Imaging of CAR T-Cells in Cancer Patients: Paving the Way to Treatment Monitoring and Outcome Prediction

Abstract

In 2013, the journal Science named cancer immunotherapy as the ‘‘breakthrough of the year’’ based on targeted approaches using chimeric antigen receptor (CAR) T-cells. CD19-specific CAR T-cell therapy has revolutionized the treatment landscape for patients with relapsed B-cell acute lymphocytic leukemia (1,2). Similar successes have not been seen in patients with solid tumors, in part because of inconsistent expression of specific tumor antigens and physical impediments to T-cell trafficking, for example, for passing the blood–brain barrier or reaching metastatic disease in bone marrow. Other factors interfering with prolonged response to CART-cell therapy include loss of target antigen and T-cell exhaustion. These resistance mechanisms may be alleviated by CARs targeting 2 or more tumor antigens (NCT03019055), more sophisticated T-cell engineering techniques, or combination therapies of CARs with various immune checkpoint inhibitors. So far, it has remained unclear why certain cell therapies succeed and even provide durable clinical responses (1,2) whereas others fail (3). Ideal monitoring of CAR T-cell therapies should include the ability to track T-cell migration, engagement with the antigenbearing tumor cells, as well as T-cell expansion and persistence at the tumor site—all essential steps for therapeutic efficacy. Imaging studies might perhaps also enable timely intervention to avoid potentially lethal systemic toxicity. Current clinical methods to monitor the infused cells include serum profiling of cytokines associated with T-cell activation, direct enumeration of tumorspecific T-cells in peripheral blood, and (repeated) tumor biopsies. Overall, the in vivo activation dynamics of engineered immune cells remain incompletely understood, as no means of real-time monitoring of the intratumoral milieu currently exists.