How Can Organoid and Mouse Models Boost Oncology Preclinical Trials? – Highlights from the Crown Biosciences Symposium

by Tyler Chen
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Preclinical trials are critical in determining the safety, efficacy, and potential toxicity of a drug. Therefore, the usage of suitable animal models or in vitro tissues would significantly enhance the accuracy of data and lower the cost of subsequent trials.

A recent symposium organized by Crown Bioscience, titled “Humanized Drug Target and Organoid Platforms for Oncology New Drug Development,” saw experts discussing some of the latest preclinical trials of oncology drugs and the impact of organoid technology in the development of cancer drugs and antibodies.


Amendments to Drug Regulations

Dr. Pan-Chyr Yang, Vice President of the Institute for Biotechnology and Medicine Industry (IBMI), shared that Taiwan’s pharmaceutical industry has witnessed a boom in the past few years with gradual improvements in innovations and regulations. The product output and R&D power of Taiwan’s startups and technology transfer companies are clearly evident, and the international competitiveness has attracted investment from several overseas biopharma.

With the growth of the pharma market, Taiwan is now at the precipice of another opportunity. At the end of 2021, the Biotech and New Pharmaceutical Development Act will be revised and updated according to the current trends and needs of the industry. Dr. Yang opined that the future emphasis must be on smart healthcare and new drug research to facilitate the ecosystem.


Capitalizing on the Potential of Organoid Technology

Representing Crown Biosciences, an expert preclinical contract research organization, Vice President Kevin Wang introduced the capabilities of his company.

CrownBio was founded in the United States in 2006 on a drug-testing platform centered around xenografts. The company established a base in Taiwan in 2014 and was listed in Taiwan’s stock market after two years. In 2018, it was acquired by Japan’s JSR as a subsidiary of its life science department.

CrownBio has assisted clients in finding over 10,000 compounds. Around 250 of them have entered preclinical trials, 30 of them have begun clinical trials, and over 10 drugs have bagged FDA approval. On top of that, CrownBio has the world’s largest PDX platform with over 3,000 animal models and over 500 cancer cells, meaning models with various tumor and gene conditions can be delivered around the world.

In 2019, CrownBio launched a tumor organoid platform after observing the growing trend and extensive research focus in the area. Tumor organoids, an in vitro tumor spheroid that resembles the tumors of patients, present a more versatile and well-rounded form of tumor model for scientists.

Even though it’s harder to culture, tumor organoids can faithfully recapitulate the originating tumor complexity. Organoids allow researchers to better study the tumor microenvironment, binding sites, and the relation to treatments and multiple cells. For these reasons, a tumor organoid is considered a more precise model for a preclinical trial, possibly leading to a higher survival rate of participants.


Strengths of the Organoid Platform

Presenting online from Belgium, Dr. Kevin Buyens, Head of Corporate Development & Strategy at CrownBio, suggested that in vitro technology is easier to scale up and apply in preclinical trials compared to in vivo. Capturing the opportunity, CrownBio expanded the organoid platform in just half a year. Presently, it boasts over 200 PDX-derived organoid (PDXO) models, over 150 models that encompass more than 15 types of cancer. Furthermore, over 130 models are ready to deliver, and CrownBio is currently developing 100 patient derived organoids (PDOs).

However, it should be noted that cancer therapies require cross-disciplinary cooperation, and CrownBio is looking forward to working with companies in Taiwan to build a more effective and sturdy supply chain.


A Lock That Can Increase Safety and Lower Toxin of Antibodies

The antibody market has reached 12.3 billion dollars in 2019 and has become one of the most popular classes of drugs to treat cancer, autoimmune and inflammatory diseases. However, the challenges reside in the fact that antigens exist in both normal and afflicted cells. If the antibody overly neutralizes the antigen in the body, the patient might express serious side effects.

Professor Tian-Lu Cheng of Kaohsiung Medical University presented a new technology where antibodies can be locked in non-disease areas by gene engineering technology. For example, remicade is able to neutralize TNF-α in the joints of rheumatoid arthritis patients to decrease inflammation, but TNF-α is also an immune molecule. If TNF-α is suppressed constantly, the immune system will weaken, making the patient more susceptible to pulmonary tuberculosis, hepatitis B, and hepatitis C.

Cheng’s team then developed a lock that can put the autologous hinge to the N side of the antibody to block the antigen binding site. In addition, the lock implements protease substrate specificity peptide to form a pro-antibody that can unlock the antibody in disease areas when protease is overly expressed. This way, the safety and specificity of antibodies are elevated.

