PII-002 - DEVELOPMENT OF A TRANSLATION PK-PD MODEL FOR IN VIVO CAR-T CELL THERAPIES USING CAR MRNA LOADED POLYMERIC NANOPARTICLE VECTOR

S. Kim¹, G. Mugundu², A. Singh²; ¹SUNY at Buffalo, ²Takeda Pharmaceuticals.

Background: Autologous and allogeneic Chimeric Antigen Receptor (CAR) T cell therapies have exhibited great success in the treatment of hematological malignancies; however, current manufacturing processes are logistically and financially challenging, and bring systemic toxicities such as lymphodepletion chemotherapy-related toxicities and Graft versus Host Disease1. As such, in vivo generation of CAR-T cells through gene-editing tools have gained traction as it mitigates the previously mentioned limitations of traditional CAR-T cells2. Here, we have generated an in vitro and in vivo pharmacokinetic-pharmacodynamic (PK-PD) model that is able to capture the in vivo generation of CAR-T cells after weekly infusion of polymeric nanoparticles loaded with mRNA encoding the 1928z CAR.

Methods: In vivo programming of T cells through in vitro-transcribed CAR mRNA data was digitized from the following study3. The model development was conducted in a systematic manner by capturing the 1) in vitro mRNA PK-PD model, 2) in vitro tumor growth, 3) in vitro tumor killing in co-culture with CAR-T cells, and 4) in vivo nanoparticle PK-PD. The nanoparticle PK from a different study that share similar physiochemical properties was digitized and characterized4 using a 2-compartment model.

Results: The developed PK-PD model was able to successfully characterize the in vitro and in vivo transient expression of 1928z CAR on T cells after exposure to mRNA encapsulated polymeric nanoparticles. Simulations at various dose levels revealed that the transient CAR expression can be sustained with an increase in dose or altering the frequency of mRNA polymeric nanoparticle dosing.

Conclusion: The developed model could be implemented towards establishing a preclinical to clinical translational framework for CAR mRNA loaded polymeric nanoparticles and could be leveraged towards discovery and development of in vivo CAR-Ts.