Klinik und Poliklinik für Innere Medizin III
TUM Klinikum Rechts der Isar
Biederstädt Junior Group - Synthetic biology-engineered Natural Killer cells for anti-cancer therapy

Our lab seeks to develop next-generation CAR-NK cell therapies with enhanced potency for anti-cancer therapy. Using CRISPR precision gene editing, we strive to build multi-engineered CAR-NK cells that can overcome internal and external restraints to therapeutic efficacy, for instance, by shielding NK cells from the hostile tumor microenvironment or by overcoming mechanisms of tumor-induced functional exhaustion. Ultimately, our group aims to translate novel NK cell therapy candidates into the clinic to combat hard-to-treat cancers and dramatically improve clinical outcomes for cancer patients.

 

Natural killer cells attacking a cancer cell. ©MD Anderson Cancer Center
Research Focus

Natural killer cells have recently emerged as attractive contenders for adoptive cell therapy approaches due to their capacity to be safely administered in an allogeneic setting as off-the-shelf products. NK cells are specialized innate immune cells primed for immediate killing across HLA boundaries. CAR-NK cells have elicited promising clinical responses in heavily pretreated patients with lymphoid malignancies and are currently being evaluated for multiple other indications. Despite these successes, several intrinsic and extrinsic factors, including the immunosuppressive tumor microenvironment, impinge on the therapeutic efficacy of infused NK cells.

In our research, we seek to explore novel strategies to overcome these barriers leveraging targeted CRISPR gene editing to rewire CAR-NK cells for enhanced anti-cancer potency. Our goal is to increase NK cell fitness and overcome various factors of immunosuppression by modulating specific gene programs. Exploiting the versatile CRISPR precision gene editing toolkit, we aim to engineer CAR-NK cells to resist the challenges faced in the tumor microenvironment and overcome mechanisms of exhaustion. Ultimately, we aim to advance the most promising next-generation CAR-NK cell candidates into phase 1 clinical testing. 

