Exploring the potential to restore cellular homeostasis in clonal hematopoiesis and immunity
Cell Biology
Final Report Abstract
The relevance of immune aging is increasing dramatically in light of global demographic changes: worldwide, the proportion of older individuals with compromised immune function is rising, leading to greater susceptibility to infectious diseases, reduced vaccine efficacy, and higher cancer incidence. The COVID-19 pandemic has underscored this vulnerability with particular clarity. Therapeutic strategies that restore the function of the aging immune system therefore hold not only medical but also societal and health-economic potential. My scientific interest is thus focused on developing an approach for organ-specific, transient immunomodulation in humans as a practicable foundation for future preventive or adjunct therapies targeting age-related immune decline. During my DFG Walter Benjamin Fellowship at the Broad Institute in Cambridge, MA, USA, my originally proposed research project aimed to rejuvenate T cells via in vivo induction of the four reprogramming factors OCT4, SOX2, KLF4, and c-MYC (OSKM). Despite intensive efforts, this approach proved unfeasible, primarily due to safety concerns related to the oncogenic potential of some OSKM components (particularly c-MYC), as well as the lack of feasible strategies for specific in vivo expression in T cells. Consequently, a shift in scientific approach was necessary to achieve the aforementioned objective. Instead, we developed an alternative strategy to restore the function of aged T cell responses through the synthetic and transient expression of thymic signals in the liver. Our main publication (in revision; as well as filed patent application) describes a novel mRNA-based system that delivers DLL1, FLT3-ligand, and IL-7 into hepatocytes using lipid nanoparticles. This liver-engineering strategy led to a significant improvement in vaccine responsiveness and tumor immunity in aged mice without observable side effects. In addition to this central project, several successful side projects were realized during the funding period, including contributions to programmable bacterial injection systems, minimally immunogenic CRISPR nucleases for gene therapy, and immune responses in the context of CAR T cell therapy and bispecific antibody therapy.
Publications
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Programmable protein delivery with a bacterial contractile injection system. Nature, 616(7956), 357-364.
Kreitz, Joseph; Friedrich, Mirco J.; Guru, Akash; Lash, Blake; Saito, Makoto; Macrae, Rhiannon K. & Zhang, Feng
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The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell, 41(4), 711-725.e6.
Friedrich, Mirco J.; Neri, Paola; Kehl, Niklas; Michel, Julius; Steiger, Simon; Kilian, Michael; Leblay, Noémie; Maity, Ranjan; Sankowski, Roman; Lee, Holly; Barakat, Elie; Ahn, Sungwoo; Weinhold, Niels; Rippe, Karsten; Bunse, Lukas; Platten, Michael; Goldschmidt, Hartmut; Müller-Tidow, Carsten; Raab, Marc-Steffen & Bahlis, Nizar J.
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The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance. Science Immunology, 9(95).
Kilian, Michael; Friedrich, Mirco J.; Lu, Kevin Hai-Ning; Vonhören, David; Jansky, Selina; Michel, Julius; Keib, Anna; Stange, Saskia; Hackert, Nicolaj; Kehl, Niklas; Hahn, Markus; Habel, Antje; Jung, Stefanie; Jähne, Kristine; Sahm, Felix; Betge, Johannes; Cerwenka, Adelheid; Westermann, Frank; Dreger, Peter ... & Platten, Michael
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Rational engineering of minimally immunogenic nucleases for gene therapy. Nature Communications, 16(1).
Raghavan, Rumya; Friedrich, Mirco J.; King, Indigo; Chau-Duy-Tam Vo, Samuel; Strebinger, Daniel; Lash, Blake; Kilian, Michael; Platten, Michael; Macrae, Rhiannon K.; Song, Yifan; Nivon, Lucas & Zhang, Feng
