Immunotherapy with T cells engineered to recognize cancer cells via chimeric antigen receptors (CARs) has shown impressive clinical efficacy against leukemias. In solid tumors, lack of adequate target antigens and barriers in the tumor microenvironment together impede the action of CAR T cell therapeutics.
We aim to develop effective combinatorial strategies to enhance the potency of CAR T cells against various pediatric solid tumors.
In an advanced project now close to clinical investigation, T cells are engineered to express a CAR with integrated secretion of IL-18, a strong functional enhancer of T cell functions and modulator of the myeloid tumor cell compartment, for local delivery to the tumor site. Whereas our lead candidate is directed against the surface ganglioside GD2, expressed in most neuroblastomas and some osteosarcomas and Ewing sarcomas, future IL-18 enhanced CAR T cells will have additional antigen recognition domains to extend the spectrum of targetable pediatric cancers.
Novel one-vector engineering strategies endow CAR T cells with additional therapeutic modes of action, for synergistic effects within the tumor niche and elimination of tumor cells also with low target expression.
Overall, we stride to translate novel CAR T cell therapies in academic pediatric clinical studies across Europe. Academic manufacturing of engineered T cell products with decentralized supply will be a key to success.
Fischer-Riepe L*, Kailayangiri S*, Zimmermann K*, Pfeifer R*, Aigner M*, Altvater B, Kretschmann S, Völkl S, Hartley J, Dreger C, Petry K, Bosio A, von Döllen A, Hartmann W, Lode H, Görlich D, Mackensen A*, Jungblut M*, Schambach A*, Abken H*, Rossig C*. *Have contributed equally. Preclinical development of CAR T cells with antigen-inducible IL-18 enforcement to treat GD2-positive solid cancers. Clin Cancer Res, accepted for publication. (IF 13.801)
Rossig C, Pearson AD, Vassal G, Scobie N, Bird N, Blanc P, Vormoor HJ, Calkoen FG, Locatelli F, del Bufalo F, Rives S, Jacoby E, Balduzzi A, Bourquin JP, Baruchel A. CAR T cell products for pediatric cancers: Why alternative development paths are needed. J Clin Oncol. 2024 Jan 20;42(3):253-257. doi: 10.1200/JCO.23.01314 (IF 45.3)
Altvater B*, Kailayangiri S*, Spurny C, Flügge M, Meltzer J, Greune L, Urban K, Schwöppe, C, Brand C, Schliemann C, Hintelmann H, Harrach S, Hartmann W, Abken H, Kuehle J, Schambach A, Görlich G, Berdel WE*, Rossig C* (* contributed equally). CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process. Cancer Gene Ther 2023, https://doi.org/10.1038/s41417-023-00642-x (IF 5.854)
Meissner, R., Wixler, V., Wulfert, F.P., Jacob, J.C., Hale, B.G., Robeck, T., Masemann, D., Boergeling, Y., and Ludwig, S. (2023). Replication-incompetent influenza A viruses armed with IFN-γ effectively mediate immune modulation and tumor destruction in mice harboring lung cancer. Mol Ther Oncolytics 31, 100741. 10.1016/j.omto.2023.100741.
Pearson ADJ*, Rossig C*, Mackall C*, Shah NN*, Baruchel A*, et al. *Joint first authors. Paediatric Strategy Forum for Medicinal Product Development of CAR T-cells in children and adolescents with cancer. ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration. Eur J Cancer 2022 Jan;160:112-133 (IF 9.162)
Altvater B, Kailayangiri S, Pérez Lanuza LF, Urban K, Greune L, Flügge M, Meltzer J, Farwick N, König S, Görlich D, Hartmann W, Rossig C. HLA-G and HLA-E immune checkpoints are widely expressed in Ewing sarcoma but have limited functional impact on the effector functions of antigen-specific CAR T cells. Cancers 2021;13(12):2857 (IF 6.639)
Kailayangiri S, Altvater B, Lesch S, Balbach S, Göttlich C, Kühnemundt J, Mikesch JH, Schelhaas S, Jamitzky S, Meltzer J, Farwick N, Greune L, Fluegge M, Kerl K, Lode HN, Siebert N, Müller I, Walles H, Hartmann W, Rossig C. EZH2 inhibition in Ewing sarcoma upregulates GD2 expression for targeting with gene-modified T cells. Mol Ther 2019;27(5):933-946
Kailayangiri S, Altvater B, Spurny C, Jamitzky S, Schelhaas S, Jacobs AH, Wiek C, Roellecke K, Hanenberg H, Hartmann W, Wiendl H, Meltzer J, Farwick N, Greune L, Rossig C. Targeting Ewing sarcoma with activated and GD2-specific chimeric receptor-engineered human NK cells induces upregulation of immune-inhibitory HLA-G. Oncoimmunology 2016;6(1):e1250050 (IF 7.719)
