MagnetoGVAX: Using Nanotechnology and MRI for Cancer Vaccine Development

D. Kadayakkara, H.I. Levitsky, J.W.M. Bulte
Johns Hopkins University School of Medicine, US

Keywords: cancer nanotechnology

Summary:

Dendritic cell (DC) cancer vaccines have entered the clinic, with Provenge® now being one of the two cellular therapeutics ever approved by the FDA. By pre-labeling DCs with superparamagnetic iron oxide (SPIO) nanoparticles, it is not only possible to follow their migration to nearby lymph nodes, but also to verify if the injections have been performed accurately. Surprisingly, in a first clinical MRI cell tracking study between Johns Hopkins and the University of Nijmegen, it was shown that the target lymph node was misinjected in 50% of cases [1]. A different kind of cancer vaccine developed at Hopkins is GVAX, which consists of lethally irradiated tumor cells engineered to secrete GM-CSF [2]. It is currently in several clinical trials, for instance as adjuvant therapy in patients with surgically resected melanoma (ClinicalTrials.gov #NCT01435499), and has been licensed by multiple companies. Previously, by pre-labeling of GVAX with SPIO, we developed “magnetovaccination” as a novel MRI technique to monitor serially over time DC antigen capture and homing of cells to draining lymph nodes [3]. Using this approach, we recently investigated the composition of Toll-Like Receptor (TLR) agonists as immunoadjuvants for boosting the innate immune system, with the goal to study their possible roll-over effect on the adaptive (magnetoGVAX) immune response. We hypothesized that different combinatorial cancer vaccine formulations differ in their ability to recruit antigen-specific DCs (the afferent arm of the immune response) and in their ability to prime cognate cytotoxic T cells (efferent arm), and that the timing of adjuvant administration is of critical importance. Most of our current knowledge on the effects of adjuvants is based on post-mortem histology and FACS analysis that cannot be used to monitor the time course and efficacy of these processes. Using magnetoGVAX and MRI to serially monitor the afferent arm, and bioluminescent imaging (BLI) of luciferase-expressing, antigen-specific transgenic T cells for imaging of the efferent arm within the same animal over time, we encountered some surprises. Depending on the timing of administration, TLR agonists were found to reduce antigen capture and delivery to the lymph nodes. However, they induced a potent immune response and better tumor-therapeutic effect. The lack of antigen delivery to lymph nodes was consistent with the lack of T cell BLI signal in the lymph nodes. In those cases, a massive extranodal T cell proliferation occurred in the liver and spleen. Our studies show how nanotechnology and imaging can be used to develop cancer vaccines and discover novel mechanisms of T cell priming and activation in the presence of TLR agonist adjuvants. [1] de Vries IJ, Lesterhuis WJ, Barentsz JO, Verdijk P, van Krieken JH, Boerman OC, et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol. 2005;23:1407-13. [2] Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993;90:3539-43. [3] Long CM, van Laarhoven HW, Bulte JW, Levitsky HI. Magnetovaccination as a novel method to assess and quantify dendritic cell tumor antigen capture and delivery to lymph nodes. Cancer Res. 2009;69:3180-7. ''