GT101: China's First TIL Therapy Granted Clinical Approval for Solid Tumors

Recently, Suzhou Gracell Biotechnologies Co., Ltd. (referred to as Gracell Bio) announced that its self-developed GT101 injection (acceptance number: CXSL2200061) has officially received the clinical trial implied permission from the National Medical Products Administration (NMPA). The GT101 injection is the first tumor-infiltrating lymphocyte (TIL) drug in China to be approved for clinical trials and is expected to become the first cell drug to conquer solid tumors.

TIL drugs belong to Adoptive Cell Transfer Therapy (ACT). ACT refers to the process of isolating immune-active cells from tumor patients, expanding them in vitro and identifying their functions, and then transfusing them back into the patient to directly kill tumors or stimulate the body's immune response to kill tumor cells. Adoptive immune cell therapy includes TIL, CAR-T, TCR-T, NK, CAR-NK, LAK, DC, CIK, DC-CIK, etc.

In recent years, the successive approvals of multiple CAR-T products have demonstrated the excellent efficacy of CAR-T in the field of hematological tumors. However, due to limiting factors such as the insufficient specificity of tumor targets, the progress of CAR-T drugs in the treatment of solid tumors has been relatively slow.In recent years, TIL therapy has emerged as a "dark horse" in the field of solid tumor treatment, demonstrating powerful efficacy in multiple clinical trials for solid tumors and showing a clear potential for drug approval, primarily due to its three main advantages:

TILs themselves are derived from tumors and have an appropriate chemokine receptor system, allowing for better infiltration of tumor tissues after infusion; TILs are non-selected tumor-specific cytotoxic T cells with strong tumor specificity, capable of targeting multiple tumor antigens and overcoming the issue of tumor heterogeneity; after in vivo selection, the vast majority of TILs specifically recognize tumor antigens without recognizing normal tissues, demonstrating good safety.

Why has such a miraculous therapy only entered the field of solid tumor treatment and begun to show efficacy in recent years? Let us unveil the mystery behind TIL therapy together and take a look at the current state of industrialization and achievements of this dark horse.

Since Steven A. Rosenberg and others first discovered in the 1980s that TIL could inhibit the progression of malignant melanoma cells in patients, TIL therapy has undergone more than 30 years of clinical development. Various research teams in Europe and the United States have observed significant clinical data on tumor killing and long-term remission in clinical trials. However, it was not until 2011 that TIL therapy truly entered the industrialization phase. Iovance, the leader in the TIL field, obtained the patent license for TIL from Professor Rosenberg in 2011 and acquired numerous patents related to compounds, production, and technological updates. From this point on, the commercial development of TIL officially began.

However, the highlight moment of TIL therapy has only started to show in recent years, for two reasons.

One is the early development limitations of the entire cell therapy industry.Before 2010, the scientific research community and the industry had not reached a consensus on whether cells could be developed into drugs, with the general belief being that cells could not become drugs. It was not until 2012, when Emily, a young girl from the United States, became the world's first pediatric leukemia patient to receive CAR-T therapy and achieved excellent clinical outcomes, that the industry began to consider the feasibility of developing cells into drugs.Another major factor is that the production system for TIL is more complex than that for CAR-T products.First, there are many challenges in obtaining tumor tissue samples from patients: which specific location of the tumor should the sample be taken from? How much should be obtained? How can the extracted T cells be stably expanded?

"Merely the issues related to cell expansion have troubled the academic community for many years. Previously, the academic community would divide tumor tissues and place them in separate culture dishes for cultivation, screening out the dishes capable of expanding a large number of T cells, and continuing the expansion and production on that basis. The entire screening and production cycle took approximately 40 to 60 days. From an industrialization perspective, the production cycle is too long, and during this period, the clinical condition of patients often deteriorates. This is the main factor limiting the further advancement of TIL therapy," Dr. Mengyang Chong, Vice President of BD and Co-founder of Grail Bio, told VCBeat.

