Dual-target CAR-T cell therapy is on the rise

Recently, Cibiman Biotechnology announced that the FDA has granted the company's cell therapy product C-CAR039 regenerative medicine advanced therapy (RMAT) designation and fast track (FT) designation for the treatment of relapsed or refractory and diffuse large B-cell lymphoma (r/r DLBCL)
.

C-CAR039 is a novel second-generation 4-1BB dual-target CAR-T that acts on both CD19 and CD20 dual targets, and can effectively eliminate CD19/CD20 single-positive or double-positive tumor cells in vivo and in vitro

At present, the FDA has approved 5 CAR-T cell therapies, and the NMPA has approved 2 CAR-T cell therapies.
Cell therapy was approved for marketing
.

However, considering the complex pathogenesis of malignant tumors, CAR-T therapy targeting a single target may not show sufficient therapeutic effect, so researchers turned their attention to dual-target CAR-T cell therapy, which is similar to the birth of double antibody There are similarities in the same way

Overview of dual-target CAR-T

Overview of dual-target CAR-T

In the context of the continuous growth of the number of cancer patients in China and the continuous improvement of payment capacity, CAR-T cell therapy has high hopes for its efficacy advantages
.

From the perspective of mechanism, CAR-T products can identify and kill tumor cells in a non-MHC-restricted manner, and overcome immune escape in a targeted manner.

Figure: Predicted market size of China's CAR-T cell therapy market (billion yuan)

Source: Frost & Sullivan

Although single-target CAR-T products have shown good efficacy in clinical studies, there are still some patients with disease progression or recurrence after receiving CAR-T therapy.
Some people believe that the root cause of disease progression or recurrence lies in Loss or reduced expression of specific targets on the tumor cell surface
.

Therefore, by adding a binding site, that is, targeting two antigens or different epitopes of antigens at the same time, bispecific targeting CAR-T is expected to improve the specificity of treatment, more accurately target tumor cells and reduce off-target toxicity, thereby reducing off-target toxicity.

Dual-target CAR-T layout

Dual-target CAR-T layout

Although no dual-target CAR-T has been approved for marketing in the world, a group of companies have high hopes for dual-target CAR-T products
.

In terms of target selection, CD19×CD22 CAR-T is the target combination that attracts the most attention.

(1) CD19×CD22 CAR-T: Both CD19 and CD22 are specifically expressed on the surface of various B cell tumors
.

At present, a number of CD19 CAR-Ts have been approved for marketing around the world, but some studies have found that some B-cell tumor patients will still experience disease progression and recurrence after receiving CD19 CAR-T therapy

Reindeer Medical's CT120 is a fully human chimeric antigen receptor T cell injection targeting CD19 and CD22.
The extracellular domain of the CAR molecule of this product contains two segments of fully human origin that can specifically bind to CD19 and CD22.
scFv sequences that reduce tumor cell escape due to loss of target antigen by recognizing tumor cells expressing CD19 and/or CD22
.

In November 2021, the FDA granted orphan drug designation to CT120.

Hengrun Dasheng's anti-human CD19-CD22 T cell injection is a genetically modified autologous CAR-T cell product targeting CD19-CD22 targets.
T cells carry CAR elements
.

This element enables the expression of anti-CD19 and CD22 antibodies on the surface of T cells, which can specifically recognize the CD19 and CD22 molecules on the surface of B cells, bind them to activate activation signals, and thus play a targeted killing effect on cells expressing CD19/CD22.

(2) CD19×BCMA CAR-T: BCMA is an effective therapeutic target for multiple myeloma.
Currently, the ADC drugs Blenrep and BCMA CAR-T Abecma targeting BCMA have been approved for marketing
.
Studies have found that although CD19 is low expressed on the surface of multiple myeloma cells, it is highly expressed in multiple myeloma progenitor cells
.
Therefore, targeting CD19 and BCMA is expected to enhance the clearance of multiple myeloma cells
.

Gracell's GC012F is an autologous CAR-T cell therapy targeting CD19 and BCMA developed based on the FasTCAR platform.
It is indicated for multiple myeloma and is currently in clinical phase
I.
At 2021 ASCO, Gracell announced the long-term follow-up data of GC012F Phase I.
GC012F achieved an ORR of 94.
7% in 19 subjects, sCR reached 84.
2%, and mDoR was not reached
.
In terms of safety, the incidence of cytokine release syndrome (CRS) of grade 3 and above was 10.
5%, and no neurotoxicity was observed
.

Figure: GC012F structure

Data source: Gracell Biotechnology

(3) CD19×CD20 CAR-T: Relapse caused by CD19 antigen loss is a challenge for CD19-targeted CAR-T therapy
.
These patients generally have a poor prognosis and have a high unmet medical need
.
CD20 is an effective target for the treatment of B-NHL, which has been validated in clinical trials
.
Therefore, CAR-T cell therapy targeting CD19 and CD20 is expected to improve the therapeutic effect of B-NHL
.

C-CAR039 of Sibman Bio is a CD19/CD20 dual-target CAR-T cell therapy product, which is currently in Phase I clinical trials
.
At the 2021 ASCO, Sibman announced the early phase I clinical data of C-CAR039 for the treatment of r/r B-NHL.
28 patients achieved an objective response rate of 92.
6%, of which CR reached 85.
2%
.
In terms of safety, only 1 patient developed grade 3 CRS, and no immune effector cell-associated neurotoxicity syndrome (ICANS) of grade 3 or above occurred
.

(4) CD33×CLL1 CAR-T: C-type lectin-like molecule 1 (CLL1) is not expressed in normal hematopoietic stem cells (HSC), but is highly expressed on acute myeloid leukemia (AML) cells and leukemia stem cells (LSCs) expression, and is closely related to the recurrence of AML
.
CD33 is highly expressed in AML cells, and Mylotarg, an ADC drug targeting CD33, has been approved for marketing
.

Professor Liu Fang from Chengdu General Hospital presented the preclinical and early phase I research data of a CLL1×CD33 CAR-T therapy at EHA in 2018 and ASH in 2019
.
By the end of 2019, Director Liu Fang's team had completed CLL1-CD33 CAR-T cell therapy for 9 patients, of which 7 patients achieved complete remission (CR)
.
In terms of safety, 8 patients developed CRS, but after active treatment and medication, the complications of all patients were effectively controlled, and none of the patients died
.

summary

summary

Although no dual-target CAR-T has been approved for marketing in the world, a group of companies have high hopes for dual-target CAR-T products, including Legend Bio, Gracell, and Reindeer Medical
.
From the perspective of clinical stage, the vast majority of dual-target CAR-T cell therapies are still in the early clinical stage
.
From the perspective of clinical data, dual-target CAR-T therapy has shown positive efficacy and safety data, and C-CAR039 of Cibiman Bio has been granted Regenerative Medicine Advanced Therapy (RMAT) qualification and Fast Track (FT) by the FDA Qualification, CT120 of Reindeer Medical has been granted orphan drug designation by FDA
.
I sincerely hope that relevant companies will make persistent efforts to rapidly advance the research and development of dual-target CAR-T products with excellent data, and provide new treatment methods for patients with advanced hematological tumors
.