of BPNSs-C70 is attributed to the synergistically improved singlet oxygen (1O2) and hydroxyl radicals (•OH) generation originated from the intramolecular electron transfer from BPNSs to C70.

Home country and firm-specific advantage influences on HRM replication versus adaptation in EMNEs operating in advanced economies: A qualitative comparative analysis

This article examines a variety of home and host-country factors and explains how they influence the global integration versus local adaptation of human resource management (HRM) in subsidiaries of emerging multinational enterprises (EMNEs) in advanced economies. The study draws on data collected from 15 multiple case studies using semi-structured interviews with senior directors and managers working in Australian subsidiaries of Indian multinational enterprises (MNEs) operating in the information technology (IT) services industry. The findings reveal that despite originating from weak institutions, Indian IT service MNEs do not face hurdles in replicating their home-country HRM model to their subsidiaries in Australia. International staffing of expatriates was a key industry-specific resource and capability enabling reverse country-of-origin effect to allow the Australian subsidiaries to be managed ethnocentrically. This article challenges the notion that EMNEs struggle to adapt their indigenous HRM systems and model due to weak institutions as it sheds light on the reverse relationship that exists between management practices and country-of-origin in leveraging home-country institutions. It also demonstrates that EMNEs derive competitive advantages mainly from their traditional firm and industry-specific resources and capabilities which allow them to achieve global integration of HRM.

Anchored Cell Sheet Engineering: A Novel Scaffold‐Free Platform for in vitro Modeling

AbstractBiofabricated in vitro models hold unrealized potential in accelerating drug discovery and reducing new drug costs, but current models are overly simplified and lack physiological relevance. Certain platforms capable of mimicking in vivo conditions face hurdles such as complexity, high costs, and non‐standardized applications. Existing cell sheet engineering methodologies, despite being physiologically relevant, have technical limitations like creating suitable 3D forms with proper anchorage. An innovative platform is introduced here, designed for in vitro modeling, which capitalizes on 2D culture systems and scaffold‐free cell sheets to create self‐assembling 3D tissue constructs. It provides precise control over cellular behavior, especially ECM production and remodeling. Scaffold‐free muscle fibers and lung epithelial cell cultures served as examples. This platform can fuse various scaffold‐free models to construct assembloids mimicking organ structures and functions. Different tissues can be linked via a fluidic system for body‐level simulations. Moreover, ECM‐rich constructs from cell sheets can create organ‐level ECM scaffolds, and the resulting cell sheet‐derived ECM (CSdECM) can be solubilized to facilitate 2D cellular behavior. This versatile platform, compatible with other cell sheet engineering techniques, is set to revolutionize in vitro modeling.

Navigating the digital divide: exploring the multifaceted 4IR challenges and technological disparities encountered by SMMEs within Kwazulu-Natal, South Africa

The dawn of the Fourth Industrial Revolution (4IR) has been a harbinger of unparalleled technological innovations, reshaping industries and economies at an unprecedented pace. While these advancements promise a new frontier of opportunities, they also bring forth a myriad of challenges, particularly for Small, Micro, and Medium-Sized Enterprises (SMMEs). This research delves deep into the multifaceted challenges and technological disparities encountered by SMMEs in the wake of 4IR, with a concentrated lens on the enterprises operating within the KwaZulu-Natal region of South Africa. At the heart of this exploration is the pronounced digital divide, which exacerbates the gulf between well-resourced corporations and SMMEs. The divide is not just technological but extends to areas like access to finance, digital literacy, infrastructure, and the agility to adapt to rapidly changing business environments. As these SMMEs grapple with the challenges of integrating into the digital economy, they face hurdles such as limited access to advanced technological tools, cybersecurity threats, the high cost of digital transformation, and a dearth of skilled manpower to navigate the complexities of 4IR. Furthermore, the research sheds light on the systemic and infrastructural challenges in the KwaZulu-Natal region, which further compound the difficulties faced by local SMMEs. From inconsistent internet access and electricity issues to the lack of tailored training programs and financial schemes, these enterprises find themselves in a precarious position, trying to bridge the chasm between traditional business models and the demands of the digital age. By offering an in-depth analysis of these challenges, this study seeks to provide a comprehensive understanding of the obstacles that SMMEs face in the current 4IR-driven economic climate. It emphasizes the need for a multi-stakeholder approach, involving governments, industry leaders, educational institutions, and financial institutions, to collaboratively develop strategies, policies, and interventions that can empower SMMEs. Through targeted support, capacity-building initiatives, and fostering an ecosystem of innovation, there's potential to not only narrow the digital divide but to position these enterprises as key players in South Africa's 4IR journey. This research, thus, serves as both a clarion call and a foundational blueprint for ensuring that no enterprise, regardless of its size, is left behind in this transformative era.

