In 2017, the U.S. FDA approved the listing of Novartis' and Kite's CAR-T therapies, creating a precedent for CAR-T therapy for cancer treatment.

What is CAR T-cell Therapy?

Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment  to get T cells (a type of immune system cell) to fight cancer by changing them in the laboratory so they can find and attack cancer cells. CAR T-cell therapy is also sometimes talked about as a type of cell-based gene therapy, because it adds the gene for a chimeric antigen receptor that binds to a certain protein on the patient’s cancer cells to the T cells to help them attack cancer.

There are several stages in the preparation of CAR-T cell therapy. T cells are isolated from the patient's peripheral blood; the T cells are genetically engineered in vitro; the modified T cells are amplified and cultured to a certain number and then transfused back to the patient to rapidly identify and kill tumor cells.

Figure 1: CAR-T Cell therapies mechanism of action

This type of treatment can be very helpful in treating certain blood cancers, and it is being studied in the treatment of other types of cancer.

Approved CAR-T Cell Therapies

CAR-T cell technology was discovered in 1986 and has been developed for more than 30 years. 2012 saw the cure of Emilie, a 7-year-old girl with leukemia, which brought unprecedented attention to CAR-T cell therapies. To date, six CAR-T cell therapies have been approved worldwide, five of which are approved by the FDA and one by the NMPA in China, as summarized in Table 1. 

Table 1: Worldwide Approved CAR-T Cell Therapies,  Source: FDA/company official website and other public information. Remarks: ALL: acute lymphoblastic leukemia; DLBCL: diffuse large B-cell lymphoma; MCL: mantle cell lymphoma; MM: multiple myeloma; LBCL: large B-cell lymphoma.

So far, the indications of the six CAR-T therapies marketed worldwide are all hematological tumors, involving lymphocytic leukemia and myeloma, etc., and do not involve solid tumors. According to statistics, the efficiency of CAR-T therapy for patients with refractory hematologic tumors for which existing therapies are ineffective is as high as 50%-70%.

CAR-T Cell Therapies Development Status

According to statistics, there are over 400 CAR-T cell products in clinical development stage, and the number of CAR-T cell varieties in different development stages worldwide is shown in figure 2.

Figure 2 Distribution of global CAR-T cell therapy products at different clinical development stages

Currently, the CAR-T cell products approved for marketing have CD19 and BCMA as their targets, and the indications are all hematological tumors, and no breakthrough has been achieved in solid tumors. However, there is no shortage of companies focusing on the development of CAR-T cell therapies on solid tumor targets, such as Claudin18.2 and GPC3, which have made initial progress in clinical studies of CAR-T cell therapies on solid tumor targets. In addition, CAR-T cell targeting HER2 is mainly used for biliary tract cancer and pancreatic cancer research, CAR-T cell targeting GD2 is used for neuroblastoma research, and CAR-T cell targeting IL13Rα2 is mainly developed for highly aggressive glioblastoma. The TOP20 target distribution of the number of CAR-T cell products in clinical development worldwide is shown in Figure 3.

Figure 3 Global TOP20 target distribution of CAR-T cell therapies

As shown in Figure 3, CD19 ranks 1st among the global CAR-T cell therapeutic development products as a target with several therapies approved for marketing. Among the top 20 targets in the global CAR-T cell field, CD19 accounts for 40% and BCMA accounts for 11%. According to Novartis and Kite annual report disclosed that Kymriah and Yescarta 2020 global annual sales are: $474 million and $563 million, respectively. Three years after the approval of the two products on the market, annual sales still have not exceeded $ 1 billion. There are two main reasons for this: CAR-T therapy is an individualized therapy with high production costs, resulting in high market pricing and low popularity among patients; CAR-T cell therapy is currently listed and approved only as a last-line treatment for hematological tumors, and the broader market for solid tumors is still blank, and the safety of CRS is significantly lower than other conventional treatments. However, global pharmaceutical companies still have high expectations for CAR-T therapies and have been conducting clinical development on mature targets such as CD19 and BCMA.

Emerging Trends in CAR-T Cell Clinical Development

To date, CAR-T cell therapy has not made a breakthrough in the treatment of solid tumors. The CAR-T cell therapy studies in clinical development for solid tumors cover popular targets such as Claudin18.2, GPC3, and EGFRvIII.

Gastric Cancer: CAR-T Cell Therapy Targeting Claudin18.2

Claudin18.2 belongs to a subtype of the tight junction protein family, and the rate of Claudin18.2 positivity in gastric cancer patients is as high as 50%-60%. Even in gastric cancer metastases, Claudin18.2 is also highly expressed, while it is not expressed in normal human tissues. Therefore, Claudin18.2 is a promising new target for gastric cancer treatment.

Hepatocellular carcinoma: CAR-T Cell Therapy Targeting GPC3

GPC3 is specifically highly expressed in 70%-80% of hepatocellular carcinoma patients. GPC3 controls the proliferation of hepatocellular carcinoma cells by affecting signaling pathways such as Wnt and YAP, which in turn affects tumor metastasis. Therefore, GPC3 is a potential therapeutic target for hepatocellular carcinoma.

Brain cancer: CAR-T Cell Therapy Targeting EGFRvIII

The world's first phase I clinical trial of CAR-T cell targeting EGFRvIII was reported to give intravenous infusion of CAR-T cells to 10 patients with MGMT-nonmethylating recurrent GBM (glioblastoma) with a median overall survival of 8 months.

A phase I/II clinical study of CAR-T cell therapy targeting EGFRvIII (NCT01454596) enrolled patients with EGFRvIII-positive malignant glioma and planned to enroll 107 patients. A Phase I clinical trial (NCT02664363) of targeted EGFRvIII CAR-T therapy for patients with newly diagnosed GBM was conducted, with a planned enrollment of 48. Both trials have not yet been completed.

With new strategies and potential solutions continue to evolve, it is believed that a path forward to more effective and safer future therapies will eventually established.

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