On September 5, 2018 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, reported preliminary safety and clinical results from its ongoing proof-of-concept study of ET140202 T-cell therapy in AFP-positive patients with hepatocellular carcinoma (HCC), the most prevalent form of liver cancer (Press release, Eureka Therapeutics, SEPT 5, 2018, View Source [SID1234529300]). The data was presented today in the late-breaking abstracts session of the CAR-TCR Summit in Boston, Massachusetts.
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The findings from the proof-of-concept first-in-human study, which is being conducted at the First Affiliated Hospital of Xi’An Jiaotong University in China, demonstrated a favorable safety profile of ET140202 T-cell therapy in six patients with no observed cytokine release syndrome (CRS) or drug-related neurotoxicity. In addition, one patient in the i.v. arm of the study had a complete response. Overall, tumor regression was observed in three out of six patients.
"We are encouraged by the safety profile and the potential efficacy of ET140202 for AFP-positive liver cancer," said Cheng Liu, Ph.D., President and Chief Executive Officer of Eureka Therapeutics. "Combining T-cell therapy with a TCR-mimic antibody to target intracellular antigens is a novel approach and can potentially represent a powerful way to treat solid tumors, and in particular, liver cancer, an area of significant unmet medical need. The initial results represent an important milestone in T-cell therapy against solid tumors, and we intend to continue to study and rapidly advance ET140202 into Phase 1 clinical trials in the United States."
Commenting on the data, liver cancer surgeon and researcher Yuman Fong, M.D. said "Hepatocellular carcinoma is a cancer where we have had great difficulties finding effective treatments. The study shows early but important data in the possibility of targeting solid tumors using T-cell therapy." Dr. Fong, the Sangiacomo Family Chair in Surgical Oncology and Chair and Professor of the Department of Surgery at City of Hope National Medical Center in Duarte, California, continued "ET140202 has demonstrated a large therapeutic window with the potential of repeat dosing, combination therapy, as well as a higher dosing level than we have seen with other T-cell programs. I look forward to seeing future data on this study."
Data from Ongoing Proof of Concept Study
As of the data cutoff date of July 2018, six patients who had previously failed multiple lines of therapy had been treated in one of three treatment arms of ET140202: intravenous (i.v.), intra-hepatic artery (i.a.) infusion or intratumoral (i.t.) injection. All patients enrolled in this study were AFP-expressing HCC patients carrying at least one HLA-A2 allele. All six patients had pre-existing cirrhosis.
In vivo T-cell expansion, which indicates T-cell activation, was observed in all six patients. Reduction of serum AFP was observed in four out of the six patients. A complete response was observed in one patient at the five-month assessment, with tumor regression observed in both the primary liver tumors and distal lung metastases after multiple treatment doses. In addition, the serum AFP of this patient returned to normal levels at the five-month assessment. The complete response was maintained at the seven-month assessment. Among other patients with one to three months of follow-up, two patients showed partial tumor regression, two patients showed stable disease and one patient showed progressive disease. Of the six patients, three died due to non-drug-related complications of liver disease. Two of these three patients showed a partial response at the one-month follow-up assessment.
Across all evaluable patients, ET140202 was generally well-tolerated. All drug-related adverse events reported by investigators were limited to Grades 1 or 2, with the most common being fever and fatigue.
About Liver Cancer
Liver cancer is the second most common cause of cancer-related deaths, with roughly 600,000 patient deaths every year worldwide, with incidence rates on the rise and limited treatment options. Between 2000 and 2016, mortality rates in liver cancer have increased 43% in the United States. Hepatocellular carcinoma is the predominant type of liver cancer with approximately 31,500 cases per year occurring in the United States. Alpha-fetoprotein (AFP) is overexpressed, specifically in liver cancer, making it an ideal target for T-cell immunotherapy. However, AFP is intracellularly expressed and secreted, and therefore, not targetable by conventional antibody-based therapies.
About ET140202 Study
ET140202 utilizes Eureka’s proprietary ARTEMIS T-cell receptor platform engineered with a proprietary human TCR-mimic (TCRm) antibody to target an AFP-peptide/HLA-A2 complex on HCC cancer cells. Using its proprietary E-ALPHA antibody discovery platform, Eureka discovered and developed a TCRm antibody to selectively bind upon fragments or peptides of the AFP protein that are broken down within the cancer cell proteasome and displayed on the cell surface by the major histocompatibility complex (MHC). Once engaged onto this complex, the ET140202 engineered T-cell is designed to be activated to kill the cancer cell. The ET140202 clinical proof-of-concept study was sponsored by Aeon Therapeutics (Shanghai) Co., Ltd. at the First Affiliated Hospital of Xi’An Jiaotong University.
About ARTEMIS T-cell Receptor Platform
Eureka’s proprietary ARTEMIS T-cell receptor platform was designed to create potentially safer and more effective T-cell therapies. In pre-clinical studies against CD19-positive malignancies, Eureka’s ARTEMIS T-cells matched the cancer killing potency of CAR-T therapies but with a dramatic reduction in the levels of inflammatory cytokines released. Cytokine release syndrome (CRS) and neurotoxicity are serious side effects associated with CAR-T therapies.