Transforming Cancer Drug Discovery With Comprehensive Tumor Models

Cancer remains a leading cause of death globally, signaling a critical need for innovative and effective treatments. This whitepaper presents MIMETAS, a frontrunner in organ-on-a-chip technology, as a key player in advancing comprehensive cancer modeling to address this need. The document explores the current landscape of cancer drug discovery, characterized by significant advancements in treatments such as immunotherapies, yet plagued by the challenge of translating preclinical success into clinical benefits. The high attrition rates in clinical trials, especially in oncology, underscore the necessity for more predictive models that can bridge the gap between laboratory research and patient outcomes. The imperative for predictive models is clear, with traditional in vivo animal models and 2D in vitro models falling short in accurately replicating the human tumor microenvironment (TME). MIMETAS’ organ-on-a-chip technology presents a paradigm shift, offering advanced 3D disease tissue models that mimic the complexity of the TME, thus facilitating the development of cancer therapies with higher translational potential. The whitepaper details MIMETAS’ capabilities through various oncology applications, showcasing their success in modeling immune cell migration, CAR T cell efficacy, and the complex interactions within the TME. These case studies illustrate the platform’s ability to replicate human physiology in vitro, providing a robust platform for drug discovery, safety testing, and regulatory approval processes. Further, the document highlights MIMETAS’ commitment to advancing cancer drug discovery through partnerships and tailored fee-forservice solutions, leveraging their OrganoCore™ Discovery Platform. A notable collaboration with Astellas Pharma Inc. is cited as an example of strategic partnership aimed at driving forward the next generation of immuno-oncology therapies. In conclusion, MIMETAS stands at the forefront of bridging the translational gap in cancer drug discovery, offering innovative solutions through its organ-on-a-chip technology. By developing more predictive models and fostering strategic partnerships, MIMETAS aims to accelerate the delivery of effective cancer treatments, ultimately benefiting patients worldwide. mimetas.com | 4 Introduction This whitepaper explores human 3D tissue and disease models as revolutionary tools for cancer research and drug discovery. The focus is on MIMETAS, a leading company in the organ-on-a-chip field, continuously driving progress in comprehensive tumor modeling. Challenges & Advances in Cancer Drug Discovery As the second leading cause of death worldwide, cancer accounted for nearly 10 million deaths in 20201 underscoring the widespread impact of the disease and the urgent need for new, effective, and targeted treatments. The current landscape of cancer drug discovery is characterized by both significant advancements and persistent challenges. Recent years have seen the approval of several groundbreaking cancer therapies that have significantly improved the outlook for patients. One notable example is the development of immunotherapies, including immune checkpoint inhibitors like anti-PD1 (Pembrolizumab and Nivolumab), antiPDL1 (Atezolizumab), anti-CTLA4 (Ipilimumab), T-cell engagers, and chimeric antigen receptor T-cell (CAR-T) therapies. These therapies work by enhancing the immune system's ability to recognize and target cancer cells, representing a paradigm shift in the treatment of cancer. Despite these breakthroughs, cancer remains a global health challenge and a leading cause of death, most notably for solid tumors. The translational gap between preclinical studies and successful clinical trials is a major hurdle in cancer drug discovery. Clinical trials, particularly in oncology, face alarmingly low success rates. While the general approval rates for drugs hover between 10-20%, the rate for oncology drugs is even lower, at just 5%, underscoring the difficulty of developing effective treatments in this field2,3. This is largely due to the difficulty of translating preclinical success into clinical benefits. The cost of drug development in the pharmaceutical industry is staggering, with estimates now reaching more than $2.6 billion per approved drug4. The high attrition rates in late-stage trials contribute to the substantial financial burden on the biopharmaceutical industry, with approximately 70% of research and development expenses associated with failed projects5. Successfully overcoming these challenges is crucial for establishing a strong drug discovery pipeline and fulfilling the increasing demand for innovative medications, particularly in the face of high cancer prevalence rates. This effort not only accelerates the pace of medical breakthroughs but also directly impacts the lives of cancer patients. mimetas.com | 5 Introduction