Recombinant, Truly Tumor-Specific, Very High-Affinity T Cell Receptor for Cancer Therapy

• Applicant: Dr. Boris Engels
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2007 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 49066289

T cell receptor (TCR)/peptide-major histocompatibility complex (p/MHC) interactions shape the TCR repertoire during thymic development: T cells with low affinity TCRs for self-p/MHC ligands are positively selected whereas T cells with high affinity TCRs for self-p/MHC are deleted (negative selection). The result is that most naturally occurring T cells have TCRs of micro-molar affinity for p/MHC ligands (usual KD range is about 1-30 μM). By genetic engineering however, extremely high-affinity TCRs of nano-molar affinity can be made. T cells engineered to express such TCRs may have extreme sensitivity for targets with low levels of p/MHC and may be better killers and cytokine producers under those conditions. In this proposal, I will determine whether such engineered very high-affinity TCRs have major advantages for (i) destroying cancer cells expressing only small amounts of the tumor-specific antigen (and thereby escaping destruction by natural T cells), (ii) generating high-avidity T cells to antigens to which natural TCRs have only very low affinity, and (iii) compensating for the loss of efficacy possibly associated with using TCR-transduced T cells instead of T cells expressing that TCR naturally. I will also determine potential serious disadvantages of using very high-affinity TCRs, i.e., whether T cells with such engineered TCRs cause serious or even lethal autoimmune reactions, because such T cells might recognize and destroy normal host tissues expressing the non-mutated self-antigens or the self-p/MHC ligands that led to the positive selection of T cells which carry the natural (wild-type) TCR. I will use the SIYRYYGL peptide as model of a tumor-specific mutant-self peptide in tumors expressing very low levels of that antigen. I will examine whether T cells expressing very high-affinity TCRs in adoptive transfer can localize to and eradicate large, long-established (>1cm diameter, >2 week-old) tumors; tumors that are histologically indistinguishable from human solid tumors and of a size detectable in patients by routine diagnostic techniques.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Hans Schreiber