How Are The 6 Domestic Solid Tumor CAR-T Therapies Progressing?

In 2021, Fosun Pharma's Akiloxetine Injection and WuXi Junuo's Ruijiorenxe Injection will be launched in China one after another, and CAR-T products will achieve "ice-breaking" in China, but these two products are aimed at both. It is a hematological tumor. At the same time, most of the CAR-T therapies that have entered the clinical stage in China are also deployed in the field of hematological tumors. In fact, the latest global cancer data in 2021 points out that about 90% of the cancer incidence is caused by solid tumors. Therefore, the treatment of solid tumors with CAR-T can be said to be one of the focuses of the current market.

Domestic companies such as Keji Pharmaceutical, Stansai, Boshengji, and Legend Bio are all deploying CAR-T for solid tumor treatment, and have or are entering the clinical trial stage.

1. Keji Pharmaceutical

Keji Pharmaceutical is undoubtedly the company with the largest and most rapidly progressing solid tumor CAR-T therapy pipeline in China. Its solid tumor CAR-T therapy includes:

CT041——an autologous CAR-T cell candidate product targeting CLDN18.2 protein, suitable for the treatment of CLDN18.2 positive solid tumors, mainly for the treatment of gastric cancer/esophagogastric junction adenocarcinoma (GC/GEJ) and pancreatic cancer (PC), It is the only CLDN18.2-targeting CAR-T cell candidate product in the world that has obtained IND/CTA approval from the U.S. FDA, the China National Medical Products Administration and Health Canada and is undergoing clinical trial research. In March this year, CT041 completed the first patient enrollment in China's confirmatory phase II clinical trial at Peking University Cancer Hospital, mainly for the treatment of Claudin18.2 (CLDN18.2) positive advanced gastric cancer/ Esophagogastric junction adenocarcinoma. Keji Pharmaceutical plans to submit an NDA to the China National Medical Products Administration in the first half of 2024, and plans to initiate a Phase 2 clinical trial in North America in the second half of 2022, and submit a BLA to the US FDA in 2024.

CT011——Potential global first-in-class CAR-T cell product candidate (humanized GPC3 CAR-T), with proof-of-concept clinical data for the treatment of hepatocellular carcinoma (HCC), has completed the phase I trial patient enrollment in China, The Phase II trial is expected to start in the second half of 2021.

CT0180 - an autologous T cell product expressing a fusion protein targeting the GPC3 antibody fused T cell receptor (aTCR). Preclinical studies have shown that in mouse xenograft models, CT0180 can effectively identify and kill GPC3-positive hepatocellular carcinoma cells and significantly inhibit HCC tumor growth. The cytokine release in vivo and in vitro is lower than that of GPC3 CAR-T cells, which improves the Safety and suitability of adoptive cell therapy.

CT0181 - an autologous T cell product targeting GPC3 antibody fused to T cell receptor and co-expressing IL-7 cytokine. Preclinical studies demonstrated that CT0181 demonstrated superior antitumor efficacy, T cell persistence, and immune memory in solid tumor xenografts with low cytokine release compared to GPC3 CAR-T cells.

In addition, Keji Pharmaceutical also has solid tumor CAR-T therapy under development for mesothelin, GFR/EGFRvIII, etc.

In terms of industrialization, Keji Pharmaceutical has production bases in Shanghai and the United States, with end-to-end plasmid, viral vector and CAR-T cell production capabilities, and can independently produce CAR-T cells to support clinical trials in China, and independently lentiviral vectors to support clinical trials worldwide. Among them, Keji Pharmaceutical has obtained the first drug production license for CAR-T cell therapy in China at its GMP production plant in Zhangjiang Jinshan Base, and is expected to support CAR-T therapy for up to 2,000 patients per year; in North Carolina, USA The state's RTP CGMP manufacturing facility successfully passed official facility inspections and will provide additional autologous CAR-T cell product capacity for 700 patients per year.

2. Stansay

In April 2022, Stansay announced that the FDA has granted its GCC-targeting autologous CAR-T therapy product GCC19CART Fast Track designation. GCC19CART is a solid tumor therapy for the treatment of relapsed, refractory, metastatic colorectal cancer (R/R mCRC), specifically designed to target and eliminate the expression of the colorectal cancer tumor marker guanylate cyclase C (GCC ) of cancer cells. A total of 35 patients with advanced colorectal cancer were enrolled in an early investigator-initiated clinical trial (IRB) of GCC19CART in China, among 8 patients who received 2X10^6 GCC19CART cells/kg in a dose escalation trial , an objective response rate of 50% was observed.

