Research progress of dual-target CAR-T in China from the perspective of the ASCO 2023

CAR-T Cell therapy had been successful in the treatment of recurrent hematological malignancy However, recurrence or progression still occurs in at least 50% of patients treated with CAR-T, The main cause lies in the limited persistence, functional inhibition, and antigen escape of CAR-T cells.

A study has shown that 30% -95% of recurrences are associated with diseases caused by the expression loss of CD19 on cell surface in patients with acute lymphoblastic leukemia (B-ALL) treated with CD19 CAR-T. 

Therefore, the investigators began to investigate dual target CAR-T, which is a CAR-T therapy that can kill tumor cells specifically against both targets. 

At the ASCO this year, Gracell Bio announced the long-term follow-up data of its multi-center clinical study of CAR-T therapy with GC012F for recurrent/refractory multiple myeloma (R/R MM) in the form of oral report at the annual meeting.

GC012F is a B cell maturation antigen (BCMA)/CD19 double target autogenous CAR-T Cell therapy developed based on Gracell Bio's proprietary FasTCAR technology platform, which is expected to revolutionize the treatment of cancer and autoimmune diseases with rapid, in-depth and lasting effects, and has security advantages of differentiation. 

In this single arm, open label, and multicenter clinical trial, a total of 29 R/R MM patients were included, with a median follow-up time of 30.7 months. The results showed that the objective response rate (ORR) of the patients was 93.1%, with 89.6% of patients achieved very good partial response (VGPR) or substantial partial remission; 82.8% of patients achieved complete remission (sCR) in the strict sense.

In addition, even though 90% of patients are at high risk, GC012F showed an effect of sustained response: The median duration of response (mDOR) was 37.0 months; The median progression free survival (mPFS) was 38.0 months; 34% of patients maintain minimal residual disease (MRD) - sCR states for more than 12 months, and it is expected that the PFS rate of these patients can reach 100% at 36 months.

In terms of safety, no new safety incidents of GC012F occurred during long-term follow-up. At present, a number of studies on GC012F is carried out, including B-cell non-Hodgkin's lymphoma (B-NHL), systemic lupus erythematosus (SLE), etc. 

At present, CD19 is the most mature target in the development of CAR-T. Therefore, double target CAR-T Cell therapy developed based on CD19 is the most common development route. Among them, the most common target combination is CD19/CD22. 

CD22 is expressed on the cell surface of most of B cell malignancy. For CD19/CD22 double target CAR-T Cell therapy, in the case of the loss of CD19, CD19/CD22 CAR-T can also control the progression and recurrence of tumor by binding with CD22. At present, companies in China that are deploying CD19/CD22 double target CAR-T include UNI-CAR, IASO Bio, Juventas, Bioheng, and others. 

UNI-CAR 

Recently, UNI-CAR presented the results of the Phase I/II clinical study of CD19/CD22 CAR-T Cell therapy in the treatment of B-ALL. A total of 219 patients were included in the study, of which 147 received CD19 CAR-T cell therapy alone, 51 received serial therapy of CD19/CD22 CAR-T cell, and 21 received sequential therapy of CD19/CD22 CAR-T cell.

The results showed that the CRs of the CD19 CAR-T therapy alone group, the CD19/CD22 CAR-T serial therapy group, and the CD19/CD22 CAR-T sequential therapy group were 83.0%, 98.0%, and 95.2% respectively. The clinical efficacy of the CD19/CD22 CAR-T serial therapy group was significantly better than that of the CD19 CAR-T therapy alone group, and the efficacy was similar to that of the CD19/CD22 CAR-T sequential therapy group. The CR of high-risk patients in the CD19/CD22 serial therapy group was higher than that of the CD19 therapy alone group (100.0% vs. 82.4%).

The 2-year OS values of the CD19 CAR-T therapy alone group, the CD19/CD22 CAR-T serial therapy group, and the CD19/CD22 CAR-T sequential therapy group were 59.2%, 76.3%, and 77.6% respectively. In patients who did not receive allogeneic HSCT transplantation (allo-HSCT), the median OS in the CD19/CD22 CAR-T serial therapy group was significantly better than that in the CD19 CAR-T therapy alone group (Not reached vs 23.5 months).

IASO Bio

CT120 is a fully human CD19/CD22 double target CAR-T product developed by IASO Bio. By the double target design, the tumor cell escaping caused by the loss of target antigen in existing CAR-T therapies can be reduced, which is expected to bring better survival benefits to patients. By using fully human antibody sequences, the in vivo ability of CAR-T can be improved.

At present, two clinical trials for CT120 has been approved in China, one for recurrent/refractory B-NHL with CD19/CD22 positive and the other for recurrent/refractory B-ALL. In a clinical study sponsored by the investigator, four patients with B-ALL achieved CR after receiving CT120 treatment, without any adverse reaction of cytokine release syndrome (CRS) of level 3 or above. 

Juventas 

HY004 is a CAR-T targeting CD19/CD22 antigen developed by Juventas. It is a cell preparation prepared in vitro by gene modification of lentiviral vector on patient's own T cells. It can directly identify CD19 and CD22 molecules on the surface of the target cells, with stronger effects of targeting killing. By reducing antigen escaping of tumor cells, it can reduce the recurrence of disease and maintains a long-term effect.

At the ASH2022, Juventas presented the efficacy data of HY004 in patients with B-cell malignancy. The results showed that 6 R/R B-ALL patients received CAR-T cell reinfusion, with an ORR of up to 100%. All 6 patients achieved remission with MRD negative, and no severe CRS (≥ level 3) or any level of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) was observed within 3 months. 

Currently, HY004 is being tested for the treatment of adult patients with R/R B-ALL and R/R NHL . 

CAR-T Cell therapy has become one of the hottest immunotherapies in the world. Although these CAR-T Cell therapies targeting a single antigen can provide a high response rate, most patients receiving these CAR-T treatments also face the problem of tumor immune escape. The loss or downregulation of antigen is the main mechanism of failure after single target CAR-T therapy. The double target CAR-T represents a new strategy that can overcome antigen regulation and reduce the risk of the recurrence of disease. However, in double target CAR-T cell therapy, CAR target selection and further optimization of CAR structure is required to achieve 1+1>2.

Main reference materials:

1. Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies. Cancers (Basel).2022 Jul; 14(13): 3230.

2. Sining Liu et al. (2023). Which one is better for refractory/relapsed acute B-cell lymphoblastic leukemia: Single-target (CD19) or dual-target (tandem or sequential CD19/CD22) CAR T-cell therapy? blood cancer journal.doi:https://doi.org/10.1038/s41408-023-00819-5.

3. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132 (2022). https://doi.org/10.1038/s41591-022-02017-5 .