Driving CAR T cells through the solid tumor brick wall is a challenge. Scientists are learning how to navigate their way around.
Harvesting T cells from blood leads to the development of highly effective therapy for cancer patients. The T cells are engineered in the lab to express cell surface receptors called “chimeric antigen receptors” or “CARs” that recognize a specific protein (antigen) expressed on cancer cells. CAR T cells transfused back into the patient mount an immune response and eliminate tumor cells.
Clinical trials investigating CAR T cells as immunotherapy for childhood leukemia (discussed here) and others like it have produced phenomenal results. However, the caveat is that CAR T cells work on blood cancers, while solid tumors present an almost impenetrable brick wall.
Solid tumors may seem impenetrable with their growth of fibrous tissues and connective tissues that combine into the desmoplastic stroma. However, T cells in the body actively degrade the main components of the subendothelial basement membrane and the extracellular matrix (ECM), including protein structures called heparan sulfate proteoglycans (HSPGs).
Could T cells expanded in cell culture outside of the human body become defective in its capacity to penetrate the ECM? A research team investigated this issue. They analyzed freshly isolated resting T cells, T cells that had been briefly activated for 24 hours, and T cells expanded in long-term cell culture similarly to CAR T cells.
Results showed that briefly activated T cells had superior ability to penetrate the ECM in comparison to freshly harvested T cells. However, long-term cultured T cells lost ~90% capacity of activated cells for penetrating the ECM.
To dissect the mechanism responsible for the observations, scientists analyzed the expression of HPSE, an enzyme responsible for degrading HSPGs in ECM. They found that indeed, HPSE was lost in long-term cultured T cells whereas it was present in fresh T cells and overnight cultures.
Therefore, T cells expanded in cell culture for cancer immunotherapy are ineffective towards solid tumors because such T cells have lost the HPSE enzyme for degrading the ECM. Moreover, as the cleavage of HSPGs in the ECM releases cytokines that guide other T cells to the tumor, expanded T cells cannot recruit other T cells in this manner.
As CAR T cells are engineered to express the CAR protein, scientists explored adding the HPSE enzyme gene. They found that CAR T cells engineered to also express the HPSE enzyme got back the ability to degrade the ECM.
The proposed strategy of engineering HPSE into CAR T cells may enhance their antitumor activity in patients with stroma-rich solid tumors. At HemaCare, we provide T cells for research and look forward to the translation of this study into the clinical setting.
- Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D, Dotti G. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015 May;21(5):524-9