Abstract
Introduction CAR-T treatments have been successfully introduced in ALL, B-cell lymphoma and Multiple Myeloma. In AML results are lagging, mainly due to the absence of AML-specific target antigens. CD123 is expressed on AML blasts as well as, to a lesser extent, on non-malignant hematological cells including neutrophils. As such, direct targeting of CD123 can lead to serious hematological toxicity which has been reported before. We developed a modular, universal CAR-T treatment, consisting of a universal CAR-T cell with CD28 costimulatory domain (UniCAR-T) and a CD123 targeting module (TM). The TM binds to the CAR-T cell via a peptide tag derived from the human La protein. Both the UniCAR-T as well as the TM are individually inert and activity can only be achieved when both are present. Toxicity can be mitigated by withholding the administration of TM which will rapidly disappear from the circulation due to its short half-life. We developed a FIH study with the objective to evaluate the safety and tolerability of UniCAR02-T-CD123 and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for subsequent clinical trials.
Methods Key inclusion criteria included rrAML patients with ECOG ≤ 1, CD123 blast expression ≥ 20% and no suitable approved treatment option available. As of July 7th, 2022, 14 patients were treated. The median patient age was 65 (18-80) years and the median number of prior treatment lines was 3 (1-7). Four patients had received a prior allogeneic hematopoietic cell transplantation. Dosing was applied using an adaptive Bayesian optimal interval design for drug-combination trials, escalating either cell dose or TM concentration based on posterior probability calculation of AEs. Four dose levels of UniCAR-T as well as TM concentration were evaluated in combination and cohort size was 1. Standard fludarabine/cyclophosphamide lymphodepletion was given on day -5 to -3 prior to treatment start. TM administration was given over 21 days as continuous infusion via a mobile pump and on day 1 UniCAR-T were administered. After initial mandatory hospitalization, patients continued to be treated in an outpatient setting from day 12. Patients benefiting from the first cycle could qualify for a subsequent cycle.
Results Fourteen patients were treated of which 12 completed treatment and 2 received shortened treatment due to disease progression or DLT. Treatment was generally well tolerated with limited treatment-related AEs. CRS was observed in 12 patients, mostly grade 1 or 2. One patient expressed a grade 2 CRES identified by a disorientation and loss of writing capability. Upon withholding TM administration, the writing capability reverted within hours. Treatment-related toxicity was shown to be reversible in all patients with interruption of TM administration. Termination of TM administration resulted in rapid resolution of symptoms in all patients. One DLT was observed at Dose level 8, presented as a drop in fibrinogen with rapid improvement after stopping TM administration. Treatment proved to be tolerable without further DLT up until dose level 16 (500 M UniCAR-T). WBC and neutrophil counts recovered in most patients with reduction of bone marrow blasts after completion of treatment. Early signs of efficacy could be detected.10 patients showed blast count reduction, including 2 CRi, 1 patient with MRD positive CR converted to level of negativity measured by flow cytometry and NGS, and 4 PR. Treatment was very tolerable with mostly mild to moderate symptoms.
Conclusions UniCAR02-T-CD123 treatment proved to be safe and tolerable with limited toxicities. CRS was mostly grade 1-2 with just 1 case of grade 3 CRS. CRES was observed only once, and symptoms rapidly resolved after stopping TM administration. Promising efficacy was observed including CRi. Hematological recovery was also observed in most patients. No clear correlation was observed between treatment effect or toxicity and cell or TM dose, respectively. The observed effects warrant further investigation and an expansion cohort will be implemented at dose level 16.
Disclosures
Ehninger:AvenCell Europe GmbH: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Support for meeting attendance. Sala:BMS: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Other; Kite Gilead: Consultancy, Honoraria, Other; Novartis: Honoraria; Takeda: Consultancy. Vucinic:Novartis, Gilead Kite, Takeda, MSD, BMS Celgene, Abbvie, Amgen: Honoraria; MSD, BMS Celgene, Novartis, Gilead Kite, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, BMS Celgene: Other: travel, accommodations, expenses. Middeke:Abbvie: Membership on an entity's Board of Directors or advisory committees. Cartellieri:AvenCell Europe GmbH: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Support for meeting attendance. Ehninger:AvenCell Europe GmbH: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Support for meeting attendance.
Author notes
Asterisk with author names denotes non-ASH members.
