Stemirna Therapeutics: Pioneering Next-Generation CAR-T Platforms for Solid Tumors with Over 100 Global Patents Filed

As a globally prominent cell therapy, the therapeutic potential of CAR-T therapy in hematologic malignancies (such as leukemia) is unquestionable. In 2017, two CAR-T therapies were successively approved by the FDA for marketing in the United States. However, research on CAR-T therapy for solid tumors (such as colorectal cancer) has been less satisfactory. This is attributed to several factors, including the inability of CAR-T cells to infiltrate solid tumors; even if they do infiltrate, T cells may become exhausted due to immunosuppressive activity within the tumor microenvironment.

ICT is committed to eradicating solid tumors by developing innovative CAR-T therapies. To address the various difficulties and challenges in treating solid tumors, the company has independently developed CoupledCAR, a therapy for solid tumors.^TMplatform technology, and has achieved good efficacy in clinical studies. ICT's products include multiple pipelines, covering various solid tumors and hematologic malignancies. The company has also independently developed Armored CAR for the treatment of lymphoma.^TMThe platform technology has also demonstrated favorable efficacy, and the product has obtained approval from the U.S. FDA for clinical trials.

In May 2020, the 23rd Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) was held online due to the impact of the novel coronavirus. The ASGCT Annual Meeting is a premier global academic conference in the field of gene and cell therapy. At the meeting, ICT unveiled its CoupledCAR^TMThe technology has demonstrated favorable safety and efficacy in the treatment of solid tumors, with two patients with thyroid cancer and two with colorectal cancer achieving partial response (PR) after CAR-T cell infusion.

Dr. Xiao Lei, the founder of ICT, has over 20 years of experience in the fields of embryonic/induced pluripotent stem cells, cell therapy, and gene editing. Dr. Xiao founded ICT in 2009 and has served as the company’s CEO on a full-time basis since early 2016. After returning to China in 2005, Dr. Xiao served as a Principal Investigator (PI) at the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences in Shanghai. Prior to this, he earned his Ph.D. from the University of Munich in Germany and subsequently conducted postdoctoral research at Johns Hopkins University. Wu Zhao, President and Co-founder of ICT, holds a Ph.D. from the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences and possesses 15 years of research and industry experience in stem cells and cell therapy. Other members of the company’s team hail from both China and the United States, bringing years of expertise in the research and development, patent protection, regulatory registration, and manufacturing of cell and gene therapy drugs.

"At its inception, ICT focused on cell therapy and gene editing technologies. 'The future development of CAR-T technology will integrate cell therapy, gene therapy, and gene editing technologies. We have mastered these technologies, possess comprehensive and systematic technical reserves, and have established a CAR-T technology platform that can be expanded to other technologies,' said Dr. Xiao Lei."

Since 2012, the ICT team has initiated CAR-T research targeting CD19-positive B-cell lymphoma. Starting from 2015, clinical trials involving 39 cases were conducted in the hematology departments of more than 10 top-tier Grade A tertiary hospitals across China, achieving a complete remission rate of 84.6% and an MRD negativity rate of 80%. Furthermore, ICT’s proprietary Armored CAR-T product, ICTCAR014, has achieved success in lymphoma treatment research and received investigational new drug (IND) approval from the U.S. FDA in December 2019. This extensive experience in treating hematologic malignancies has laid a solid foundation for ICT’s subsequent successes in solid tumors. Clinical trials targeting solid tumors such as colorectal cancer and thyroid cancer have also been launched at multiple hospitals.

In 2016, ICT completed its Series A financing round with investments from CDH Ventures and Jianqiao Capital. By the end of 2017, ICT had secured RMB 180 million in its Series B round, with investors including Volcanic Stone Capital, GTJA Investment, and SoftBank China. In November 2019, the company closed its Series B+ round, led by Linghang Xinjie.

For a long time, CAR-T therapy has faced numerous challenges in the treatment of solid tumors. Dr. Xiao Lei told VCBeat that four key issues need to be addressed for CAR-T technology to effectively treat solid tumors: CAR-T cell trafficking and infiltration, limited in vivo amplification, restricted cytotoxic capacity, and T cell exhaustion hindering in vivo persistence.

