Translational Cell Therapy
© Susanne Dürr
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Since the first bone marrow transplantation, adoptive T cell therapy (ACT) has developed over the last 80 years to a highly efficient and specific therapy for infections and cancer. Genetic engineering of T cells with antigen-specific receptors now provides the possibility of generating highly defined and efficacious T cell products. The high sensitivity of engineered T cells towards their targets, however, also bears the risk of severe off-target toxicities. Therefore, different safety strategies for engineered T cells have been developed that enable removal of the transferred cells in case of adverse events, control of T cell activity or improvement of target selectivity. Receptor avidity is a crucial component in the balance between safety and efficacy of T cell products. In clinical trials, T cells equipped with high avidity T cell receptor (TCR)/chimeric antigen receptor (CAR) have been mostly used so far because of their faster and better response to antigen recognition. However, over-activation can trigger T cell exhaustion/death as well as side effects due to excessive cytokine production. Low avidity T cells, on the other hand, are less susceptible to over-activation and could possess better selectivity in case of tumor antigens shared with healthy tissues, but complete tumor eradication may not be guaranteed. In this review we describe how 'optimal' TCR/CAR affinity can increase the safety/efficacy balance of engineered T cells, and discuss simultaneous or sequential infusion of high and low avidity receptors as further options for efficacious but safe T cell therapy.
D'Ippolito, E.et al: T cell engineering for adoptive T cell therapy: safety and receptor avidity.(link is external)
Targeting of tumor neoantigens has emerged as the new frontier for a more efficient and safer adoptive T cell transfer (ACT), including TCR-based therapies. This increase in precision has been gained, however, at the expensive of a more generic therapy, as tumor neoantigens are extremely patient-specific. Only a small fraction of patients shares public neoantigens in similar HLA restrictions, for which treatments with “off-the-shelf” TCRs would still represent a valid option to pursue. For the remaining majority, functional and safe TCRs have to be de novo identified within a narrow temporal window after the mapping of patient-derived neoantigens, in order to manufacture autologous TCR-engineered T cells in time for therapy. By combining whole exome sequencing and DNA-barcoded pMHC multimer libraries, it is nowadays possible to rapidly get access to hundreds of candidate immunogenic neoantigens and cognate TCRs.
MHC multimer technology allows both identification and isolation of epitope-specific T cells. Especially with the help of the recently developed reversible MHC-multimer staining (Streptamers) it may be possible to purify and adoptively transfer epitope-specific T cell populations into recipients, a technique that would have broad clinical applications. We are pursuing the development of methods to efficiently purify tetramer-positive T cells and prepare them for adoptive transfer. Adoptive transfer of epitope-specific T cells will initially be tested in the murine Listeriosis model in order to address some basic experimental questions: Is it possible to transfer pathogen-specific protective immunity into naïve individuals by adoptive transfer of purified tetramer-positive, epitope-specific T cells? What are the minimal requirements (absolute number, epitope specificity, lineage, functional status) for effective adoptive transfer of protective immunity? Similar studies will be performed in other experimental models (e.g. chronic infections).