Background
The success of CAR-T cell therapy in treating solid tumors has faced several limitations. Key factors limiting CAR-T efficacy in the hostile tumor microenvironment (TME) are lack of T cell persistence and poor durability due to the immunosuppressive and hypoxic milieu. To equip CAR-T cells with attributes that improve their function against solid tumors, we have developed a novel method to condition CAR-T cells during ex vivo expansion. Without the need for complex engineering, our conditioning regimen is a radically simple and effective way to epigenetically program CAR-T cells for long-term persistence and durable effector function, proven in in vivo models. Our proprietary conditioning regimen generates a unique brand of OUTLAST™ CAR-T cells (OTX), that exhibit superior effector function against solid tumors.
Methods
OTX CAR-T cells were engineered and expanded ex vivo in our proprietary OUTLAST conditioning media. This ex vivo conditioning epigenetically skews T cells to exhibit favorable attributes. Briefly, T cells are isolated from peripheral blood, activated via CD3, tranduced with lentivirus vector to express the CD70 CAR and expanded for 10 days in the OUTLAST conditioning media.
Results
Our first OTX CAR-T product is an autologous anti-CD70 CAR-T to treat clear cell renal cell carcinoma (ccRCC). When compared to conventional T cell (Tconv), we have demonstrated that OTX CD70 CAR-T cells have 1) superior metabolic fitness, 2) superior activation state (by CD25 MFI) in the presence of target cells, 3) lower exhaustion state after repeated stimulation (by PD-1, LAG-3 and KLRG1 MFI), 4) superior resistance to TGFβ suppression and 5) superior control of tumor cells in vivo in an aggressive repeat challenge model.
Conclusions
Overall, we show that OTX CD70 CAR-T cells exhibit multiple attributes desired of CAR-T cells for effective and superior function in the solid tumor microenvironment, and that they ‘outlast’ conventional CAR-T cells leading to more durable control in vivo.