THE IMPACT OF REMOTE WORK ON HR PRACTICES: NAVIGATING CHALLENGES, EMBRACING OPPORTUNITIES

The COVID-19 pandemic has enhanced the rise of remote work, revolutionized organizational operations, and significantly impacted human resources (HR) practices. This paper explores the profound effects of remote work on HR functions, addressing both challenges and opportunities in this new paradigm. The shift to remote work has increased flexibility for the workforce and opened access to a global talent pool. However, it has not been without its challenges for HR professionals. They now face hurdles in engaging employees, managing performance effectively, and promoting team collaboration. Ensuring a unified organizational culture and cultivating a solid connection among remote workers have become pressing concerns. This research emphasizes the significance of HR departments adapting to the realities of remote work. It proposes a need for redefining talent acquisition, training, performance evaluation, and employee engagement strategies. By analyzing real-world case studies and expert insights, this study offers valuable guidance to HR leaders and practitioners in effectively navigating challenges and optimizing remote work arrangements. Embracing remote work provides clear advantages for organizations that enhance resilience and attract top talent. In this regard, HR professionals must proactively adopt technology and acquire new skill sets to optimize remote work environments. As organizations navigate the challenges of remote work, the HR function plays a fundamental role in shaping work's future and nurturing a thriving workforce. This study offers valuable insights, empowering HR practitioners to position their organizations for success amid this evolving landscape.<p> </p><p><strong> Article visualizations:</strong></p><p><img src="/-counters-/soc/0056/a.php" alt="Hit counter" /></p>

Improving Access and Equity in a Post-Dobbs World

Improving Access and Equity in a Post-Dobbs World

First in human phase Ⅰ study of BMS-986299 as monotherapy and combined with nivolumab and ipilimumab in advanced solid tumors.

e14584 Background: Immune checkpoint inhibitors (ICIs) face hurdles in overcoming the immunosuppressive tumor microenvironment. BMS-986299 is first-in-class, NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasome agonist enhancing adaptive immune and T cell memory responses. In-vivo studies demonstrated BMS-986299 synergy with ICIs and induction of durable immunological memory. Methods: This multicenter, open-label, phase I [NCT03444753] study assessed safety and tolerability of intra-tumoral (IT) BMS-986299 monotherapy (Part 1A) and in combination (Part 1B) with the programmed death 1 receptor antibody nivolumab (N), and the anti-cytotoxic T lymphocyte associated protein 4 antibody ipilimumab (I) in advanced solid tumors. Eligible patients (pts) regardless of prior ICI with accessible solid tumors (≥ 2 lesions) received IT BMS-986299 administered on day 1, 8, 15, 22, 29 for Cycle 1 (C1) and on days 1, 29 until C2, 8 weeks apart across 7 dose escalation cohorts in Part 1A (75μg-4000μg; Bayesian Logistic Regression Model (BLRM). In Part 1B, BMS-986299 was given across 3 dose escalation cohorts (75μg-2000μg; BLRM Copula) with nivolumab 480 mg q4weeks and ipilimumab 1 mg/kg q8weeks (fixed dosing) from day 1 up to 24 months (m). Cross-over (CS) was allowed from Part 1A to Part 1B. Results: The study was terminated early, unrelated to safety, due to the COVID-19 pandemic and did not complete enrollment. From April 2018 to February 2022, 50 pts were treated (33; Part 1A and 17; Part 1B). Eleven pts crossed over to Part 1B. Median age of pts enrolled was 59 years and with preponderance in female gender (58.0%) and white (80.0%) pt. participation. Forty-two pts (70%) had treatment related adverse events (TRAEs). Grade (G)3/G4 TRAEs included tubulointerstitial nephritis (1; Part 1A), hepatitis (1; CS), colitis, diabetic ketoacidosis, elevated liver enzymes (1 each; Part 1B). No G5 TRAEs or dose limiting toxicities were seen. In Part 1A, 3 pts (melanoma; bladder; anal) achieved stable disease (SD). In CS cohort, 1 triple negative breast cancer (BC) pt had partial response (PR; -60%) for 27.4 m and 3 had SD (breast; cSCC, squamous oropharynx). In Part 1B, 3 pts had PR including 2 pts with hormone positive BC (1 pt with -86%; 3.2m and 1 pt with -39%; 2m) and 1 pt with cutaneous squamous cell cancer (cSCC) (-43%; 1m). Four pts in part 1B had SD (2 breast, 1 lung, 1 chondrosarcoma). All 4 responders received the combination of BMS-986299 with N + I with 3 responders receiving BMS-986299 at 2000μg and one at 300μg. 3 responders (2 breast; 1 cSCC) had prior ICI therapy. Conclusions: BMS-986299 in combination with ICI resulted in modest clinical activity in select tumor types and carried a manageable toxicity profile. However, definitive conclusions could not be drawn as the study was not powered for inference testing. Further exploration is warranted to define the role of this novel agent in the ICI refractory population. Clinical trial information: NCT03444753 .

