First, in collaboration with the laboratories of Dr. Jamey Weichert (UW-Radiological Sciences, Bioimaging and Pharmaceutics) and Dr. Fotis Asimakopoulos (UW-Medical Oncology, Multiple Myeloma program) our lab is investigating the tumor-targeting, anti-cancer properties of the novel phospholipid ether CLR1404, a molecule developed at UW-Madison and the University of Michigan. In radioiodinated variants, the highly tumor selective CLR1404 molecule is in clinical trials at UW for PET/CT imaging and radiotherapy for certain solid malignancies. CLR1404 has shown to be strongly tumoricidal in doses higher than used for imaging purposes, which is in part attributed to strong AKT inhibition and subsequent induction of robust apoptosis. Therefore, we are evaluating this compound in malignancies that are strongly driven by this particular pathway which includes the pediatric solid tumor neuroblastoma and other pediatric tumors which have an urgent need for better treatment options.
Second, we seek to develop adoptive cellular cancer therapies specifically using gd T cells.
gd T cells also have potent anti-leukemic and anti-tumor effects and appear to play a crucial role in cancer immunosurveillance. gd T cells are not alloreactive, and facilitate engraftment after transplantation in rodent models without causing GVHD. We have previously developed methods to clinically –scale enrich human gd T cells and shown that a combination with other immunostimulatory agents can significantly prolong survival in rodent models of disseminated neuroblastoma. Our lab is now investigating further strategies to increase the cytotoxic effect of ex vivo expanded gd T cells. E.g. we are evaluating the role of killer cell inhibitory receptors (KIR) and certain stimulating agents in the context of gd T cell mediated immunotherapies to increase natural and antibody-dependent cytotoxicity (ADCC).
Third, we design and test tumor-specific iron-oxide nanoparticles as diapeutic anti-cancer agents. Nanomedicine, the science and technology of diagnosing, treating and preventing disease using nano-sized particles is rapidly evolving, especially in the area of cancer and offers a new dimension and novel therapeutic opportunities for targeted cancer treatments.
I have a broad scientific background in the development of cellular and antibody-based immunotherapies for cancer. As a postdoctoral research fellow in the division of stem cell transplantation at St. Jude Children’s Research Hospital, my collaborators and I developed methods to clinical-scale enrich human Natural Killer (NK) and γδ T cells, which are potent immune effector cells capable of killing tumor cells, on a clinical scale. In published work in a rodent xenograft model of disseminated neuroblastoma we have shown that cellular therapy with these cells leads to a significant survival benefit, especially when combined with an anti-GD2 antibody (hu14.18) and supporting cytokines. We could also show that a variant GD2 antibody, hu14.18K322A, induces potent antibody-dependent cytotoxicity (ADCC) with much decreased complement-dependent cytotoxicity (CDC). We have also shown that complement activation seems to be responsible for antibody-elicited pain in a rat model and that hu14.18K322A can significantly reduce allodynia.
I am a co-investigator in a phase I study with this new antibody at St. Jude, and our results confirm that several fold higher doses of this antibody can be given safely and without significant allodynia experienced by the patients. Therefore, it is only logical that we explore this antibody in the context of nano-oncology. I have previously co-developed paclitaxel-delivering gold nanoparticles conjugated to an anti-GD2 antibody targeting neuroblastoma cells. The particles demonstrated their specificity for GD2-expressing tumors, drive tumor cells to the G2/M phase of the cell cycle, and thus making them highly vulnerable to radiation-induced cell death in vitro. We are now evaluating superparamagnetic nanoparticles conjugated to an anti-GD2 antibody in vitro and in vivo for simultaneous tumor imaging, immunotherapy, drug or small molecule delivery and other theranostic applications such as hyperthermia.
Our goal in all of this work is to: a) test novel targeted therapies in vitro and in animal models, b) elucidate their biological and molecular mode of action in vitro, c) further develop how to improve their efficacy without increasing toxicity, d) translate these concepts into clinical trials and assess safety, potential toxicity and ultimately their efficacy as anti-cancer treatments.