Furthermore, Dr. Xiao Lei stated: “Although CAR-T cells can only recognize cell surface antigens, which constitute less than 20% of the total cellular antigen pool, experience in hematologic malignancies has shown that targeting a single cell surface antigen is sufficient for the treatment of a given blood cancer. For instance, CD19 and BCMA serve as therapeutic targets for leukemia and multiple myeloma, respectively. Therefore, in principle, identifying just one effective target is sufficient for treating a specific solid tumor. Given the abundance of cell surface antigens, it should be possible to identify numerous suitable targets for solid tumors. For example, we have identified GUCY2C as a target for colorectal cancer and TSHR as a target for thyroid cancer. Consequently, the inability of CAR-T cells to recognize intracellular antigens should not be considered a barrier to their application in solid tumors, nor should it be interpreted as evidence that CAR-T therapy is potentially less effective than TCR-T or TIL technologies. In fact, if appropriate targets are identified for all three platforms, they will face similar challenges, such as the immunosuppressive tumor microenvironment. Due to its simplicity and ease of operation, CAR-T technology is poised for more rapid development and improvement, ultimately emerging as the superior platform among the three.”

ICT has independently developed CoupledCAR for solid tumors.^TMplatform, and holds over 100 global patents and patent applications in the field of CAR-T technology. “In simple terms, CoupledCAR^TM“This approach addresses the challenges of CAR-T cells struggling to infiltrate solid tumors, expand in vivo, and effectively kill tumor cells,” explained Dr. Xiao Lei.

CoupledCAR^TMThe platform employs a dual-CAR approach to stimulate the immune system and promote CAR-T cell expansion; it enhances the expression of genes associated with tumor cell migration, thereby overcoming the challenge of impaired CAR-T cell migration and infiltration into tumors. CoupledCAR also boosts the cytotoxic efficacy of CAR-T cells within the tumor microenvironment. Upon entering solid tumors, CoupledCAR stimulates the body to generate and recruit additional immune cells, eliciting a more potent and durable response.

Currently, the company has leveraged this platform technology to collaborate with multiple Grade A tertiary hospitals in China, conducting clinical studies (IRB trials) on solid tumors such as colorectal cancer and thyroid cancer. These efforts have fully validated the product's safety and demonstrated highly encouraging efficacy. Patients with advanced solid tumors enrolled in the study showed significant responses after receiving CAR-T cell infusion, with an overall response rate (CR+PR) exceeding 80%. This included four patients with advanced colorectal cancer, one of whom achieved a complete response (CR) and three of whom achieved partial responses (PR). Earlier this year, ICT completed preparations with the U.S. FDA for launching CoupledCAR^TMPre-IND Consultation for Solid Tumor Clinical Trials: Actively Preparing for IND Submission

Typically, activated T cells express checkpoint proteins such as PD-1 and CTLA-4 to regulate T cell activity and prevent autoimmunity. In the tumor microenvironment, tumor cells suppress T cell activity through PD-L1; therefore, combining PD-1/PD-L1 pathway blockade with CAR-T cell therapy has emerged as a prominent combination treatment strategy for cancer. However, this approach faces numerous challenges. For instance, PD-1/L1 antibodies are costly and can cause severe side effects. Alternatively, genetic knockout of PD-1 on the T cell surface to achieve blockade carries risks of off-target effects, is technically demanding, and incurs high costs. To address these issues, the company has independently developed ArmoredCAR.^TMPlatform Technology.

ArmoredCAR^TMArmored CAR: Ingeniously enabling T cells to express CAR while simultaneously expressing a dominant negative PD-1 (dnPD1) molecule, thereby relieving the suppression of CAR-T cells by the PD-1/PD-L1 signaling pathway, enhancing T cell function, and improving anti-tumor efficacy in vivo.^TMThe technology not only successfully utilizes PD-1 immunotherapy, but also offers advantages such as ease of operation, low side effects, and superior efficacy compared to other approaches. ICT has successfully secured patents for this platform technology in multiple countries and regions, including China, the United States, Europe, Japan, Russia, and Singapore.

ICT’s pipeline product ICTCAR014, developed via the ArmoredCAR+ platform for the treatment of CD19 and PD-L1 double-positive non-Hodgkin lymphoma (NHL), has received Investigational New Drug (IND) approval from the U.S. FDA and has officially entered clinical trials. It is reported that domestic Institutional Review Board (IRB) clinical trial results have demonstrated favorable efficacy, with an overall response rate of 92% among 13 subjects with refractory/relapsed lymphoma.

Currently, ICT is undergoing Series C financing, with the funds primarily allocated to several key areas: advancing IRB-approved clinical trials for solid tumors in China and further validating CoupledCAR.^TMEfficacy and safety of solid tumor technologies; concurrently advance the Investigational New Drug (IND) application for the solid tumor pipeline with the U.S. FDA; and promote the initiation of Phase I clinical trials for the ICTCAR014 pipeline in the United States.