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Background: Conventional CAR-T cells targeting CD123 in rrAML have achieved objective responses, but led to long-lasting myelosuppression due to expression of CD123 on progenitor cells. UniCAR-T-CD123 is a rapidly switchable two-component CAR-T therapy. An inert universal CAR-T cell (UniCAR-T) is combined with a CD123-specific soluble targeting module with a short half-life (TM123). By administering or withholding the continuous infusion of TM123, the UniCAR-T-cell can be rapidly switched on and off. Within the ongoing Phase IA study in rrAML, we investigated the expansion kinetics of UniCAR-T cells during TM123 administration in peripheral blood and bone marrow as well as cytokine profiles of treated patients. Methods: Prior to administration of autologous UniCAR-T cells, patients received a standard Flu/Cy lymphodepletion regimen at day -5 to -3. TM123 was administered as continuous infusion over 24 days starting at day 0. At day 1 a single dose of UniCAR-T cells was given. Dosing started with 1 x 108 UniCAR-T cells and 0.5 mg TM123 per day in patient 1. Patient 2 received the same TM123 dose and a UniCAR-T dose of 2.5 x 108 cells. Patient 3 received the same cell dose as patient 2 but a higher TM123 dose (1 mg/day). Pharmacokinetic of UniCAR-T and TM123 was determined from peripheral blood and bone marrow by droplet digital PCR and TM123-specific ELISA, respectively. Cytokine levels were measured by microfluidic immunoassay. Results: All 3 patients treated so far achieved an objective response, with one showing a PR and two a CRi. Treatment proved to be tolerable, no DLTs were observed to date and adverse events were mild. Grade 1 CRS (fever) was observed in 2 patients but subsided within 48 h after use of antipyretics. Myelosuppression was observed starting after lymphodepletion, which immediately recovered after TM123 withdrawal on day 24 in all patients, providing evidence for the rapid off-switch of UniCAR-T cells post TM123 administration. UniCAR-T cells expanded in all patients in peripheral blood and bone marrow comparable to data reported for conventional CD123 CAR-T products, and were so far detectable for up to 6 months after administration. Expansion kinetics were TM123-dependent. Patients showed periods of transient increase of IL-6, IFN-γ and TNF-α levels preceding peak expansion and decreasing after termination of TM123 administration. One patient showed additional coinciding momentary elevation of GM-CSF and IL-2. Conclusions: The initial clinical and translational results of UniCAR-T-CD123 represent, to our understanding, a first time evidence for a well-tolerated and effective rapidly switchable CAR-T product. Even though the number of patients treated so far is limited, the data obtained provide clinical proof-of-concept for the opportunity to abrogate side effects by withdrawal of TM123. Enrollment into the Phase IA study is ongoing. Citation Format: Armin Ehninger, Julia Riewaldt, Cordula Gründer, Kristin Franke, Maria Schreiber, Martin Wermke, Sabrina Kraus, Carla Kreissig, Jan Koedam, Michael Pehl, Gerhard Ehninger, Marc Cartellieri. Expansion kinetics and cytokine profiles of UniCAR-T-CD123, a rapidly switchable two-component CAR-T therapy, in patients with relapsed/refractory AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1506.

Virtually all solid tumors are dependent on a vascular network to provide them with the right amount of nutrients and oxygen. In that sense, low oxygen tension or hypoxia leads to an adaptive response that is transcriptionally regulated by the hypoxia-inducible factors (HIF), which are tightly controlled by the HIF prolyl hydroxylases (PHD). In this study, we show that inhibition of the oxygen sensor PHD2 in tumor cells stimulates vessel formation but paradoxically results in a profound reduction of tumor growth. This effect relies on the antiproliferative nature of the TGFβ signaling pathway, in a largely HIF-independent manner. Moreover, our findings reveal that PHD2 has an essential function in controlling the dual nature of TGFβ during tumorigenesis and may offer an alternative opportunity for anticancer therapy. Cancer Res; 71(9); 3306–16. ©2011 AACR.