The primary focus of the Krebs Laboratory is the development and preclinical evaluation of theranostic (imaging and therapeutic) agents in conjunction with cellular engineering. Our bench-to-bedside research program includes chemistry, cellular biology, immunology, animal research, and clinical translation. We are developing a non-invasive, sensitive, and specific methodology to monitor genetically altered human immune cells after they have been transferred into patients to treat cancer. We are also investigating theranostic approaches that target markers on the tumor and in the tumor microenvironment, for instance for glioma and lymphoma.
Interrogating the in vivo pharmacokinetics of tumor-directed T cells with radiohapten capture
Chimeric antigen receptor (CAR) – and T-cell receptor (TCR) – modified T cells are rapidly emerging as viable treatment options for cancer patients. However, these cell therapies have demonstrated highly variable efficacies and sometimes severe and fatal toxicities. Current methods to monitor the adoptively transferred T cells in patients do not provide the needed real time dynamic and spatial information. Direct visualization of T cell trafficking in vivo could map their biodistribution, accumulation at the tumor site or other tissues, expansion, contraction and persistence in real time and in the whole body. Furthermore, we have no good tools available to augment the tumor-directed T cells’ killing capacity in case of imminent treatment failure.
We have developed a DOTA-antibody reporter that binds to a clinically employed radiometal complex (DOTA), and we are exploring this tool for tracking transfused T cells to determine their location and study their functionality. In the event of imminent treatment failure, we aim to exploit these engineered T cells to deliver a deadly payload to the tumor with the goal of improving the anti-tumor efficacy of CAR and TCR T cell therapy. By combining tumor-directed T cells with molecular imaging and targeted radionuclide therapy, we can potentially equip these “living” drugs with novel attributes to significantly increase their therapeutic potency and safety.
This interdisciplinary project leverages the expertise of the Scheinberg, Larson, and Krebs laboratories, with support from colleagues in Medical Physics and Pathology.