Kurzfassung

This project aims to improve cancer immunotherapy by combining adoptive innovative cellular therapeutics with targeted inhibition of tumor metabolism by systemic depletion of the amino acid arginine (Arg). We propose to target multiple myeloma (MM) and melanoma tumor cells by (i) T cells redirected with an optimized MDM2-specific TCR and (ii) a CAR-engineered variant of the human NK cell line NK-92 recognizing the ErbB2/HER2 antigens. Arg depletion will be induced in vivo by two...This project aims to improve cancer immunotherapy by combining adoptive innovative cellular therapeutics with targeted inhibition of tumor metabolism by systemic depletion of the amino acid arginine (Arg). We propose to target multiple myeloma (MM) and melanoma tumor cells by (i) T cells redirected with an optimized MDM2-specific TCR and (ii) a CAR-engineered variant of the human NK cell line NK-92 recognizing the ErbB2/HER2 antigens. Arg depletion will be induced in vivo by two pharmacologically optimized variants of the enzymes arginine deiminase (ADI-PEG20) or arginase (rec-Co2+huArgI), which are both in clinical development for various cancer entities. We will first characterize in vitro the influence of Arg depletion on the phenotype and function of TCR / CAR-redirected T and NK cells as well as the tumor cells. The combination of the T / NK cell-based tumor antigen-specific cellular immuno-therapeutics together with enzymatic Arg depletion will be studied in xenograft mouse tumor models. The potential synergistic effect of the combined immuno- metabolic approach could directly be translated into a clinical treatment protocol, since the Arg-depleting drug ADI-PEG20 is already in phase III clinical trials and ErbB2-specific NK CAR cells are available in GMP format.

Funding: location Mainz € 110.000, location Frankfurt € 40.000
 
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