The Imperative for Predictive Models A key contributing factor to the high attrition rates seen in cancer drugs is the lack of predictive models. In vivo animal models, such as patient-derived xenografts (PDXs), while providing important insights, fail to recapitulate the tumor microenvironment (TME) and suffer from limited translational value to human conditions12,13 (figure 1). Moreover, animal models in general face increasing ethical debates. On the other hand, the limitations of traditional 2D in vitro models have become apparent, including a lack of critical components including vasculature, extracellular matrix (ECM) and neighboring cells, resulting in less effective research models. While the field has also seen developments in 3D tissue models such as cell line spheroids and organoids, most 3D in vitro models also lack a comprehensive TME such as immune components or vascularization14,15. As such, these models fail to accurately reflect the complexity of solid tumors16 and fail to translate safety and efficacy of novel therapeutics to human trials17-20. This discrepancy underscores the urgent need for more advanced and representative models in the early stages of drug development that can accurately predict human responses. Bridging this gap will not only improve success rates in clinical trials but also expedite the delivery of innovative treatments to patients in need. Figure 1. Efficacy of models in cancer drug discovery hampers the success of novel cancer drugs 6-11. Advances in Organ-on-a-Chip Models Recent strides in organ-on-a-chip technology indicate promising potential to revolutionize cancer research, with the pharmaceutical industry seeing an increased adoption of organ-on-a-chip models to impact pipeline decision-making21. Organ-on-a-chip models mimic complex interactions between cancer cells, stromal components, and the immune system, bridging the gap between simplistic 2D cultures and complex animal studies by recapitulating a realistic TME (figure 2). This allows for better assessment of drug penetration, efficacy, and toxicity. Furthermore, patient-derived tissues in these models bridge the gap between preclinical studies and actual patient responses, offering a personalized approach to cancer treatment. This is crucial, given the heterogeneity of cancer and the need for treatments that are effective across diverse patient populations. The increased adoption of organ-on-a-chip models was further emphasized by the FDA Modernization Act 2.022. The recent legislative changes brought about by this act, explicitly permitting companies to submit non-animal data, including results from organ-on-a-chip technologies, seeking approval of new therapies, underscore a pivotal shift away from traditional animal-based testing in recognition of the value of novel technologies. Translational gap widens • Species difference • Immune component • Micro-environment Chemo- • Cancer heterogeneity therapy +Targeted therapy (Errb2, TKI) 2d cell lines, xenosgrafts +Immuno-therapy (CPI, TCE, CAR-T) Humanized mice, organoids Cancer therapeutics model requirements Drug discovery models ...1960 1980 2000 2020 Advancement in Cancer Treatments & Models Year Phase 1 to approval of cancer drugs remains below 10% 100 90 80 70 60 50 40 30 20 10 0 2005 2010 2015 2020 The main cause of attrition in clinical trials is lack of efficacy Percentage (%) Year mimetas.com | 6 Stromal shielding Inflammation Vascularization Metastasis Tumor growth By enabling the study of human physiology in an in vitro setting, organ-on-a-chip models allows for a deeper understanding of tumor progression mechanisms and provide robust and representative platforms for drug discovery, safety testing, and seeking regulatory approval for effective cancer therapeutics. Figure 2. MIMETAS' proprietary microfluidic platform, the OrganoPlate®, uniquely recapitulates human tissues by combining relevant cell types to reconstruct the functional niche of native tissues with a fit-for-purpose throughput, capabilities rarely found across the organ-on-a-chip industry. MIMETAS’ platform enables diverse and unique in vitro tissue cultures and applications and is distinctively devoid of artificial membranes, allowing cells to interact and migrate freely under flow conditions in real-time. Cancer-associated fibroblasts mimetas.com | 7 Whitepaper overview This whitepaper showcases MIMETAS’ capabilities in leveraging their advanced Organ-on-a-Chip technology to develop 3D disease tissue models, offering an innovative approach to cancer drug discovery (figure 3). It includes case studies that tackle the primary challenges encountered in models used in cancer drug discovery: modeling the TME, overcoming the lack of immune competence, and addressing cancer cell heterogeneity. Through their cutting-edge technology and deep expertise, MIMETAS aims to revolutionize the discovery of novel cancer treatments, bridging the translational g