Project Summary
A critical step in the success of adoptive cell transfer (ACT) T cell immunotherapy in solid cancers is achieving
trafficking and persistence of T cells at tumor sites, while avoiding toxicities due to T cell attack of off-target
tissues and organs. Non-invasive quantitative imaging would be a powerful tool to understand mechanisms of
action and failure of T cell immunotherapies, evaluate the impact of T cell modifications and delivery routes,
monitor off-target T cell accumulation, and stratify response to therapy on the basis of measures of T cell tumor
accumulation. This Bioengineering Research Grant project will pioneer non-invasive and quantitative tracking of
adoptive T cell cancer immunotherapy using magnetic particle imaging (MPI), a new molecular imaging modality
that enables non-invasive, unambiguous, and tomographic analysis of the whole-body distribution of
superparamagnetic iron oxide nanoparticles (SPIONs). Preliminary results demonstrate non-invasive
quantitative tracking of ACT T cells in solid intracranial tumors, synthesis of tracers with enhanced MPI sensitivity,
and current sensitivity of 5x103 T cells. The proposed work aims to improve sensitivity to 5x102 T cells and
demonstrate the accuracy of MPI in quantifying T cell biodistribution in mouse models of cancer. Modeling of
MPI physics by the PI demonstrates that tracers optimal for MPI must have uniform physical and magnetic
properties and low magnetocrystalline anisotropy, to enable fast dipole switching at large SPION diameters. The
PI has developed a new synthesis that yields defect-free SPIONs with uniform magnetic properties and low
magnetocrystalline anisotropy. The proposed work (Aim 1) will couple this new synthesis with modeling of MPI
physics and comprehensive physical and magnetic characterization to gain fundamental understanding of the
relation between SPION properties and MPI performance and to obtain SPIONs with superior sensitivity. Imaging
approaches to track T cells must not compromise their viability or function and T cells pose unique challenges
for nanoparticle labeling. The proposed work (Aim 2) will define an upper limit for labeling primary T cells with
MPI tracers without compromising viability or function using tracers that associate with T cells through charge
interactions. Preliminary studies demonstrate non-invasive tracking of T cell biodistribution in mice using MPI,
and that SPION-labeled T cells reach solid tumors after systemic administration in murine models. The proposed
work (Aim 3) will validate in vivo tracking of ACT T cell therapy using MPI against T cell counting using flow
cytometry and will evaluate dynamics of T cell accumulation in tumors longitudinally using MPI. The proposed
biomaterials-development research plan is enabled by the complementary expertise of the PI (SPIONs and MPI
physics) and Co-I (ACT T cell therapies) and access to state-of-the-art instrumentation to characterize SPION
MPI performance ex vivo and in vivo. Achieving the target sensitivity of 5x102 T cells will provide an order-of-
magnitude improvement in quantitative cell tracking sensitivity over other whole body quantitative imaging
technologies, establishing MPI as a powerful tool in the immunoimaging toolbox.