CERSI Collaborators: Sridhar Nimmagadda, PhD
FDA Collaborators: Raj K. Puri, MD, PhD; Bharat Joshi, PhD; Carolyn Wilson, PhD
Project Start Date: June 2018
Regulatory Science Challenge
Lymphocytes (white blood cells) are a group of different types of immune cells that protect the body from infections and cancer. One type of lymphocytes, called T-cells, can be isolated from a patient’s body and modified ex vivo to improve their ability to recognize and kill that individual’s cancer cells. These modified T cells are called CAR-T (chimeric antigen receptor T) cells. When injected back into the body, CAR T-cells fight some forms of blood cancer that begin in blood-forming tissues, such as the bone marrow. But CAR-T cells could have serious and sometimes fatal side effects on some patients by causing the release of certain chemicals called cytokines and growth factors. The release of these chemicals may trigger a dangerous condition known as cytokine release syndrome (e.g., fever, headache, trouble breathing). CAR-T cell therapy could also have toxic effects on the neurological system, among other side effects. The cause of CAR-T cell side effects is not well understood, nor is it known about 1) how long CAR-T cells stay in contact with the tumor (persistence); 2) how CAR-T cells travel to other organs in the body (disposition); 3) the movement and distribution of CAR-T cells in the brain and other organs; and 4) the relation between CAR-T cell movement/disposition and their biological activity (proliferative activity, cell-killing activity, and potency).
Project Description & Goals
The aim of these ongoing JHU CERSI and FDA collaborative studies is to increase our understanding of the serious side effects that occur during CAR-T cell immunotherapy treatment of certain types of cancer. This study will address the issues stated above using noninvasive positron emission tomography and computerized tomography (PET/CT) to track, in real time, the movement of CAR-T cells in the body. To facilitate detection by PET/CT, the CAR-T cells are labeled with radioisotopes to make CAR-T cells detectable in tissues that accumulate them in high level. This is a non-invasive way to monitor the movement, persistence, and disposition of CAR-T cells within the body. We will conduct a two-phase study in a mouse model. In phase 1, we will develop and optimize protocols to radiolabel CAR-T cells and examine key quality attributes of the final radiolabeled CAR-T cells. The quality attributes examined will include identity, viability, proliferative activity, cell-killing activity, and potency of CAR-T cells. In phase 2, we will evaluate trafficking and persistence of radiolabeled CAR-T cells in the body and study its association with side effects. These imaging studies will be further validated by collecting and analyzing cells from tissues by flow cytometry. Flow cytometry is a technique used to detect and measure cellular properties based on surface markers expressed on cells. Collectively, these studies will provide insights into underlying mechanisms of efficacy and toxicity associated with CAR-T cell therapies.