Abstract 188: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, built on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with simultaneously expanded paired tumor infiltrating lymphocytes (TIL) as a source of tumor reactive cells. Our system allows robust expansion of TIL with preserved T-cell receptor repertoires and has an establishment rate of 75%. Paired resources allow for screening of immune-modulatory therapies under physiologic conditions not depending on peptide-pulsing and allo-reactivity. For this purpose, we developed a organoid-TIL co-culture system which quantifies and characterizes tumor organoid apoptosis by combining image-based analysis with flow cytometry and cytokine release assays as measurements of T-cell cytotoxicity against tumor (and normal-matched) organoids. Our system offers a powerful tool for the development and validation of cancer immunotherapy and may help to stratify cancer patients for susceptibility of various types of immunotherapies. Citation Format: Soura Mardpour, Claudia Beaurivage, Jane Sun, Lorenz Jahn, Rene Overmeer, Lars-Eric Fielmich, Pleun Hombrink, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 188.

Abstract 908: Tumour organoid-t cell co-culture assay to evaluate CAR t cell cytotoxicity

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, build on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumour microenvironment, we developed an assay in which various types of tumour organoids are co-cultured with T cells modified with chimeric antigen receptors (CAR T cells) to assess the cytotoxic potential. CAR-T cell therapy has been demonstrated to be efficacious against many hematological malignancies, however therapeutic application to treat solid cancers remains challenging. Our organoid-T cell co-culture assay offers a good platform to study the response of tumour organoids on the CAR T cells and will greatly contribute to our understanding of the critical factors that determine a successful CAR T cell therapy. In collaboration with GSK, HUB tested the cytotoxicity of GSK CAR T cells which target specific target antigen on human colorectal cancer (CRC) organoids. Six HUB CRC organoid models were selected based on differential expression levels of target antigen that was confirmed by FACS antibody staining. To evaluate GSK CAR T cell mediated organoid killing, caspase 3/7 expression was monitored at various timepoints and IFNγ secretion was measured by ELISA. For control, staurosporine and nonspecific-CAR T cells were included. Detected CRC-organoid killing demonstrated to be in line with antigen expression levels, indicating the specificity of the tested CAR T cells. Nevertheless, some CRC-organoid models demonstrated more resilient to CAR T cell mediated killing and further evaluation revealed upregulation of check point molecules such as PD-L1. This study reveals that tumour organoid-T cell co-culture assay hold value for preclinical development of CAR T-cell products and for evaluating tumour-evasion strategies. Moreover, this platform could potentially predict patient specific responses to CAR- T-cell therapy. Citation Format: Soura Mardpour, Mirella Georgouli, Ana Pereira Puri, Ravit Oren, Joshua Audu-Evans, Farzin Pourfarzad, Sara Brett, Pleun Hombrink, Sylvia F. Boj. Tumour organoid-t cell co-culture assay to evaluate CAR t cell cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 908.