▎WuXi AppTec Content Team Report

In China, there are currently many new forces devoted to the development of TIL therapy, and Grail Bio is one of them.Grail Bio was founded in 2019, focusing on tumor immunotherapy and has developed a pipeline represented by TIL drugs.Since its establishment, the company has built a TIL drug preparation process, a cell drug development system, and multiple technical platforms applied to the development of next-generation TIL drugs. Currently, the first-generation TIL product in Grail Bio's research pipeline is about to enter the pivotal Phase 2 clinical trial, the second-generation gene-edited TIL product has been approved for clinical trials in China, and there is also a third generation in the works.The series of next-generation gene-edited TIL products are in the early stages of development. Recently, the company also completed a 400 million yuan Series B financing round led by a fund under CICC Capital to support its innovation.Development of TIL Therapy Pipeline.

As a rising star in the CGT field, TIL therapy is still in the early stages of development globally. What are the main challenges currently faced in the development of TIL therapy? Which pain points in current cancer treatment could Grail Bio's 1st to 3rd generation TIL product pipelines potentially address? Looking ahead, what transformative therapies might emerge in the cell and gene therapy sector? With these questions in mind, the WuXi AppTec content team recently interviewedLiu Yarong, Ph.D., Co-founder and Chief Executive Officer (CEO) of Grail BiotechnologyDr. Yarong Liu has many years of experience in various research fields such as viral vectors and CAR-T products.

Image Source: Provided by Grail Bio, Produced by the WuXi AppTec Content Team

WuXi AppTec Content Team: Why did you choose to start a business in the field of Tumor-Infiltrating Lymphocyte (TIL) therapy?

Dr. Yarong Liu: Before founding Grail Bio, I worked on CAR-T product development at a cell therapy company, where I witnessed firsthand the therapeutic effects of cell therapy in hematologic tumors. The positive feedback from patients further strengthened my confidence in cell therapy. However, my true research interest lies in solid tumors. Although many PD-1/L1 inhibitors have been launched, a significant number of patients with solid tumors still cannot benefit from them, representing a huge unmet need in this field.TIL therapy, as an active drug based on patients' autologous tumor-infiltrating lymphocytes, is a great breakthrough point for the treatment of solid tumors.Around 2019, TIL therapy also saw significant positive progress globally, including impressive clinical data presented at academic conferences. In the same year, I co-founded Grail Bio, with the goal of bringing safe and effective TIL therapy to patients with solid tumors.

WuXi AppTec Content Team: What unique advantages does Grail Bio's tumor immunotherapy pipeline have? What pain points in current cancer treatments do they have the potential to address?

Dr. Yarong Liu:The first advantage of TIL therapy isStrong tumor specificity, which can overcome the issue of tumor heterogeneity by targeting multiple tumor antigens. Unlike other cell therapies such as CAR-T or TCR-T that can only recognize 1~2 antigens, TIL therapy is derived from the patient's tumor tissue and naturally possesses the ability to recognize heterogeneous tumor antigens, an advantage that other cell therapies cannot easily surpass through genetic modification. The second advantage of TIL therapy isTumor infiltration is good, Since TILs are derived from the tumor itself, they already possess an appropriate chemokine receptor system, allowing this type of therapy to better infiltrate tumor tissues after infusion. Additionally, TIL therapyHigh SafetyThe vast majority of TILs specifically recognize tumor antigens but not normal tissues, thus having relatively good safety.

WuXi AppTec Content Team: What are the key challenges to fully realizing Grail Bio's potential in tumor immunotherapy cell treatment products? And what are the potential solutions?

Dr. Yarong Liu: At present, the development of TIL therapy is not an easy task,Drug-formability is the main challenge faced by the first-generation non-gene-edited TIL products.Therefore, when Grail Bio was established, it focused on building a highly complementary team and collaborated with more than 10 tertiary hospitals to obtain nearly 400 batches of tumor clinical samples for extensive process development. The high heterogeneity of tumor samples compelled us to invest substantial resources and manpower into research. We also established a functional evaluation system with immunologists to determine which processes can cultivate high-quality TIL products that may potentially correlate with clinical efficacy. Additionally, we are studying certain biomarkers to help select suitable targets and patient populations, as well as for future clinical efficacy monitoring and product quality control.

Another major challenge in TIL product development is that immune cells with killing capabilities are easily suppressed by the tumor microenvironment in vivo, and their killing ability significantly weakens after being reinfused into the body.In response, Grail Bio is developing next-generation products through various gene-editing strategies. Our first-generation product is optimized only at the process development level; the second-generation product uses viral transduction of TIL cells to overexpress fusion proteins, enhancing cell persistence and killing ability in vivo; the third-generation product employs the CRISPR-Cas system to knock out inhibitory genes within the cell, thereby overcoming the immunosuppressive tumor microenvironment. Currently, Grail Bio has establishedPlatform for Discovering Intracellular Inhibitory Targets，Two screening platforms, in vivo and in vitro, can be used to establish different tumor models, simulating the survival environment of TIL cells in vivo. By applying different screening pressures, the pathway that most inhibits TIL cells can be identified, allowing for targeted editing.

