| A03 |

Project Area A
Title

Targeting neoantigens in multiple myeloma by TCR-transgenic T cells

Research Area

Hematology, Oncology, Immunotherapy

Project Summary

Adoptive T cell therapy especially using T cells transgenic for chimeric antigen receptors (CAR) has shown high efficacy in hematological malignancies. This is in fact also true for multiple myeloma although response rates and duration are inferior compared to other diseases. Reasons are currently not well understood and could be associated to target, microenvironment or constructs currently used.

Adoptive transfer of T cells transgenic for T cell receptors (TCR) is not yet clinically approved although TCR may harbor advantages compared to CAR. In particular, T cells can specifically recognize aberrant tumor cells in the context of neoantigen presentation at very low antigen levels. We have previously developed a mass spectrometry-based approach for neoantigen identification and characterized neoantigen-specific TCR harboring diverse qualities with respect to functionality and longevity of neoantigen-specific T cells. In this project, we aim to investigate these TCR exemplarily in the context of myeloma. TCR will be transferred into effector T cells by retroviral gene transfer and CRISPR-based orthotopic TCR replacement (OTR) and investigated with respect to functional analyses and transcriptional profiles after coincubation with myeloma cells in vitro and in vivo. T cells modified by neoantigen-specific TCR will be compared with myeloma-specific CAR focusing especially on the role of antigen sensing. Moreover, the impact of disease-specific therapeutics with known immune-modulatory effects will be investigated in combination with TCR- or CAR-transgenic T cells regarding functionality and transcriptional profiles aiming to optimize constructs and define optimal combinatorial strategies. In parallel, novel neoantigen-specific TCR with primary reactivity against myeloma-derived neoantigens will be isolated and investigated based on our well established neoantigen identification pipeline. Taken together, we will thereby provide novel strategies to target multiple myeloma by neoantigen-specific TCR-transgenic T cells and prospectively plan to deliver TCR-engineered T cells to patients with relapsed/refractory multiple myeloma.
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Project-Related Publications

Albers, J.J., Ammon, T., Gosmann, D., Audehm, S., Thoene, S., Winter, C., Secci, R., Wolf, A., Stelzl, A., Steiger, K., Ruland, J., Bassermann, F., Kupatt, C., Anton, M., and Krackhardt, A.M. (2019). Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection. Life Sci Alliance 2.

Audehm, S., Glaser, M., Pecoraro, M., Braunlein, E., Mall, S., Klar, R., Effenberger, M., Albers, J., Bianchi, H.O., Peper, J., Yusufi, N., Busch, D.H., Stevanovic, S., Mann, M., Antes, I., and Krackhardt, A.M. (2019). Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer. Frontiers in immunology 10, 1485.

Bassani-Sternberg, M., Braunlein, E., Klar, R., Engleitner, T., Sinitcyn, P., Audehm, S., Straub, M., Weber, J., Slotta- Huspenina, J., Specht, K., Martignoni, M.E., Werner, A., Hein, R., D, H.B., Peschel, C., Rad, R., Cox, J., Mann, M.*, and Krackhardt, A.M.* (2016). Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nat Commun 7, 13404.

Hoffmann, T., Krackhardt, A.M., and Antes, I. (2015). Quantitative Analysis of the Association Angle between T-cell Re- ceptor Valpha/Vbeta Domains Reveals Important Features for Epitope Recognition. PLoS Comput Biol 11, e1004244.

Klar, R., Schober, S., Rami, M., Mall, S., Merl, J., Hauck, S.M., Ueffing, M., Admon, A., Slotta-Huspenina, J., Schwaiger, M., Stevanovic, S., Oostendorp, R.A., Busch, D.H., Peschel, C., and Krackhardt, A.M. (2014). Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands on myeloid leukemia cells by TCR-transgenic T cells. Leukemia 28, 2355-2366.

Krackhardt, A.M., Anliker, B., Hildebrandt, M., Bachmann, M., Eichmuller, S.B., Nettelbeck, D.M., Renner, M., Uharek, L., Willimsky, G., Schmitt, M., Wels, W.S., and Schussler-Lenz, M. (2018). Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies-the German Cancer Consortium approach. Cancer immunology, immunotherapy
: CII 67, 513-523.

Mall, S., Yusufi, N., Wagner, R., Klar, R., Bianchi, H., Steiger, K., Straub, M., Audehm, S., Laitinen, I., Aichler, M., Peschel, C., Ziegler, S., Mustafa, M., Schwaiger, M., D’Alessandria, C., and Krackhardt, A.M. (2016). Immuno-PET Imaging of Engineered Human T Cells in Tumors. Cancer research.

Mayer, K.E., Mall, S., Yusufi, N., Gosmann, D., Steiger, K., Russelli, L., Bianchi, H.O., Audehm, S., Wagner, R., Braunlein, E., Stelzl, A., Bassermann, F., Weichert, W., Weber, W., Schwaiger, M., D’Alessandria, C., and Krackhardt, A.M. (2018). T-cell functionality testing is highly relevant to developing novel immuno-tracers monitoring T cells in the context of immunotherapies and revealed CD7 as an attractive target. Theranostics 8, 6070-6087.

Weber, J.S., D’Angelo, S.P., Minor, D., Hodi, F.S., Gutzmer, R., Neyns, B., Hoeller, C., Khushalani, N.I., Miller, W.H., Jr.,
Lao, C.D., Linette, G.P., Thomas, L., Lorigan, P., Grossmann, K.F., Hassel, J.C., Maio, M., Sznol, M., Ascierto, P.A., Mohr, P., Chmielowski, B., Bryce, A., Svane, I.M., Grob, J.J., Krackhardt, A.M., Horak, C., Lambert, A., Yang, A.S., and Larkin,
J. (2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet. Oncology.

Yusufi, N., Mall, S., Bianchi, H.O., Steiger, K., Reder, S., Klar, R., Audehm, S., Mustafa, M., Nekolla, S., Peschel, C., Schwaiger, M., Krackhardt, A.M.*, and D’Alessandria, C.* (2017). In-depth Characterization of a TCR-specific Tracer for Sensitive Detection of Tumor-directed Transgenic T Cells by Immuno-PET. Theranostics 7, 2402-2416.
* joined last authors

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