Research
Developing CAR T cells for cancer therapy We are developing CAR T cells against new tumor antigens, novel CAR constructs for simultaneous therapy and imaging, and various ways to augment the potency of CAR T therapy against solid cancers. Our recent success include demonstration of somatostatin receptor-2 (SSTR2) for imaging T cell distribution and activity in vivo using PET/CT, and developing micromolar affinity CAR T cells to be selective to antigens over-expressed in tumor/tumor stroma while sparing normal cells with basal expression of the same antigen. Our CAR T cells developed to treat aggressive, refractory thyroid cancer are being evaluated for safety and efficacy in a phase I study (NCT04420754). Specific questions concerning CAR T research include:
- Tune affinity of CAR to be selective to tumors with overexpressed antigens while sparing normal cells
- T cell activation-dependent secretion of cytokines to compensate for the loss of activity due to affinity-tuning without altering CAR selectivity
- CAR T cell mediated pretargeting and delivery of radionuclide therapeutics
New formats of antibodies for imaging and bispecific recognition Antibodies are an important class of biologic drugs in oncology and inflammatory disease settings, either in native forms or in modified forms to carry small molecules or to recognize more than one antigens. Antibodies can also be modified for molecular diagnosis agents for real-time imaging of diseased cells and tissues in the body. We use in vitro techniques such as phage and yeast display systems, and apply molecular engineering principles to optimize antibodies' affinity, specificity, size, and shape for imaging and therapy applications. Specific examples include:
- 18F-labeled nanobodies for molecular imaging by PET
- Bispecific nanobodies for cancer therapy
Automated, walk-away, POC cell therapy device Current practice for manufacturing T cell therapy drugs involves blood collection and shipment to a manufacturing site, trained technologists working in a cleanroom environment under GMP, analytical assays for drug release, and the final shipment of frozen product back to the treatment site. The cost and time involved in this process, including regulatory approval, e.g., chemistry, manufacturing and controls (CMC), delays the iterative process of bench-to-bedside and back to bench and creates a bottleneck to rapid, high volume translation of early phase, innovative products. A device that implements a point of care (POC) walk-away operation in a closed system would reduce the cost, time, and regulatory burden of cell therapy manufacturing by omitting cryopreservation and shipment of incoming material and final product, eliminating the need for a GMP cleanroom environment, and minimizing the need for trained technologists who perform installation, intermittent operation, and quality control assays.
Magnetic Resonance contrast agent for molecular imaging and hyperthermia Two major hurdles in cancer therapy are early detection of tumor in the body and efficient delivery of drugs to the tumor cell target. The use of contrast agents modified to recognize unique and over-expressed markers on tumor cell surface shows a great potential in cancer diagnostics. Delivery platform is built on liposomes, polymer, and magnetic nanoparticles with their surface modified for the conjugation of antibodies and peptides for target recognition. The choice of specific nanoplatforms are based on the type of payload ferried by the nanoparticles and imaging modality such as magnetic resonance imaging (MRI), optical whole body imaging (near-infrared fluorescence dye, bio-lumininescence), and computed tomography (CT). For instance, we develop MR contrast agent such as superparamagnetic iron oxide (SPIO) nanoparticles, and coat them with targeting ligands to selectively localize to target cells via specific molecular interactions. Besides MR detection of diseased cells and tissues, we also explore hyperthermia induced cell killing by applying alternating magnetic field to cause SPIO to heat up and elevate temperature locally. Quantitative susceptibility mapping (QSM) technique (developed by Dr. Yi Wang) is used to quantify the biodistribution and concentration of SPIO across whole body.