Moreover, due to the natural progression of the disease and the poor baseline status of patients, the indications for TIL products with potential efficacy remain relatively limited globally.In response, Grail Bio has conducted systematic analyses and extensive process development for 15 indications, hoping to discover potential expandable indications for TIL. Apart from expanding indications,We also hope that immune cells with tumor-killing capabilities will persist in the body for a long time., but most cytotoxic T cells are effector T cells, which do not survive for long. To address this, we optimize through editing or process improvements: on one hand, enabling effector T cells to rapidly target and kill tumors in the short term to suppress tumor growth and achieve tumor shrinkage; on the other hand, retaining some memory T cells with the potential to differentiate into effector T cells, thereby providing patients with long-lasting anti-tumor effects.

WuXi AppTec Content Team: In the next few years, what milestone developments are expected in Gracell Biotechnologies' R&D pipeline?

Dr. Yarong Liu: In the next few years, there are still many important developments in our R&D pipeline worth looking forward to, including:1) The first-generation TIL product GT101 has been approved in China., and quickly bring it to market to benefit more patients;2) The second-generation TIL product GT201 is undergoing clinical trials in different diseases., especially exploring some solid tumor indications for which efficacy has not been reported globally;3) The Third Generation of TIL ProductsGT316Entered clinical stage in both China and the United States, The product is currently undergoing process development and has shown good preclinical performance, but its novelty may also present CMC challenges.In addition, Grail Bio is also exploring other R&D projects, such as cancer vaccines or universal cell therapies., hoping to leverage our understanding of immunology to benefit patients at different stages and with different indications.

WuXi AppTec Content Team: Regarding the entire field of cell and gene therapies (CGT), what do you believe are the current challenges and opportunities?

Dr. Yarong Liu: The main challenge in this field currently lies in the high costs of research, development, and production, which could affect the sustainability and longevity of enterprises' innovation capabilities. However, the potential of CGT products cannot be ignored as they are expected to bring long-term survival benefits with a single injection, saving substantial clinical costs and reducing the use of other auxiliary drugs. Therefore, addressing this issue from the perspective of pharmacoeconomics requires joint exploration by the industry and all segments of the ecosystem. At present, the sector is seeking various ways to reduce the R&D and production costs of CGT products, including expanding production capacity and developing universal cell therapies, to improve patient accessibility.

WuXi AppTec Content Team: How do you view the role and impact of "collaboration" in the current biopharmaceutical innovation ecosystem? Specifically, in the cell and gene therapy field where Gracell Biotechnologies is located, in which aspects do you think collaboration is mainly reflected? And what kind of collaboration is most needed to better promote innovation?

Dr. Yarong Liu: No matter what stage a company is at, cooperation is very important. For Grail Bio, collaboration manifests in multiple dimensions. One is cooperation with universities and research institutions; we are highly interested in the innovative discoveries from these organizations in fundamental scientific research. Another form of collaboration is with other Biotech companies—Grail Bio's research achievements in areas like targets could potentially help other companies expand their product pipelines, while other companies' technology platforms may also assist us in developing new molecules. Additionally, we place great importance on collaborating with upstream and downstream suppliers, which can also accelerate the R&D and market launch of products.

WuXi AppTec Content Team: In the field of cell and gene therapies, what transformative treatments do you believe will emerge in the next 10 years?

Dr. Yarong Liu: In my opinion,In the next decade, an increasing number of products in the CGT field will be approved for marketing, and the speed will be faster than before.In terms of therapeutic areas, these products will cover a wide range of patient populations, including rare diseases, oncology, autoimmune diseases, and more. In addition to personalized products,Universal cell therapy products will also see significant breakthroughs within the next decade., including finding the appropriate target group or application scenarios, and promoting the rapid market launch of the product.

In addition, CGT products are also expected to see significant changes in their manufacturing processes. The process is an integral part of the product, defining the product itself, but its complexity also makes the product more intricate. Currently, cell processing may be the biggest factor limiting the rapid market entry of cell therapy products. As the development of CGT is still in its early stages, the industry’s understanding of these processes needs further exploration, and active communication and collaboration in this area are underway. Ten years from now, I believe the processing aspect of CGT products will also experience tremendous progress.

WuXi AppTec Content Team: If we were to discuss the development of this industry again 10 years from now, what topics or achievements do you think we would be talking about?

Dr. Yarong Liu: I am quite optimistic and believe that in ten years, technological advancements will far exceed our imagination. The issues we discuss today may all be resolved, such as conquering advanced solid tumors, expanding CGT to various indications, and more.In the future, cancer will become a chronic disease, and people may focus on how to improve their quality of life and prolong their lifespan.This prediction is based on the fact that about a decade ago, the short-term goal of the industry was to find treatments that could help patients survive with tumors for five years, until new products or technologies emerged. In fact, through early diagnosis, screening, and active treatment, this goal has already been achieved for many indications today. We have reason to believe that as technology continues to accumulate and R&D efficiency keeps improving, certain diseases may see greater breakthroughs in treatment, and even potential cures.

WuXi AppTec Content Team: As an entrepreneur in the innovative drug field, what other viewpoints and messages do you wish to convey to the industry?

Dr. Yarong Liu: No matter what kind of environment we are in, we should maintain our original aspirations and remain optimistic. Although we cannot change the external environment, we can positively influence our own field through hard work, whether it is within a company or a specific niche. Because I believe that challenges often contain opportunities, and what we need to do is to discover and seize them.

If you are interested in TIL cell therapy and want to learn more about companies dedicated to developing TIL cell therapy, you canScan the QR code below, obtain global financing information in this field over the past five years.