UniCAR T cell theranostics for diagnostic imaging and therapy of prostate cancer

CAR T-cell therapy achieved unparalleled clinical success rates for treatment of patients with hematological
malignancies. However, progress and clinical translation towards solid tumors is slow and hampered by many
factors e.g. increased complexity, high heterogeneity and an immunosuppressive tumor microenvironment.
Thus, CAR T-cell therapy alone might not result in durable antitumor responses. Combinatorial approaches are
promising strategies to improve CAR T-cell efficacy in solid tumor treatment. In this regard, we here aim to
combine conventional cancer theranostics with CAR T-cell immunotherapy in one single approach.

By using the well-established UniCAR system, a novel, multifunctional tool termed PSCA-IgG4 target module
(TM) was developed for dual prostate cancer theranostics. It comprises a human PSCA-specific binding
domain, the hinge and Fc-domain of human IgG4 molecules as well as the UniCAR epitope E5B9. As shown by
in vitro assays with PSCA-positive and PSCA-negative prostate cancer cells, the novel TM redirected UniCAR T
cells for efficient tumor cell lysis in a strictly antigen- and TM-dependent manner. After radiolabeling with
copper-64 or actinium-225, the novel PSCA-IgG4 TM was successfully applied for diagnostic imaging and
targeted radioimmunotherapy. The 64Cu-labeled PSCA-IgG4 TM showed maximal tumor accumulation with
optimal tumor-to-background ratios after 1.5 days. Furthermore, targeted alpha-therapy with the 225Aclabeled
TM significantly delayed the outgrowth of established tumors in mice.

In summary, the here presented, novel PSCA-IgG4 TM is a promising candidate for dual theranostics of
prostate cancer that may help to overcome present hurdles in solid tumor therapy. After radiolabeling it
facilitates not only targeted alpha-therapy and diagnostic imaging of PSCA, but can be also repurposed as a
TM for UniCAR T-cell immunotherapy.