Sunday, March 16, 2025
3/16/2025
SUMMARY Chimeric antigen receptor (CAR) T cell therapies represent a major advancement in the cancer immunotherapy (IOT) field and have shown remarkable success particularly for treating hematologic malignancies. Despite their meteoric rise, these “living drugs” face a number of challenges that have limited their widespread utility (especially for solid tumors), including the inability to discern cell fate after infusion. Growing investment in developing new CAR T cell therapies and the desire to optimize existing ones highlights the urgent unmet need for techniques that permit non-invasive, longitudinal monitoring of CAR T cell fate. An imaging method that enables sensitive detection of activated T cells, including CAR T cells, in vivo has the potential to reveal mechanisms underlying failures, thus enhancing our ability to design and optimize IOTs. Immuno-positron emission tomography (immunoPET), a rapidly expanding area of molecular imaging that combines ultra-specific antibodies or antibody fragments with PET radioisotopes, has enormous potential to shed light on the in vivo spatiotemporal distribution and functional status of CAR T cells. Unfortunately, there are no clinically approved gold-standard immunoPET radiotracers, or other imaging techniques, that target T cell activation markers. Recently, we identified OX40 and ICOS (two cell-surface antigens that are highly and specifically upregulated on activated T cells) as promising biomarkers for imaging T cell responses. Subsequently, we developed the first PET radio tracer s to image murine OX40 and ICOS by radiolabeling monoclonal antibodies (mAbs) with 64Cu or 89Zr and demonstrated their utility for quantifying and tracking activated T cells in a variety of cancer IOT models. We also verified that both OX40 and ICOS are significantly upregulated on activated human and murine CD19- CAR T cells, and that ICOS immunoPET enables visualization of the latter in vivo. In this R01, we propose to build on our promising preclinical data by developing the first human-specific radiotracers for OX40 and ICOS, utilizing mAbs and F(ab’)2 fragments. We have performed preliminary 89Zr- radiolabeling of human-OX40 and - ICOS mAbs and demonstrated their specificity for human activated T cells. Additionally, we have acquired highly encouraging in vivo imaging and stability data for our novel human OX40-mAb radiotracer. Aim 1 involves optimizing radiolabeling for ICOS and OX40 mAbs, generating and labeling F(ab’)2 fragments, in addition to thoroughly assessing stability, affinity, and immunoreactivity of all four new radiotracers. We will then investigate potential biological effects and in vivo binding of these radiotracers to activated human T cells (Aim 2) and to CAR T cells, the latter engineered to target liquid and solid tumors (Aim 3). Finally, we will assess the safety of these radiotracers for CAR T cell imaging (Aim 3). Completing these experiments will provide invaluable data on the sensitivity and specificity, as well potential biologic effects, of all four imaging agents, guiding their optimization for our long-term goal of clinical translation. Such OX40 and ICOS PET radiotracers will afford a new approach for monitoring CAR T cells and other IOTs with great potential to increase their clinical success.
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