Allogeneic CAR-T AVC-201 Cleared by European Medicines Agency for Trial in R/R AML

AvenCell Therapeutics’ AVC-201 (Allo-RevCAR01-T-CD123), an allogeneic CD123-directed chimeric antigen receptor T-cell (CAR-T) intended to treat relapsed/refractory (r/r) acute myeloid leukemia (AML) and certain other CD123-expressing hematological malignancies, has received clearance of a clinical trial application (CTA) for a phase 1 study (NCT05949125) from the European Medicines Agency (EMA).¹

AVC-201 utilizes the company’s UniCAR switchable technology platform and consists of T-cells from donors that have been engineered with CRISPR/Cas9 to express a reversed, universal CAR that remains completely biologically inert until activated via binding of a recombinant antibody derivative targeting molecule, R-TM123, to its extracellular peptide epitope. The planned phase 1 trial will seek to recruit approximately 35 patients at sites across Germany including Berlin, Ulm, Würzburg, Marburg, and Dresden. The open-label, dose-escalation trial will treat patients at multiple dose levels with the goal of determining a recommended phase 2 dose. Participants in the study will undergo lymphodepletion followed by administration of R-TM123 over the course of 20 days. Approximately 4 hours following the initiation of R-TM123 administration, patients will receive a single dose of the cellular component of AVC-201, referred to as Allo-RevCAR01-T, via intravenous infusion. AVC-201 also incorporates an in-licensed technology platform from Intellia Therapeutics that is intended to prevent graft versus host disease and rejection of cells from unrelated donors.

“We are excited to build on the early success and promising activity and safety of our ongoing switchable autologous clinical program in AML (AVC-101) by now including what we believe is the most scientifically-compelling allogeneic technology in the industry,” Andrew Schiermeier, the president and CEO of AvenCell Therapeutics, said in a statement.¹ “With the application of both platform technologies, we are the first company in this space to completely separate the manufacture of cells from the ultimate patients and cancer indications they will be targeted to. This modular approach allows for unparalleled future flexibility and reduction in cycle times, massive scaling of supply, and meaningful reductions in cost of goods, all of which will dramatically advance the field of cell therapy for patients.”

Earlier this year, AvenCell presented data from preclinical research on AVC-201 at the American Association for Cancer Research (AACR) Annual Meeting 2023, held April 14-19, 2023, in Orlando, Florida.² First author Armin Ehninger, PhD, the chief scientific officer of AvenCell Therapeutics, and colleagues reported that Allo-RevCAR01-T's activation was found to be strictly dependent on the presence of R-TM123 and CD123-expressing cells. Furthermore, in both in vitro and mouse models, the activated CAR T-cells demonstrated efficient lysis of CD123-expressing AML cells.

“In conclusion, the preclinical data support the clinical exploration of AVC-201 in a first in human study,” Ehninger and colleagues wrote.² “The established manufacturing process yielding high level of fully edited cells turns AVC-201 into a promising off-the-shelf treatment option for patients with CD123- positive hematologic and lymphatic malignancies.”

AvenCell is also developing AVC-101, an autologous CAR-T that utilizes the UniCAR platform.³ AVC-101 is currently being evaluated for the treatment of AML in a first-in-human phase 1/2 clinical trial (NCT04230265). Gerhard Ehninger, MD, a professor of internal medicine at University Hospital Dresden, presented data from the trial at the 64th Annual American Society of Hematology (ASH) Meeting, held December 10-13, 2022, in New Orleans, Louisiana. In an interview with CGTLive™ at the conference, Ehninger discussed the results seen with the switchable technology.

“We gave our first report on this adapter CAR system with our dose escalation trial. It was great what we saw, we were able to show proof-of-concept that we can stop cytokine release syndrome immediately when we withdraw the target module. It can be stopped and started again when the cytokine release storm is over. Or, when severe transaminitis is coming, we can stop it very rapidly,” Ehninger told CGTLive.

REFERENCES
1. AvenCell Therapeutics announces EMA approval of clinical trial application (CTA) for AVC-201, a novel allogeneic CD123-directed switchable CAR-T investigational therapy for the treatment of relapsed/refractory acute myeloid leukemia and other CD123 hematological malignancies. News release. AvenCell Therapeutics, Inc. July 24, 2023. Accessed July 28, 2023. https://avencell.com/avencell-therapeutics-announces-ema-approval-of-clinical-trial-application-cta-for-avc-201-a-novel-allogeneic-cd123-directed-switchable-car-t-investigational-therapy-for-the-treatment-of-relapsed-r/
2. Ehninger A, Spehr J, Loff S, et al. Preclinical characterization of switchable allogeneic CAR-T cells to support first in human clinical study in CD123-positive hematologic and lymphatic malignancies (AVC-201. Presented at: AACR Annual Meeting. April 14-19, 2023; Orlando, FL.Abstract #4095
3. Ehninger G, Kraus S, Sala E, et al. Phase 1 dose escalation study of the rapidly switchable universal CAR-T therapy Unicar-T-CD123 in relapsed/refractory AML. Presented at: 64th Annual ASH Meeting, December 10-13, 2022, New Orleans, Louisiana. Abstract #979