Eureka Therapeutics Announces Publication of Preclinical Study Validating its ARTEMIS Platform Designed to Mitigate the Risk of Cytokine Release Syndrome (CRS) and Neurotoxicity
Eureka Therapeutics, Inc., a clinical stage biopharmaceutical company with the goal of curing cancer by developing novel T-cell therapies that harness the evolutionary power of the immune system, today announced the publication of a preclinical study of itsARTEMIS antibody-TCR (AbTCR) Receptor Platform inCell Discovery. The data in this publication demonstrates the ability of AbTCR-expressing T-cells to match the cancer-killing potency of anti-CD19 chimeric antigen receptor (CAR) T-cells but with a significant reduction in inflammatory cytokine release. The publication is co-authored with Dr. Stephan A. Grupp and Dr. David Barrett of the Children’s Hospital of Philadelphia.
While CAR-T-cell therapies have shown remarkable efficacy in CD19 positive blood cancer such as lymphomas and leukemias, life-threatening side effects such as CRS and neurotoxicity have limited CAR-T therapy to specialized centers and to later lines of treatment. The study discusses the design of the ARTEMIS AbTCR receptor and why its novel design contributes to a lower release of cytokines as compared to CAR-T-cells.
CRS is the result of the uncontrolled overstimulation of the CAR-T-cell after engagement with the target antigen. In CAR-T-cells, the signaling domain (CD3 zeta) and costimulatory domains (CD28 or 4-1BB) are fused into the CAR receptor construct. Upon engagement with the target antigen, such as CD19, the CAR-T-cell is activated and produces cytokines in the process of killing the cancer cells. The uncontrolled production of cytokines, however, can lead to CRS and neurotoxic side effects.
The ARTEMIS receptor, on the other hand, does not utilize a CD3 zeta to CD28/4-1BB fusion. Instead, the ARTEMIS receptor comprises an antibody-based antigen binding domain of a Fab fragment engineered onto portions of the effector domains of γ (gamma) and δ (delta) TCR chains. This allows the ARTEMIS receptor to form a multimeric T-cell signaling complex with the endogenous CD3 chains, utilizing the natural activation and regulatory pathways of the TCR receptor to control the production of cytokines.
The study compared ARTEMIS AbTCR T-cells to CAR-T-cells (CD28/CD3-based and 4-1BB/CD3-based) expressing the same human anti-CD19 antibody (ET190L1). In both in vitro and preclinical tumor models, the ARTEMIS ET190L1-AbTCR T-cells maintained comparable anti-tumor potency to ET190L1-CAR-T-cells yet produced lower concentrations of inflammatory cytokines. Moreover, the ARTEMIS AbTCR T-cells were shown to be more naïve/stem-cell like and less exhausted compared to CAR-T-cells, suggesting the potential for longer persistence of T-cells when translated into the clinical setting.
“The data suggest a critical step toward the introduction of a potentially safer T-cell therapy than the current iteration of CAR-T therapy. It is exciting to see the potential of Eureka’s ARTEMIS technology as CRS and related adverse events remain a major challenge today for physicians using CAR-T therapy,” said Dr. Stephen A. Grupp.
“Conventional wisdom has been that CRS is a necessary evil for the efficacy of CAR-T therapies. We have shown that efficacy and CRS have the potential to be decoupled. A safer T-cell therapy could result in a larger therapeutic window for patients, as well as a lower direct and indirect cost to patients and the healthcare system overall,” said Dr. Cheng Liu, President and Chief Executive Officer of Eureka Therapeutics.
Dr. Liu continued, “Our ARTEMIS AbTCR receptor serves as the backbone to which additional components can be added with the goal of optimizing T-cell activation and expansion. It is a very versatile platform. We can engineer the ARTEMIS receptor not only with conventional binding domains against cell surface antigens, but also with TCR-mimic antibody binding domains that target intracellular antigen peptides presented on the MHC complex to address solid tumors, an area that has been poorly addressed by current CAR-T therapies.”
In May 2018, Eureka presented positive preliminary results at the American Society of Clinical Oncology (ASCO) annual meeting from a proof-of-concept study of ARTEMIS T-cells engineered with Eureka’s proprietary human anti-CD19 binder (ET190L1-ARTEMIS) in patients with relapsed and refractory (r/r) B-cell lymphoma. In September 2018, Eureka presented positive preliminary results at the CAR-TCR Summit from a proof-of-concept study of ARTEMIS T-cells engineered with Eureka’s proprietary human anti-AFP TCR-mimic binder (ET140202) in patients with AFP-positive hepatocellular carcinoma (HCC), the most prevalent form of liver cancer. In both studies, the ARTEMIS T-cells were well tolerated in patients with no observed CRS or neurotoxicity. In the liver cancer study, tumor regression was observed in three out of six patients, and one patient with lung metastases achieved a complete response (CR).
About Eureka Therapeutics, Inc.
Eureka Therapeutics, Inc. is a privately held clinical stage biopharmaceutical company focused on developing novel T-cell therapies that harness the evolutionary power of the immune system. Its core technology centers around its proprietary ARTEMIS™ T-cell receptor platform and E-ALPHA® antibody discovery platform for the discovery and development of potentially safer and more effective T-cell therapies for the treatment of multiple solid and hematologic tumors.
Eureka Therapeutics, Inc. is headquartered in the San Francisco Bay Area. For more information on Eureka, please visit www.eurekatherapeutics.com.
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