Dr. Mengyang Zhong continued: "Around 2010, Professor Rosenberg's team developed a production system for the rapid cultivation of TIL without the need for screening, significantly shortening the entire production cycle and addressing the challenge of the overly long production time for TIL therapy. Building on Professor Rosenberg’s patented technology, Iovance developed a scalable and industrialized TIL therapy production process, which has demonstrated excellent clinical efficacy across multiple solid tumor types."

For the industry, the most important turning point was 2019. At the 2019 ASCO conference, Iovance announced significant clinical trial results of its TIL product pipelines LN-145 and LN-144 in treating patients with recurrent metastatic cervical cancer and malignant melanoma. This was the first time that the potential of TIL products manufactured under an industrial production system for treating solid tumors was demonstrated to the industry, regulatory agencies, and cancer researchers in a clinical study. In the same year, the FDA found the clinical data to be outstanding, addressing a significant unmet clinical need, and granted Iovance's LN-145 Breakthrough Therapy Designation for the treatment of patients with recurrent, metastatic, or persistent cervical cancer after chemotherapy. This was the first time a cellular immunotherapy for solid tumors received such an honor.

Based on Iovance's breakthrough, the industrialization of TIL has been completely ignited.

Gracell Biotherapeutics decided to enter the TIL therapy field in 2019 after seeing the clear efficacy of Iovance, said Dr. Mengyang Zhong: "We saw a cell therapy with clear drug-like properties, simple and controllable process methods, and its astonishing efficacy in the solid tumor field can meet significant clinical needs."

Currently, multiple companies globally have entered the TIL therapy field, including Iovance, Obsidian, Grail Bio, Cartier Healthcare, JunCell Bio, JF Bio, Lanma Medical, and CBMG Biotech. The industry as a whole is thriving.Grail Bio's recently approved GT101 injection has also become the first TIL drug approved for clinical use in China.

Compared with other companies, Grail Bio has its own unique advantages and differentiated layout.First, Gracell Biotechnologies has a certain first-mover advantage.The company entered this field in 2019. After more than three years of accumulation, Grail Bio's CMC system has been stabilized, and it has filed for and obtained relevant patents. Especially in terms of patents, Grail Bio hired an external independent law firm at the beginning of its establishment to jointly develop the process system and conduct strict FTO analysis to confirm the independence of Grail Bio’s patents.Currently, all TIL-related platform technologies of Grail Bio are independently developed by Grail Bio. All projects have been filed for patent applications in accordance with the PCT, obtaining global intellectual property protection.

Grail Bio also has a first-mover advantage in terms of technology.Grail Bio has a T-cell editing and modification platform technology comparable to leading American cell therapy companies, aiming to develop next-generation precision lymphocyte drug products for cancer treatment. Currently, the fastest progress among American companies is the recent IND filing, while Grail Bio's next-generation product, GT201, has already initiated investigator-initiated clinical trials. It is expected to file for IND by the end of this year, presenting an opportunity to compete in the international market. Based on current data, the second-generation product, after gene editing, demonstrates significantly superior clinical efficacy compared to the first-generation non-gene-edited product.

Gravel Bio has a first-mover advantage in the construction of its core team.Dr. Yarong Liu, CEO and co-founder of Grail Bio, is a virologist with over 10 years of academic and practical experience, and has extensive industrial development experience at Amgen and Hengrui Dason. In 2018, Dr. Yarong Liu led the successful IND applications for three CAR-T projects in China, and has rich R&D and process development experience in the field of cell therapy. Dr. Mengyang Chong has more than 10 years of experience in oncology discovery and development, having led multiple investment and licensing deals in cell and gene therapy, and participated in the development of several TCR-T and CAR-T pipelines.

Overall, the core R&D team of Gracell Biotechnologies has diverse leadership experience in the biopharmaceutical field and possesses the capability to develop cell therapy projects in both China and the United States. The core team has collectively driven the approval and market launch of more than 20 drugs, including several internationally and domestically marketed CAR-T products.

