April 28, 2023
Breaking into Solid Tumors with Armored CAR-T Cells
Solid tumors and the tumor microenvironment (TME) present unique challenges for cell therapies. CAR-T cells have been effective in blood cancers, but the TME poses a significant barrier in solid tumors. Tumors can reduce the anti-cancer activity of immune cells in the TME, reducing the effectiveness of anticancer therapies.
CAR-Ts known as Armored CARs can potentially circumvent this problem. Armored CARs also secrete cytokines or express cytokine receptors to provide a stronger immune response to solid tumors by reactivating immune cells that have been “turned off”.
For example, researchers have engineered CAR-T cells to constitutively secrete IL-12, a cytokine that activates NK cells, and stimulates T cells to differentiate into Th1 cells that stimulate the immune system, rather than Th2 cells which have the opposite effect. This causes a positive immune activation feedback loop where the newly stimulated Th1 cells and NK cells induce the release of more IL-12 from macrophages. This has the capability to enhance CAR-T efficacy on solid tumors by ultimately “turning on” immune cells in the TME.
In another type of Armored CAR known as a “Self-driving Armored CAR” the CAR-T cells express “armor proteins”, and when the cell encounters tumor antigens, it ramps up the production of more CAR receptors and armor proteins. The armor proteins protect the cell from immunosuppressive cytokines which are typically found in the TME. This could provide new possibilities in overcoming the TME.
There are 8 active armored CAR-T clinical trials, most of which are in phase 1 and targeting liver cancer. Like in vivo cell therapies, the armored CAR-T space is relatively new. Most work is being done at universities or cancer centers.
Two companies stand out in this space: Juno Therapeutics and Tmunity. Tmunity has multiple assets in its pipeline, 3 of which are Armored CARs, and has 3 total CAR-T assets in phase I clinical trials. Juno was acquired by Celgene which is now owned by Bristol Myers. in 2016, their pipeline included work on 3rd generation armored CAR-T cell therapies. They are now collaborating with Memorial Sloan Kettering Cancer Center on a phase 1 trial for patients with relapsed CD19+ hematologic malignancies.
Most of the active clinical trials began in the past 3 years. While this niche field is small now, clinical trial data will decide the future of the armored CAR-T approach. Kineticos will certainly keep an eye on this exciting field.