Solid tumor-targeted CAR-T therapeutics: CAR-T cell technologies have been rapidly advancing, with leukemia as one main target. However, development of CAR-T cell therapeutics for solid tumors has lagged. One major reason is the lack of a target that is highly selective for solid tumors.
However, CAR-T cells being developed by Liminatus target GCC, which is a demonstrated cancer cell-selective target. For this reason, GCC CAR-T cells are anticipated to lead clinical trials as opposed to other solid tumor cancer CAR-T approaches.
Utilization of Third-Generation CAR-T Technology
CAR-T cells have evolved to include intracellular costimulatory domains that allow the engineered cells to replicate and persist. Thus, with engagement of their target, they create a large number of CAR-T cells that attack cancer cells and last for a long period of time.
In first-generation CARs, transmission of signals and stimulation of T cells was limited because CD3ζ was the only intracellular costimulatory domain included. As the technology evolved, CD28, 4-1BB, OX40, etc. signaling domains were added in second- (CD3ζ plus one other signaling domain) and third- (CD3ζ plus two other signaling domains) generation CARs to enhance their ability to recognize and kill cancer cells.
Third-generation CARs incorporate CD3ζ plus two other costimulatory domains supporting robust expansion of CAR-T cells. However, enhancement of the ability of CAR-T cells to recognize and kill cancer cells and persist and expand using third-generation constructs has been associated with increased side effects with respect to normal cells. Even commercialized products (CD18-targeted CAR-T cells) have been associated with side effects and mortality in patients.
In this regard, the development of GCC CAR-T cells by Liminatus is significant because the target (GCC) is a highly compartmentalized antigen in normal tissues which, in turn, reduces concerns of autoimmunity and normal tissue injury characteristic of other CAR technologies and products.