Repurposing PSMA PET to Image CAR T Cell Immunotherapy

Take-Away Points

• ■ Major focus: Investigating prostate-specific membrane antigen (PSMA) as an imaging reporter gene for chimeric antigen receptor (CAR) T cell therapy in a mouse model of leukemia.

• ■ Key result: Engineering CAR T cells with a signaling-inactive mutant of PSMA allows serial PET imaging of cell trafficking and localization.

• ■ Impact: PSMA reporter gene and PET imaging provide a clinically translatable imaging method to monitor CAR T cell immunotherapy.

Immunotherapy with chimeric antigen receptor (CAR) T cells involves removing T lymphocytes from a patient, modifying these cells to express a tumor-selective antigen receptor, and infusing these cells back into the same patient. CAR T cell immunotherapy produces remarkable outcomes in some patients with hematologic cancers, with ongoing efforts to extend these benefits to solid tumors. CAR T cells also cause severe toxicities in subsets of patients. Mechanisms controlling success or failure of CAR T cell immunotherapy largely remain unknown, at least in part because investigators lack an approach to noninvasively monitor transferred T cells over time. Minn et al reported a clinically translatable imaging solution to quantitatively track distributions of CAR T cells. By leveraging ongoing development of PET radiotracers for prostate-specific membrane antigen (PSMA) focused on prostate cancer, this group modified T cells with a CAR for CD19, a marker for B lymphocytes, and human PSMA as an imaging reporter gene. Use of human PSMA reduces future risk of immunogenicity in patients. The research team also mutated PSMA to eliminate intracellular signaling, reducing possible interference with functions of CAR T cells. Using a mouse model of B cell acute lymphoblastic leukemia, imaging with fluorine 18 DCFPyL, a PET radiotracer for PSMA, detected as few as 2000 CAR T cells in a 50-μL volume. Imaging revealed trafficking of infused CAR T cells and time-dependent infiltration into metastatic tumors. Clinical trials and practice currently rely on repeated peripheral blood samples to assess numbers of CAR T cells as a marker for therapy. Notably, numbers of CAR T cells infiltrating tumors did not correlate with numbers of these cells in peripheral blood or bone marrow, suggesting PET imaging as a potentially more informative biomarker for treatment efficacy. The combination of human PSMA as a reporter gene and matched PET radiotracers already in late-stage clinical trials offers a highly promising, clinically translatable approach to image CAR T cell therapy in patients.

Highlighted Article

• Minn I, Huss DJ, Ahn HH, et al. Imaging CAR T cell therapy with PSMA-targeted positron emission tomography. Sci Adv2019; 5(7):eeaw5096. doi: 10.1126/sciadv.aaw5096.