RootPath Secures $11 Million Series A Funding Led by Matrix Partners China and Origin Ventures to Advance Personalized TCR-T Therapies for Solid Tumors

VCBeat has learned that biotech company RootPath recently closed an $11 million Series A financing round, co-led by Matrix Partners China and Yuanhe Yuandian. RootPath is dedicated to leveraging its proprietary Synthetic Immunology Platform to develop next-generation, tumor-reactive T-cell therapies. The company will use the proceeds from this round to validate its tumor-reactive T-cell receptor (TCR) discovery pipeline, demonstrate safety and efficacy in animal models, and lay the technical foundation for manufacturing processes. Existing investors Sequoia Capital China, Volcanic Stone Capital, Nest Bioventures, and Baidu Ventures also participated in this financing round.

RootPath was incubated and established in 2017 by Nest.Bio Ventures. Its core technology, the “Synthetic Immunology Platform,” comprises a series of proprietary technologies that enable rapid, cost-effective functional reconstruction of T-cell immune repertoires in vitro, simulating their antigen-guided evolutionary processes. This platform serves as the foundation for the company’s ongoing development of next-generation, personalized, tumor-reactive T-cell therapies.

“While cell therapies represented by CAR-T have demonstrated significant success in hematologic cancers, their efficacy in solid tumors remains very limited. ‘The bottleneck to success lies in identifying safe, effective, and tumor-reactive recognition tools for these T cells, whether such tools are CARs or TCRs,’ said Chen Xi, Co-founder and CEO of RootPath. ‘Due to the unique manner in which T cells recognize tumors, we may need to develop bespoke recognition tools tailored to each individual cancer patient or each small subgroup of patients. Achieving this with existing technologies is cost-prohibitive. Therefore, we spent two years developing a synthetic immunology platform. This platform leverages numerous cutting-edge technologies from the field of synthetic biology to overcome many inherent challenges in current immunology research and drug development.’”

“We are deeply honored to have secured the support of Matrix Partners China, Yuanhe Yuandian, and our existing investors, as we continue to advance the clinical translation of our synthetic immunology platform,” Chen Xi continued.

“The limitations of traditional single-target CAR-T and TCR-T therapies in treating solid tumors have become increasingly apparent. We believe that multi-target, personalized approaches with shortened manufacturing cycles will define the future direction of cancer cell therapy. RootPath’s proprietary technology, based on single-cell analysis, effectively achieves all three of these objectives. From the broader perspective of the immunotherapy industry, this approach holds significant potential to deliver substantial breakthroughs in the cell-based treatment of solid tumors,” said Yu Zhiyun, Managing Director at Matrix Partners China.

“Solid tumors have long been a cunning, ever-shifting fortress that is difficult to conquer. RootPath’s synthetic immunology platform offers personalized, multi-target T-cell therapies. We are highly optimistic about the engineered approach it is striving to implement, which holds promise as a potent therapeutic solution for solid tumors. Meanwhile, we also expect RootPath to generate stronger synergies with other tumor immunotherapy companies in Yuanhe Yuandian’s investment portfolio,” said Yang Aiying, South China Partner at Yuanhe Yuandian.

Dr. Chen Xi earned his bachelor’s degree from Shanghai Jiao Tong University and his Ph.D. from the University of Texas at Austin. He subsequently conducted postdoctoral research in Professor Peng Yin’s laboratory at Harvard Medical School, focusing on the biophysics and biochemistry of nucleic acids. In 2016, Dr. Chen joined Nest BioVentures as an early team member, aiming to forge a commercialization path that addresses unmet medical needs in immunotherapy and cell therapy through molecular-level technological innovation. “Applying single-cell technologies to immunotherapy could open up new directions for innovative cancer treatments,” said Dr. Chen. In 2017, Nest BioVentures incubated and founded RootPath. Dr. Chen and his co-founder, Dr. Ely Porter, joined the company full-time to begin developing its synthetic immunology platform. In 2018, RootPath completed a $7 million seed funding round led by Sequoia Capital China.

