Current chemotherapeutic approaches for cancer therapy have predominantly focused on intracellular molecular targets that contribute or maintain tumorgenicity, proliferation or survival. Due to the heterogeneity of cellular dependences on signaling pathways and the potential development of drug resistance, there is an emerging recognition that future cancer therapy will require individualized drug combinations to produce long term remission. In addition, to truly address metastasis and relapse, methods of targeting quiescent tumor initiating cancer stem cells (CSC) , which are resistant to chemotherapy and radiation, is of critical importance. Consequently, new methods that can target both primary tumor cells and  CSC are needed. Our group has developed a unique protein based approach for the preparation of multispecific chemically self-assembled nanorings (CSANs). Recently, we have prepared anti-EpCAM/anti-CD3 CSANs, which target triple negative cancer (TNBC) primary tumor cells, and anti-CD133/anti-CD3-CSANs, which target TNBC cancer stem cells. The bispecific CSANs rapidly (min) and stably (days) bind to CD3 on T-cell membranes, thus forming chemically self-assembled prosthetic antigen receptor (PAR) T-cells. Upon incubation of CD133+ or EpCAM+ TNBC cells with the CSANs rapid and selective cell killing was observed. We have also demonstrated with an orthotopic murine cancer model that anti-EpCAM and anti–CD133 CSANs are non-toxic and able to cause T-cell induced eradication of TNBC primary tumor and CSC <i>in vivo</i>.  A unique safety feature of our approach is the ability to remove the CSANs from the T-cells by dosing with an FDA-approved non-toxic antibiotic at clinically relevant concentrations, thus allowing us to deactivate the cells pharmacologically and reduce cytokine release. Taken together, our results demonstrate that CSAN modified T-cells can be deployed as a potential novel immunotherapy for the eradication of both primary tumor cells and CSCs.  (NCI-CA185627)<br/>

Using the power of protein based nanotechnology based immunotherapy to target cancer

256th National Meeting (2018)

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