Disease specific engineering of CAR T cells utilizing chemokine receptors

Research Area

205-14 Hämatologie, Onkologie, Transfusionsmedizin (Hematology, Oncology, Transfusion Medicine)

Project Summary

CAR-based T cell therapies have been approved for treatment of acute lymphoblastic leukemia (ALL) and aggressive B-cell lymphoma. The translation of the success of CD19-directed CAR T cells in B-cell malignancies to other hematological as well as solid malignancies has been hampered by the lack of suitable target antigens and by limited specific homing to the tumor site. The challenge is to improve CAR T cell specificity and trafficking simultaneously.

We previously showed that T cell efficacy can be enabled by engineering T cells to express receptors to chemokines released by cancer cells. The aim of the project is to design CAR T cells equipped with tumor-associated CAR and disease related chemokine receptors. As pilot indication we will focus within the solid tumors on colon cancer and within the hematological entities on acute myeloid leukemia (AML). We will identify, characterize and test disease-specific chemokine receptors for each entity. Chemokine-modified CAR T cells will be generated, characterized and functionally analyzed using mouse models and primary in vivo cultures of human samples. We aim to define disease-specific chemokine receptors to enhance efficacy of CAR T cell therapy in various disease entities. Our long-term goal is to initiate first-in-human clinical trials utilizing chemokine receptor modified CAR T cells for adoptive transfer in a broad range of different disease entities.

Project-Related Publications

Haubner, S., Perna, F., Köhnke, T., Schmidt, C., Berman, S., Augsberger, C., Schnorfeil, F.M., Krupka, C., Lichtenegger, F.S., Liu, X., Kerbs, P. Schneider, S., Metzeler, K. H., Spiekermann, K., Hiddemann, W., Greif, P. A., Herold, T., Sadelain, M., and Subklewe, M. (2019). Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML. Leukemia 33, 64–74.

Karches, C.H., Benmebarek, M.R., Schmidbauer, M.L., Kurzay, M., Klaus, R., Geiger, M., Rataj, F., Cadilha, B.L., Lesch, S., Heise, C., Murr, R., vom Berg, J., Jastroch, M., Lamp, D., Duewell, P., Niederfellner, G., Sustmann, C., Endres, S., Klein, C., and Kobold, S. (2019). Bispecific antibodies enable synthetic agonisti receptor-transduced T cells for tumor immunotherapy. Clin. Cancer Res. 25, 5890–5900.

Herrmann, M., Krupka, C., Deiser, K., Brauchle, B., Marcinek, A., Ogrinc Wagner, A., Rataj, F., Mocikat, R., Metzeler, K.H., Spiekermann, K., Kobold, S., Fenn, N.C., Hopfner, K.P., and Subklewe M. (2018). Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia. Blood 132, 2484–2494.

Rataj, F., Kraus, F.B.T., Chaloupka, M., Grassmann, S., Heise, C., Cadilha, B.L., Duewell, P., Endres, S., and Kobold, S. (2018). PD1-CD28 Fusion Protein Enables CD4+ T Cell Help for Adoptive T Cell Therapy in Models of Pancreatic Cancer and Non-hodgkin Lymphoma. Front. Immunol. 9, 1955.

Lichtenegger, F.S., Krupka, C., Haubner, S., Köhnke, T., and Subklewe, M. (2017). Recent developments in immunother- apy of acute myeloid leukemia. J. Hematol. Oncol. 10, 142.

Rapp, M., Grassmann, S., Chaloupka, M., Layritz, P., Kruger, S., Ormanns, S., Rataj, F., Janssen, K.-P., Endres, S., Anz, D., Kobold, S. (2016). C-C chemokine receptor type-4 transduction of T cells enhances interaction with dendritic cells, tumor infiltration and therapeutic efficacy of adoptive T cell transfer. Oncoimmunology 5, e1105428.

Kobold, S., Steffen, J., Chaloupka, M., Grassmann, S., Henkel, J., Castoldi, R., Zeng, Y., Chmielewski, M., Schmollinger, J.C., Schnurr, M., Rothenfußer, S., Sustmann, C., Niederfellner, G., Klein, C., Bourquin, C., and Endres, S. (2015a). Se- lective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer. J. Natl. Cancer Inst. 107, 364.

Kobold, S., Grassmann, S., Chaloupka, M., Lampert, C., Wenk, S., Kraus, F., Rapp, M., Düwell, P., Zeng, Y., Schmollinger, J.C., Schnurr, M., Endres, S., and Rothenfußer, S. (2015b). Impact of a New Fusion Receptor on PD-1- Mediated Immunosuppression in Adoptive T Cell Therapy. J. Natl. Cancer Inst. 107, 146.