Dr. Ely Porter is an expert in RNA biochemistry, engineering, and analysis. He holds a Ph.D. in Biochemistry from the University of Colorado and conducted postdoctoral research at MIT under the mentorship of Dr. Ron Weiss, an expert in synthetic biology, and Dr. Darrell J. Irvine, an expert in immune engineering. During his doctoral and postdoctoral studies, he led the development of multiple biotechnology patents, which were licensed to several NASDAQ-listed companies. He currently serves as Vice President of Research and Development at RootPath. In addition, the company’s core team includes several scientific co-founders from Harvard University and the Massachusetts Institute of Technology. Another full-time core member, Dr. Yue Zhao, completed his postdoctoral training at Vanderbilt University and previously served as Director of Research and Development at Burning Rock Biotech before joining RootPath.

Among existing innovative cancer therapies, CAR-T and TCR-T cell therapies have garnered significant attention. Examining the developmental trajectory of oncology therapeutics—from small molecules to biologics and finally to cell therapies—it becomes evident that cell therapy can achieve certain characteristics unattainable by other pharmacological interventions. Taking CAR-T as an example, genetically engineered CAR-T cells, once reinfused into the patient, can establish long-term immunological memory in vivo. Upon cancer recurrence, these cells can reactivate, proliferate, and expand to attack malignant cells, without being eliminated through drug metabolism.

However, one of the challenges in applying existing CAR-T therapies to solid tumors lies in the fact that CAR-T cells can only recognize proteins on the cell membrane surface. There are only a few hundred extracellular proteins that could potentially serve as therapeutic targets, and among these, it is difficult to find proteins that are exclusively expressed in tumor tissues and not in normal cells. Therefore, from the perspective of target selection, there is significant resistance to using CAR-T therapy for treating solid tumors.

TCR-T cells can recognize intracellular antigens, offering greater flexibility in target selection. However, a major challenge of TCR-T therapy is that TCR-recognized antigens must be presented by MHC molecules. Given the extensive polymorphism of MHC in humans and inter-individual variations in antigen expression, traditional TCR-T developers often opt for a single TCR to target a fixed, single antigen. This approach, however, has a significant drawback: tumor cells may evade immune attack by downregulating antigen or MHC expression. Therefore, for TCR-T therapy to succeed, it is necessary to establish a large TCR library or screen for patient-specific TCRs tailored to individual patients. With current technologies, both strategies are highly resource-intensive, requiring substantial manpower, time, and cost, while also posing significant challenges in research and development and regulatory approval.

TIL (tumor-infiltrating lymphocyte) cell therapy is another highly differentiated, customized, and targeted immunotherapy, originally developed by Dr. Steven A. Rosenberg, a pioneer in cell therapy. “TIL therapy is a non-genetically modified cell therapy. Tumor tissue obtained through surgery can be enzymatically digested into single cells. These single cells include both tumor cells and a small number of immune cells, such as T cells. The core hypothesis of TIL therapy is that within the population of T cells present in tumor tissue, there must be a subset capable of recognizing tumor cells. Therefore, after the T cells from the tumor tissue are expanded and infused back into the patient, they may effectively attack the tumor,” explained Dr. Chen Xi.

In 2011, the U.S. biotechnology company Iovance entered into an agreement with the NCI (National Cancer Institute) to license TIL technology from Dr. Rosenberg’s team. By simplifying and scaling up the manufacturing process for TILs, Iovance’s TIL cell therapy drug LN-145 received Breakthrough Therapy Designation (BTD) in May 2019 for the treatment of patients with recurrent, metastatic, or persistent cervical cancer following chemotherapy. At the ASCO (American Society of Clinical Oncology) annual meeting in June 2019, Iovance presented its research findings on TIL cell therapy for solid tumors, reporting an objective response rate (ORR) of 44% for LN-145 in cervical cancer. Prior to this, there were virtually no effective treatment options for advanced, metastatic, chemotherapy-refractory cervical cancer. Undoubtedly, the emergence of LN-145 has brought new hope to these patients.

