Uni-Tübingen

P10: Tailoring cGMP signals to improve therapeutic efficacy of cellular immunotherapies (from 01.01.2024)

Aims

Dissecting the role of cGMP signaling and cGMP-modulating drugs for CAR T cell therapy to identify novel therapeutic strategies in cancer.

Questions and Methods

cGMP and CAR T cell therapy

  • Analysis of cGMP signaling components in T cells and CAR T cells without and after co-culture with leukemia and solid tumors: Determine expression in different T cell subsets that are important for therapeutic efficacy and in different CAR constructs.
  • FRET-based cGMP imaging in CAR T cells. Analyse responses in different CAR constructs to diverse stimuli including different antigen densities on leukemia and solid tumor cells. Correlate responses to functional and phenotypic CAR T cell characteristics.
  • Gene editing/ engineering to modify cGMP signaling in CAR T cells and subsequent in vitro and in vivo analysis, including cytotoxicity, proliferation, cytokine/ chemokine and transcriptional profiles, T cell activation, phenotype and exhaustion.
  • Determine impact of cGMP-modulating drugs on CAR T cells in combined treatment approaches against leukemia and solid tumors: Evaluate effect of cGMP-modulating drugs on CAR T cell function and phenotype.
  • Evaluate combined treatment of selected cGMP-modulating drugs and CAR T cells in vitro and in vivo. Effect on tumor microenvironment i.e., vascularization, tumor growth, metastasis and CAR T cell infiltration in murine melanoma and lung cancer models.

Boston Internship

Fukumura Lab

In the Fukumura lab in Boston, the doctoral researchers will be trained in cancer biology, in animal models of breast cancer and glioblastoma as well as in state-of-the art techniques to analyze the tumor microenvironment and vascularization. 

Boston Co-mentor

Assoc. Prof. Dai Fukumura MD, PhD

link to Boston researcher lab

Doctoral Students

t.b.a.

Key Publications

Jain N, Zhao Z, Feucht J, Koche R, Iyer A, Dobrin A, Mansilla-Soto J, Yang J, Zhan Y, Lopez M, Gunset G, Sadelain M. 2023. TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature 10.1038/s41586-022-05692-z

Odak A, Yuan H, Feucht J, Cantu VA, Mansilla-Soto J, Kogel F, Eyquem J, Everett JK, Bushman FD, Leslie C, Sadelain M. 2023. Novel extragenic genomic safe harbors for precise therapeutic T cell engineering. Blood 10.1182/blood.2022018924

Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, Mansilla-Soto J, Boyer JA, Li X, Giavridis T, Kulick A, Houlihan S, Peerschke E, Friedman SL, Ponomarev V, Piersigilli A, Sadelain M, Lowe SW. 2020. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583:127-32. doi:10.1038/s41586-020-2403-9

Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, Dobrin A, Cabriolu A, Hamieh M, Sadelain M. 2019. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med 25:82-8. doi:10.1038/s41591-018-0290-5

Mansilla-Soto J, Eyquem J, Haubner S, Hamieh M, Feucht J, Paillon N, Zucchetti AE, Li Z, Sjostrand M, Lindenbergh PL, Saetersmoen M, Dobrin A, Maurin M, Iyer A, Garcia Angus A, Miele MM, Zhao Z, Giavridis T, van der Stegen SJC, Tamzalit F, Riviere I, Huse M, Hendrickson RC, Hivroz C, Sadelain M. 2022. HLA-independent T cell receptors for targeting tumors with low antigen density. Nat Med 28:345-52. doi:10.1038/s41591-021-01621-1

Feucht J, Sadelain M. 2020. Function and evolution of the prototypic CD28zeta and 4-1BBzeta chimeric antigen receptors. Immunooncol Technol 8:2-11. doi:10.1016/j.iotech.2020.09.001