? Like antibodies, T cell antigen receptors (TCRs) recognize a huge diversity of molecular targets. The range of cancer related targets that T cells can recognize is even greater than what antibodies recognize, because intracellular proteins, such as transcription factors and other proteins that are modified in cancer, are processed and presented on the cell surface as peptide/MHC complexes that T cells recognize, whereas antibodies recognize only proteins that function on the cell surface. In addition, T cells have properties of active mobility that allow them to penetrate the blood brain barrier and migrate through solid tumors that antibodies will not readily penetrate. Phase I will test two ideas: (1) because iron strongly alters MRI signals, a clonal population of T cells loaded with iron nanoparticles can be used as an imaging agent in cancer, particularly brain tumors. Only tumor cells expressing a particular tumor associated peptide will be identified by the T cells. (2) Certain iron nanoparticles generate intense heat when exposed to alternating magnetic fields; this property can be used therapeutically. """"""""Suicide bomber"""""""" T cells loaded with iron nanoparticles will specifically bind to tumor cells. Once their presence in the tumor is confirmed by MRI, alternating magnetic fields can be applied to produce damage in the surrounding cells, generating heat shock proteins and tumor antigens that will instigate a stronger immune response. Phase II tests two ideas: (1) the immune response generated by heating intratumor iron will be greatly enhanced if combined with danger signals, such as CpG oligonucleotides, that increase antigen presentation in lymph nodes. (2) Both of these uses of iron loaded T cells, imaging and therapy, will be enhanced by transfecting T cells with genetically engineered T cell receptors with higher affinity for tumor associated epitopes. High affinity T cell receptors for a model tumor antigen have been generated by yeast display technology, and experiments will determine if these high affinity T cell receptors enhance the imaging and therapeutic potential of iron loaded T cells. ? ?
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