Dr. Liu Yarong joked: "We currently have more than 80 core employees covering all stages of drug research and industrialization, including clinical development, early development, translational science, CMC, PD, clinical registration, quality control, and business development. The team as a whole is highly complementary and experienced, and many colleagues are even more experienced and mature in scientific research and industrialization than Meng Yang and I. As a pioneer in a niche field, the first person to try new things always has to put in more effort to communicate with regulatory authorities, using professional knowledge and extensive data to convince them of the risk-benefit profile of TIL. Therefore, a highly complementary and experienced team is essential."

Based on the above advantages, Grail Bio quickly gained attention from investors. Since its establishment, Grail Bio has completed three rounds of financing, accumulating 250 million yuan, with investment institutions including Sherpa Healthcare Partners, Junshi Biosciences, Apricot Capital, Decheng Capital, Matrix Partners China, and Gaoling Venture Capital.On this basis, Grail Bio has currently established three major technology platforms:

StemTexp® Technology Platform, a highly scalable TIL expansion process technology platform.This technology platform can significantly enrich central memory T cells (TCM) and stem memory T cells (TSCM) in TIL products, potentially enhancing the clinical efficacy of the product.

ImmuT Finder® Technology Platform, for the discovery of immunomodulatory targets.Based on this platform, Grail Bio is establishing multiple high-throughput screening platforms for TIL-based products to identify potential novel targets, optimize the in vivo function of T cells, and enhance their clinical efficacy. Additionally, based on newly discovered T cell targets, Grail Bio can rapidly develop new pipelines or collaborate with other cell therapy companies, such as those specializing in CAR-T and TCR-T, by leveraging these new targets.

StaViral® Technology Platform, an efficient TIL editing and modification platform.Grail Bio combines its proprietary viral production capabilities with experience in the cell therapy industry to launch a series of clinical trials based on next-generation TIL therapies for the treatment and management of various indications, while significantly reducing production costs.

The three technology platforms complement each other, helping Grail Bio quickly establish and advance its pipeline. Grail Bio has currently built 5 pipelines based on this.

Core pipeline GT101, based on Grail Bio's proprietary TIL cell stemness expansion platform StemTexp, amplifies and prepares TIL cell drugs with a high proportion of memory phenotype from small amounts of patient tumor tissue samples, meeting clinical infusion requirements, showcasing Grail Bio's unique advantages in manufacturing processes.GT101 is about to officially launch its Phase I clinical trial, at which time it will recruit end-stage solid tumor patients from the public.

In the investigator-initiated trial (IIT) conducted in the early stage, the GT101 injection demonstrated good drug safety and significant tumor killing and clinical efficacy. Notably, the first end-line cervical cancer patient who received a reinfusion showed a remarkable reduction in tumor burden after being treated with GT101. The efficacy evaluation (RECIST 1.1) after the first cycle indicated a partial response (PR). In the PK analysis targeting this patient, the Grail team observed a substantial release of cytokines associated with T-cell cytotoxicity following the GT101 reinfusion. This data indirectly supports the effectiveness of GT101 in tumor treatment.GT101 is expected to become an important treatment for patients with melanoma, cervical cancer, non-small cell lung cancer, and other solid tumors in China.

Grail Bio is also rapidly advancing its other pipelines. Among them, GT201 and GT202 have completed preclinical proof-of-concept and are currently undergoing regulatory submission preparations, with plans to file for dual submissions in China and the United States by mid-next year. GT307 and GT316 have demonstrated excellent efficacy in various animal models, and the Grail team is optimizing the manufacturing process to push more product pipelines into the clinical validation stage as soon as possible.

Speaking about the future, Dr. Liu Yarong said: "We will bring the GT101 product to clinical patients at an accessible price as soon as possible and rapidly advance its industrialization and commercialization. We will also quickly push forward the regulatory submissions for the next-generation pipeline in both China and the United States, continuously providing better TIL therapies for patients worldwide. Of course, Grail Bio will not limit itself to the TIL therapy field. Relying on our technology platform and based on the urgent needs of clinical patients, we will gradually expand our cell therapy pipeline."

We look forward to cell therapy companies like Shale Biology bringing remarkable hope to the field of solid tumors. Perhaps in the future, many patients with currently untreatable serious illnesses may be able to regain their health through cell therapy.