Autologous T-cells genetically engineered to express Chimeric Antigen Receptors (CARs) represent an emerging, high value immunological therapy that can target and destroy cancer cells displaying “personalized” fingerprints. CAR-T cells represent a significant new therapeutic paradigm because they can harness the power of antibody-based cancer cell targeting without the following limitations of traditional monoclonal antibodies: 1) they are not dependent upon the patient’s immune system to evoke cancer cell killing through ADCC (Antibody-dependent cell-mediated cytotoxicity); this is significant because cancer patients’ immune systems are frequently weakened both by the cancer and standard oncology treatments, 2) they’re not dependent upon altering tumor cell signaling, for which cancer cells frequently develop resistance through mutations of the targeted receptor or downstream signaling molecules, and 3) challenges identifying cancer targets and/or antibodies amenable to internalization of antibody-toxin conjugates.
Current CART Therapeutic approaches feature challenges associated with toxicity, unreliable efficacy, and uneconomical manufacturing. Solving these challenges requires the integration of multiple biological solutions, including but not limited to: 1) improved ex vivo
expansion of autologous T Cells, 2) controlled proliferation and/or persistence of CARTs in vivo
, 3) reduced off-target toxicities (including attack of healthy cells with low levels of antigens up-regulated in tumors as well as unregulated expression of deleterious cytokines), 4) expanded utility for treating solid tumors, 5) coordinating CART function with synergistic therapeutic modalities, and 6) accelerated transition from an autologous approach to a standardized, scalable “universal” T Cell platform. Because the majority of CART product candidates currently employ retro/lentiviruses for gene delivery, the limited payload capacity of these delivery systems significantly hinders the number and types of biological solutions available for improving a single CART product candidate. The scientific team at Intrexon has the technology and know-how to overcome these challenges.
Intrexon’s UltraCART Initiative integrates a number of proprietary synthetic biology technologies including RheoSwitch®
, Protein Engineering, and Laser-Enabled Analysis and Processing (LEAP™
) platforms to overcome these limitations. Most significantly, utilization of our orally bioavailable small molecule-activated RheoSwitch Therapeutic System®
facilitates exquisite regulation of multiple bioeffectors in CAR-T Cells, enabling physicians to control the effects of systemically-administered cell therapies by delivering minimally invasive oral activator ligands. Intrexon possesses the integrated technology platforms, molecular engineering, systems biology, and cell engineering capabilities required to actualize the potential of CAR-T Cell therapies.