Project 2
Arming IPSC-derived NK cells with a CAR for treatment of AML
Prof. Dr. med. Marion Subklewe
Medizinische Klinik III, KUM
Prof. Dr. med. Michael von Bergwelt
Medizinische Klinik III, KUM
PD Dr. rer. nat. Thomas Nerreter
Medizinische Klinik II, UKW
Prof. Dr. rer. nat. Gabriele Multhoff
Zentralinstitut für Translationale Krebsforschung der Technischen Universität München
Prof. Dr. med. Michael Hudecek
Medizinische Klinik II, UKW
Prof. Dr. med. Hermann Einsele
Medizinische Klinik II, UKW
Project Summary
Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with limited therapeutic options and poor prognosis in the relapsed or refractory situation [1]. So far, specific, safe and effective use of immunotherapy in AML has not been achieved. For other hematologic neoplasms, the use of Chimeric antigen receptor (CAR) modified T cells has been well established; unfortunately, with AML, initial results from clinical trials suggest a highly unfavorable risk profile [2, 3]. This is mainly due to the lack of suitable targets that allow discrimination between blasts from healthy hematopoiesis.
A major challenge for immunotherapies lies in the fact that such therapies are highly personalized; therefore, many patients do not qualify for them. These are because CAR-modified T cells are either unable to be generated or cannot be generated fast enough [4]. Taken together, there is a huge medical need for innovative AML therapies, in particular for the development of off-the-shelf approaches, which could enable a faster deployment at a lower cost [5, 6].
The present project aims to use a CAR that can discriminate between healthy and malignant bone marrow cells. This could be possible, for the first time, thanks to our preliminary work, which was able to identify antigens with a predicted superior selectivity for AML blasts [7]. The CAR will be optimized for expression and function on NK cells. The optimized CAR will be incorporated into induced pluripotent stem cells (iPSCs) from which CAR-expressing NK cells (CAR-iNK cells) will be differentiated. The in vitro function of CAR-iNK cells will be analyzed to assess their potential as a cell therapy product. NK cells derived from iPSCs offer the opportunity to manufacture allogeneic cell products with consistently high quality and scalable quantities. This would allow the use of such CAR-modified cells in a patient-independent, so-called off-the-shelf manner.
1. Sung, H., et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 2021. 71(3): p. 209-249.
2. Roddie, C., et al., Manufacturing chimeric antigen receptor T cells: issues and challenges. Cytotherapy, 2019. 21(3): p. 327-340.
3. Kenderian, S.S., et al., CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia, 2015. 29(8): p. 1637-47.
4. Benjamin, R., et al., Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet, 2020. 396(10266): p. 1885-1894.
5. Shimoni, A., et al., Donor selection for a second allogeneic stem cell transplantation in AML patients relapsing after a first transplant: a study of the Acute Leukemia Working Party of EBMT. Blood Cancer J, 2019. 9(12): p. 88.
6. Tambaro, F.P., et al., Autologous CD33-CAR-T cells for treatment of relapsed/refractory acute myelogenous leukemia. Leukemia, 2021. 35(11): p. 3282-3286.
7. Gottschlich, A., et al., Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia. Nat Biotechnol, 2023.