Stansay plans to initiate a Phase I clinical trial in the United States to evaluate the safety, tolerability and efficacy of GCC19CART in patients with relapsed, refractory and metastatic colorectal cancer in mid-2022.

3. Bo Shengji

In April 2022, the clinical trial application for B7-H3-targeting chimeric antigen receptor (CAR)-T cell injection (R&D code: TAA06 injection) developed by Boshengji was accepted by CDE for the treatment of neuroblasts tumor. This is also the first B7-H3-targeted CAR-T cell product accepted by CDE.

The expression level of B7-H3 is low in normal human tissues, but in human malignant tumors such as pancreatic cancer, prostate cancer, ovarian cancer, lung cancer, clear cell renal cancer, osteosarcoma, Ewing sarcoma, glioma and other solid tumors abnormally high expression. It is reported that TAA06 injection has obtained excellent data in the early in vitro and in vivo pharmacodynamic research and safety evaluation. The product has been granted orphan drug designation and rare disease designation by the FDA in March 2022.

At the same time, TAA06 injection is also the first product declared by Boshengji for solid tumor indications. At present, Boshengji has built a fully automatic CAR-T cell production base of about 10,000 square meters in compliance with GMP standards, which is a CAR-T cell production base for CAR-T cells. The commercialization of the drug lays the groundwork.

4. Legendary creatures

Among the domestic CAR-T therapies targeting CLDN18.2, Legend Bio's LB1908 follows Keji Pharmaceutical's CT041.

LB1908 utilizes a nanobody design that ensures high specificity for CLDN18.2. Preclinical studies have shown that the antigen-binding region of LB1908 CAR specifically binds to CLDN18.2 with high affinity. The antitumor effects of LB1908 in vitro and in vivo (human tumor xenograft mouse models) were target-specific. LB1908 was only cytotoxic to cells expressing CLDN18.2, but not primary human cells or cells expressing Claudin 18.1. In preclinical studies, LB1908 showed significant antitumor effects in a cell-derived xenograft (or CDX) gastric tumor mouse model and a CDX pancreatic tumor mouse model.

At present, this CAR-T therapy has entered a dose-escalation phase I clinical trial, and in the first patient who received the lowest dose of LB1908, it showed good safety and preliminary anticancer activity.

It is reported that Legend Bio plans to further expand its clinical trials in China and is preparing to submit an IND application in the United States in the first half of 2022.

LB2101 is Legend Bio's "armed" CAR-T therapy targeting GPC-3. In addition to expressing a chimeric antigen receptor (CAR) targeting GPC-3, it also expresses a transmembrane protein that is activated by signals in the tumor microenvironment. Therefore, it does not affect CAR-T cell specificity and also improves cell infiltration, proliferation and persistence. In vitro and in vivo studies have shown that LB2101 has potent tumor-killing effects in a target-dependent manner without off-target cytotoxicity.

5. Chongqing Precision Biology

In September 2021, Chongqing Accurate Bio's CAR-T product C-4-29 cell preparation for targeted treatment of "advanced renal cell carcinoma with positive CD70 expression" received an implied license for clinical trials, which is also the first domestic drug targeting renal cell carcinoma CAR-T products for cancer solid tumors.

It is reported that the CD70 target is the first development of Chongqing Precision Bio in China, and it is an innovative target with dual application scenarios of blood and solid tumors. The C-4-29 cell preparation developed according to this can be used for the treatment of patients with relapsed/refractory multiple Myeloma (MM) or advanced/metastatic renal cell carcinoma (RCC). Its first indication (MM) clinical trial was granted the implied approval for clinical trials by the Center for Drug Evaluation of the State Drug Administration on December 10, 2020, and Phase I clinical research has been initiated.

6. Xinda Biology

In February 2022, Innovent announced that it developed the world's first universal "modular" anti-claudin 18.2 (Claudin18.2) chimeric antigen receptor T cell injection (development code: IBI345) in the treatment of advanced Claudin18.2 First patient dosed in a clinical trial in positive solid tumors.

According to reports, the potential advantages of IBI345 compared to traditional CAR-T cells include: 1) By using the "targeting" effect of antibodies to amplify the antigen target signal, guide CAR-T cells to enter the tumor and initiate recognition and killing effects. 2) By regulating antibody administration and regulating CAR-T cell activity, the purpose of controlling toxic and side effects is achieved. 3) "Modular" CAR-T is versatile and can be combined with different antibodies to treat solid tumors with highly heterogeneous antigen expression or antigen deletion through sequential or simultaneous administration of more than one antibody targeting different antigen targets. Therefore, it is expected to achieve breakthroughs in CAR-T treatment of solid tumors, reduce the cost of CAR-T cell therapy, and improve the accessibility of CAR-T cell therapy for patients.