Next Generation CAR-T Technologies
We are developing many types of T cells with dual CARs, including “parallel CARs” and “split CARs” to tackle the outstanding relapse issue and to improve specificity of tumor killing. We are also developing CAR-T cells with ability of navigating through inhibitory “tumor microenvironment” (TME).
1. Parallel CAR-T
CAR-T therapy has demonstrated impressive anti-tumor effects in children and adults with relapsed and/or refractory B cell malignancies, especially in B-ALL and NHL. However, the likelihood of durable remission remains uncertain. Although CD19/CD20 are expressed by essentially all case of B cell malignancies, relapses with loss or diminished cell-surface expression of CD19/CD20 seem like the main cause of treatment failure. Meanwhile, a solid tumor comprises a heterogeneous population of cells that are differ from each other on the type of surface molecules. CAR-T cell therapy targeting only one antigen may not be able to have sustainable efficacy.
We seek to generate a durable T cell therapy with dual CAR desigh that could simultaneously recognize two or more cell-surface antigen, which could be more effective at inducing remissions and less susceptible to relapse associated with antigen escape.
Another form of the dual CARs is to co-express a second inhibitory CAR specific for an antigen expressed on normal, but not tumor, tissue to provide negative signaling in the presence of normal tissue. The negative feedback mechanism prevents on-target/off-tumor toxicity, protecting normal tissue from CAR-T cell-mediated attack.
2. Split CAR-T
A major challenge in CAR-T therapy is ensuring elimination of tumor cells while sparing normal tissue and minimizing toxicity.
Unfortunately, most targets identified so far are not entirely restricted in tumor tissues. CAR-T activation requires two or more simultaneous signal integration in T cells. We are developing a split CAR-T co-expressing two or more different tumor associated antigen (TAA) binding domains which splitting the two or more signals. Split CAR-T cells can be activated only when two or more TAAs exist, which will improve targeting specificity over that of single-input CARs.
3. Switchable CAR-T
CAR-T cell therapy has produced promising results in clinical but has been challenged by the inability to control CRS and neurotoxicity.
Switchable CAR-T cells allow to be switched on and off in a controlled manner by splitting the antigen –binding and signaling domain of conventional CAR-T. It consist of two separate components, (1) the effector module, which is a genetically engineered T cells expressed a universal CAR targeting a unique molecule(X) and (2) a targeting module, which is a fusion molecule of a binding domain directing against a tumor associated antigen and the same molecule(X). Switchable CAR-T cell activation can be controlled by dosing of the targeting module. Hence, switchable CAR-T cells with precise controllability and flexibility could limit on-target/off-tumor toxicities and side effects such as CRS, effectively. Since the targeting module is solely responsible for the recognition of the TAA, switchable CAR-T cells can be redirected to various TAAs by exchanging the TAA binding domain of targeting module.
CAR-T co-expressed a conditional suicide gene is another form of switchable CAR-T, which also allow to eliminate CAR-T cells rapidly once the suicide gene is activated by the substrate molecule. We are also developing a switchable CAR-T with a suicide gene system. We believe it will improve the safety of CAR-T therapy by preventing the unlimited proliferation of CAR-T cells.
4. Strategies to overcome tumor microenvironment (TME)
The solid tumor microenvironment (TME) is immunosuppressive and a critical obstacle for CAR-T cell therapy. Various factors in TME can negatively regulate in vivo persistence and antitumor activity of CAR-T cells, such as regulatory T cells and inhibitory checkpoint like PD-1. Programmed cell death protein 1 (PD-1) is a cell surface receptor that plays an important role in down regulating the function of T cells, which has two ligands, PD-L1 and PD-L2. We are developing a secretory CAR-T armed with the ability to secrete PD-L1 that will bind to PD-1 in TME and relieve the PD-1 checkpoint inhibition. Moreover, secretory PD-L1 will alter the TME and educate immune cells within the hostile tumor tissue to fight against the tumor with CAR-T cells.