Tracking Adoptive T Cell Therapy Using Magnetic Particle Imaging

Abstract

Adoptive cellular therapy (ACT) is a potent strategy to boost the immune response against cancer. ACT is an effective treatment for blood cancers, such as leukemias and lymphomas, but faces challenges treating solid tumors and cancers in locations like the brain. A critical step for success of ACT immunotherapy is achieving efficient trafficking of T cells to solid tumors, and the non-invasive and quantitative tracking of adoptively transferred T cell biodistribution would accelerate its development.Here, we demonstrate the use of Magnetic Particle Imaging (MPI) to non-invasively track ACT T cells in vivo. Labeling T cells with the superparamagnetic iron oxide nanoparticle tracer ferucarbotran did not affect T cell viability, phenotype, or cytotoxic function in vitro. Following ACT, ferucarbotran-labeled T cells were detected and quantified using MPI ex vivo and in vivo, in a mouse model of invasive brain cancer. Proof-of-principle in vivo MPI demonstrated its capacity to detect labeled T cells in lungs and liver after intravenous administration and to monitor T cell localization in the brain after intraventricular administration. Ex vivo imaging using MPI and optical imaging suggests accumulation of systemically administered ferucarbotran-labeled T cells in the brain, where MPI signal from ferucarbotran tracers and fluorescently tagged T cells were observed. Ex vivo imaging also suggest differential accumulation of nanoparticles and viable T cells in other organs like the spleen and liver. These results support the use of MPI to track adoptively transferred T cells and accelerate the development of ACT treatments for brain tumors and other cancers. METHODSAnimals and cell lines: C57BL/6 wild type mice were obtained from Jackson Laboratory. Transgenic pmel specific DsRed C57BL/6 mice were obtained from breeding a DsRed transgenic mouse (B6.Cg-Tg(CAG-DsRed*MST)1Nagy/J) and a pmel transgenic mouse (B6.Cg-Thy1a/Cy Tg(TcraTcrb)8Rest/J) to obtain the DsRed pmel-specific mouse colony. The pmel-specific T cell receptor of these mice recognizes the gp100 antigen expressed by the studied murine glioblastoma cell line, and the DsRed fluorescence allows ex vivo identification of transferred T cells. The murine glioblastoma cell line KR158B-Luc was a kind gift from Tyler Jacks. 30

A Perspective on Cell Tracking with Magnetic Particle Imaging

“…In early MPI cell tracking, commercially available SPIONs used for MRI were evaluated, including ferucarbotran and ferumoxtyol. Ferucarbotran improved MPI characteristics ( 35 – 37 ), and it has been used in MPI studies of mice to detect mesenchymal stem cells ( 35 , 36 , 38 – 40 ), neural stem cells ( 40 ), neural progenitor cells ( 29 ), pancreatic islets ( 41 ), T-cells ( 42 ), and macrophages ( 25 , 37 , 43 ). Although widely used, ferucarbotran is no longer considered optimal for MPI because it has a bimodal size distribution, predominantly containing small cores ∼5 nm in diameter (70%) with a small fraction (30%) of multicore aggregates with an effective size of 24 nm ( 44 ).…”

Magnetic Nanostructures as Emerging Therapeutic Tools to Boost Anti-Tumour Immunity

“…In addition, this technique has demonstrated to be safe since it does not use ionizing radiation, and SPIO tracers break down in vivo and the released iron can be processed and metabolized by the body as iron cofactors (i.e., heme, iron–sulphur clusters, and simple iron ions). On this matter, Rivera-Rodriguez et al performed a proof-of-principle study, demonstrating the potential of MPI to track lymphocytes by labelling them ex-vivo with a commercially available MR tracer (ferucarbotran) [ 27 ]. The nanoparticles were taken-up by the T cells and localized at the cytosolic compartment, as confirmed by Prussian blue staining.…”

“…Among the magnetic class of materials, iron oxide-based nanoparticles are the only nanomaterials that have been approved by the Food and Drug Administration (FDA) for medical applications [ 26 ]. Magnetic nanomaterials are particular appealing for cancer immunotherapy due to their unique features, which include (i) the traceability of their signal by magnetic resonance imaging (MRI) or by magnetic particle imaging (MPI) techniques [ 27 ]; (ii) their exploitation as carriers to promote the accumulation and the efficient delivery of biotherapeutic compounds, such as genes and peptides, into a specific target cell or tissue; (iii) their ability to mediate the destruction of cancer cells through the production of a local thermo-ablative effect when exposed to an external alternating magnetic field, referred to as magnetic hyperthermia therapy (MHT) [ 25 , 26 , 27 , 28 ]; and (iv) their intrinsic immunomodulatory properties that can be harnessed to further promote or modulate the immune function.…”

A method for the efficient iron-labeling of patient-derived xenograft cells and cellular imaging validation

“…The signal strength detected is linearly proportional to the number of SPIONs, allowing for quantitation (19). Presently, MPI has been used as a cell tracking modality for immortalized cancer cell lines (20,21), stem cells (22–25), pancreatic islets (26), T-cells (27) and macrophages (28,29), however, no studies exist studying the growth of patient-derived xenografts labeled efficiently with an SPION in vivo .…”