TIL therapy also faces numerous bottlenecks. Currently, the success of TIL therapy is limited to tumors with high immunogenicity, such as melanoma and cervical cancer. The response rate to TIL therapy is extremely low in tumors with moderate or low immunogenicity, including lung cancer, breast cancer, colorectal cancer, and ovarian cancer. “The current industry consensus is that in these tumors with lower immunogenicity, the proportion of T cells within TILs that can specifically recognize tumor cells is very small, possibly only ranging from one in a thousand to one in a hundred. Therefore, even after expanding TILs, the proportion of T cells capable of recognizing tumors remains low, resulting in suboptimal therapeutic efficacy,” stated Dr. Chen Xi.

RootPath is committed to addressing the challenges associated with TIL and TCR-T cell therapies through its core synthetic immunology platform. By integrating technologies such as gene editing, single-cell sequencing, and industrial-scale T cell manufacturing, this platform functionally reconstructs the T cell immune repertoire. This transformation elevates conventional TCR therapies, which typically target a single antigen, into personalized, multi-target TCR-T therapies that are either tumor-specific or neoantigen-specific. From the perspective of TCR-T therapy, this novel approach attacks tumor cells via multiple targets, offering greater efficacy than conventional single-target TCR-T therapies. Furthermore, because the tumor-specific or neoantigen-specific TCR sequences are endogenous, they provide enhanced safety profiles. From the standpoint of TIL cell therapy, the functional reconstruction of the T cell immune repertoire can be used to enrich tumor-reactive T cells. This holds promise for overcoming the limitation of TIL therapy being effective primarily against highly immunogenic tumors, thereby expanding the applicability of TIL therapy to a broader range of solid tumors.

Currently, RootPath is collaborating with multiple research institutions in China, the United States, and Europe to jointly develop next-generation, personalized TCR-T therapies. The indications in the company’s pipeline are all focused on solid tumors, are currently in the preclinical research stage, and are expected to enter clinical trials in 2021.

RootPath is a preclinical-stage biotechnology company dedicated to leveraging its proprietary Synthetic Immunology Platform to develop next-generation, personalized T-cell therapies for the treatment of solid tumors. Incubated and established in 2017 by Nest.Bio Ventures, RootPath has secured seed and Series A financing totaling $18 million from investors including Sequoia China, Matrix Partners China, Yuanhe Origin Capital, Volcanic Stone Capital, Baidu Venture Capital, and Nest.Bio Ventures. Currently, RootPath has established R&D centers in Cambridge, Massachusetts (USA), as well as in Guangzhou and Hangzhou, China.

Matrix Partners China, established in 2008, is an investment firm focused on emerging industries and has been deeply rooted in the Chinese market for over 11 years. To date, Matrix Partners China has invested in more than 600 companies across sectors including artificial intelligence, industrial internet, healthcare, enterprise services, fintech, consumer internet, and education. Positioning itself as a “proactive investor who best understands entrepreneurs and provides support without causing disruption,” Matrix Partners China has built a post-investment value-added services team around the pain points of its portfolio companies, committed to creating value through active post-investment management and value-added services.

Yuanhe Origin is a member enterprise of Suzhou Yuanhe Holdings Co., Ltd. Established in 2013, it is a market-oriented, specialized early- to mid-stage equity investment platform that focuses on investment opportunities in startups and growth-stage companies within the Healthcare and TMT sectors. With an investment style characterized by a focus on early-stage ventures and a preference for technology-driven businesses, Yuanhe Origin boasts a professional investment team, extensive investment experience, and substantial resource accumulation in the healthcare sector. It is committed to providing diverse value-added services to its portfolio companies to achieve mutual success. Its portfolio includes Ascentage Pharma, CStone Pharmaceuticals, Biocytogen, JW Therapeutics, Singleron, and Ruipai Medical, among others.