At present, the lock can operate with different drugs to lower the toxin, such as remicade, humira for rheumatoid arthritis, prolia for osteoporosis, stelara for psoriasis and herceptin, yervoy, opdivo for cancer.

The team intends to apply the lock to antibodies that fail clinical trials because of excessive toxins.


Single Cell Derived Organoids in Precision Medicine

Talking about the impact of single cell derived organoids in precision medicine, Academia Sinica researcher Dr. Ying Chih Chang stated the importance of using rapid rare cell 3D expansion (R3CE) technology to enlarge tumor organoid, stem cell or immortalized cell line in circulating tumor cell (CTC), derived from biopsy to form a 3D single cell derived organoid platform.

R3CE is a crystal substance that is easy to observe, maintain and prepare on the petri dish. Therefore, it is great for cell culture and analysis. The R3CE platform enables the expansion of cell lines to 400 times the size of the original sample after just 7 days of proliferation.

Besides, the R3CEplatform is quite similar to the 2D cell culture in terms of operating the system but provides a 3D spheroid that is more accurate and detailed in observation. R3CE-cultured cells can be employed in animal trials, and the tumor inside can grow faster without the help of extracellular matrices to build the cell.

Ultimately, R3CE can perform screening and development on tumor drugs, picking up cancer drugs with better prognosis potentials. For example, Stanford University has screened 14 breast cancer drugs on the R3CE-CTC-Spheroid platform and found out that 13 drugs increased drug resistance, among which one was effective to treat cancer. The result also matches with the clinical result.


How PDX, PDXO Models Impact Drug Development?

Presented from China, Dr. Xiaoxi Xu, Head of organoid platform at CrownBio, outlined the promise of PDX and PDXO models that accelerated tumor drug development.

PDO, also known as tumor organoid, originates from a patient’s organ and includes primary and metastatic breast, colorectal, lung, pancreatic cancer, and healthy organoids.

CrownBio has obtained exclusive licenses of Hubrecht Organoid Technology (HUB) PDO and has incorporated them into the PDX platform. The HUB Organoid Technology was discovered by the pioneer of the field, Dr. Hans Clevers. According to a paper published in Science, the PDO model from HUB has an overall drug effective prediction rate of 90% and a drug failure prediction rate of 100%.

If combined both the in vitro and in vivo models, the trials would be more clinically relevant and precise for the examination of drugs. Hence, CrownBio created the world’s biggest database with PDX and PDXO models for in vitro and in vivo trials.

What’s more, CrownBio is eligible to access biobank with high HUB expressed tumors and normal organoids, enabling it to provide a variety of supports in preclinical trials and capable of evaluating histopathology, molecule, and tumor heterogeneity of organoids.

CrownBio’s organoid biobank can also be used for gene editing, high throughput drug screening, co-culture platform, building in vivo model, resulting in a better success rate in trials.


Four Ways to Implement Tumor Organoid Platform

Lastly, Dr. Hongjuan Zhang, Senior Scientist of cancer biology and immunology of CrownBio, emphasized the application of tumor organoid co-culture platform in cancer immunotherapy.

It is well understood that tumor organoids provide a more well-rounded and flexible environment for tumor research. Observing current research, Dr. Zhang indicated that it is mainly applied in four settings.

Firstly, scientists examine the efficacy of immunotherapy by using autologous and nonautologous T cells on tumor organoids. Research has shown that anti-cancer PBMC cells can be used in tumor organoids to understand the response of the immune system when facing specific antigens. She pointed out that autologous T cell co-culture is trendy in the pharmaceutical industry, but the downsides are that it is not easily scalable, and most of the patients do not possess enough anti-tumor T cells in PBMC for the autologous T cell to be properly co-culture.

Secondly, tumor organoids are used to observe how CAR-T, TCR T cells, or Natural killer cells respond to tumors. But it is important for researchers to pick models with specific mutations so that they can learn if the CAR-T therapy can target the tumor.

Thirdly, ADCC effects against tumors can be investigated with organoids. Finally, tumor organoids can prompt the bispecific T cell engager research, enhancing the prediction value of efficacy and specificity in trials.

Tumor organoid is undoubtedly a powerful tool in preclinical trials. Not only can it be used to predict drug efficacy, but it can offer scientists increasingly precise data to boost future research. Biotech and pharmaceutical companies are now investing more in the technology for precise experimentation, reduced failure rate, and benefiting the lives of millions of cancer patients.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Organoids to Model Human Disease – Prof. Hans Clevers




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