Key Publications
  • Acharya S, Basar R, Daher M, Rafei H, Li P, Uprety N, Ensley E, Shanley M, Kumar B, Banerjee PP, Melo Garcia L, Lin P, Mohanty V, Kim KH, Jiang X, Pan Y, Li Y, Liu B, Nunez Cortes AK, Zhang C, Fathi M, Rezvan A, Montalvo MJ, Cha SL, Reyes-Silva F, Shrestha R, Guo X, Kundu K, Biederstädt A, Muniz-Feliciano L, Deyter GM, Kaplan M, Jiang XR, Liu E, Jain A, Roszik J, Fowlkes NW, Solis Soto LM, Raso MG, Khoury JD, Lin P, Vega F, Varadarajan N, Chen K, Marin D, Shpall EJ, Rezvani K. CD28 costimulation augments CAR signaling in NK cells via the LCK/CD3Z/ZAP70 signaling axis. Cancer Discov. 2024 Jun 20. doi: 10.1158/2159-8290.CD-24-0096. Epub ahead of print. PMID: 38900051.
  • Dill V, Blüm P, Lindemann A, Biederstädt A, Högner M, Götze KS, Bassermann F, Hildebrandt M. Comparison of two autologous hematopoietic stem cell mobilization strategies in patients with multiple myeloma: CE plus G-CSF versus G-CSF only: A single-center retrospective analysis. Transfusion. 2024 May;64(5):871-880. doi: 10.1111/trf.17829. Epub 2024 Apr 10. PMID: 38600674.
  • Biederstädt A, Manzar GS, Daher M. Multiplexed engineering and precision gene editing in cellular immunotherapy. Front Immunol. 2022 Nov 22;13:1063303. doi: 10.3389/fimmu.2022.1063303. PMID: 36483551; PMCID: PMC9723254.
  • Li Y, Basar R, Wang G, Liu E, Moyes JS, Li L, Kerbauy LN, Uprety N, Fathi M, Rezvan A, Banerjee PP, Muniz-Feliciano L, Laskowski TJ, Ensley E, Daher M, Shanley M, Mendt M, Acharya S, Liu B, Biederstädt A, Rafei H, Guo X, Melo Garcia L, Lin P, Ang S, Marin D, Chen K, Bover L, Champlin RE, Varadarajan N, Shpall EJ, Rezvani K. KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nat Med. 2022 Oct;28(10):2133-2144. doi: 10.1038/s41591-022-02003-x. Epub 2022 Sep 29. Erratum in: Nat Med. 2024 Mar;30(3):906. doi: 10.1038/s41591-023-02770-1. PMID: 36175679; PMCID: PMC9942695.
  • Laskowski TJ, Biederstädt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022 Oct;22(10):557-575. doi: 10.1038/s41568-022-00491-0. Epub 2022 Jul 25. PMID: 35879429; PMCID: PMC9309992.
  • Biederstädt A, Rezvani K. How I treat high-risk acute myeloid leukemia using preemptive adoptive cellular immunotherapy. Blood. 2023 Jan 5;141(1):22-38. doi: 10.1182/blood.2021012411. PMID: 35512203; PMCID: PMC10023741.
  • Biederstädt A, Rezvani K. Engineering the next generation of CAR-NK immunotherapies. Int J Hematol. 2021 Nov;114(5):554-571. doi: 10.1007/s12185-021-03209-4. Epub 2021 Aug 28. PMID: 34453686; PMCID: PMC8397867.
  • Lorenzen S, Biederstädt A, Ronellenfitsch U, Reißfelder C, Mönig S, Wenz F, Pauligk C, Walker M, Al-Batran SE, Haller B, Hofheinz RD. RACE-trial: neoadjuvant radiochemotherapy versus chemotherapy for patients with locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction - a randomized phase III joint study of the AIO, ARO and DGAV. BMC Cancer. 2020 Sep 15;20(1):886. doi: 10.1186/s12885-020-07388-x. PMID: 32933498; PMCID: PMC7493344.
  • Biederstädt A, Hassan Z, Schneeweis C, Schick M, Schneider L, Muckenhuber A, Hong Y, Siegers G, Nilsson L, Wirth M, Dantes Z, Steiger K, Schunck K, Langston S, Lenhof HP, Coluccio A, Orben F, Slawska J, Scherger A, Saur D, Müller S, Rad R, Weichert W, Nilsson J, Reichert M, Schneider G, Keller U. SUMO pathway inhibition targets an aggressive pancreatic cancer subtype. Gut. 2020 Aug;69(8):1472-1482. doi: 10.1136/gutjnl-2018-317856. Epub 2020 Jan 30. PMID: 32001555; PMCID: PMC7398468.

View full publication list.

Team
Dr. med. Alexander Biederstädt
Dr. med. Alexander Biederstädt
E-Mail -

 

We are building a closely integrated group of researchers driven by the shared goal of accelerating the discovery of innovative NK cell therapies for the treatment of cancer patients. As a new lab situated within the highly collaborative TranslaTUM research cluster (Central for Translational Cancer Research) and the Department of Internal Medicine III - Hematology & Medical Oncology, we benefit from exciting collaborations with other labs, cutting-edge core facilities, access to clinical patient samples as well as integration with our in-house state-of-the-art GMP cell manufacturing facility and early clinical trials unit (ECTU) to enable the discovery and development of novel cell therapy candidates for phase 1 clinical translation. 

Open Positions

Technician (research assistant) and Ph.D./Postdoctoral positions are currently available in the Biederstädt Lab. Inquiries should be sent to Dr. Alexander Biederstädt.

Third-party Funding

Deutsche Forschungsgemeinschaft (DFG)

 

Please inquire how your donation can enable cutting-edge cell therapy research and transform patients’ lives - your gift will make a tremendous difference. 

 

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