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TCR T-cell Therapy Trial for MAGE-A1-Positive Solid Tumors Doses First Patient

In preclinical research, T-cells bearing TK-8001's TCR showed better in vivo antitumor activity than T-cells incorporating human donor-derived TCRs.

The first patient has been dosed in the phase 1/2 IMAG1NE clinical trial (NCT05430555) of T-knife Therapeutics’ TK-8001, a T-cell receptor (TCR) engineered T-cell therapy (TCR-T) directed at melanoma-associated antigen gene-A1 (MAGE-A1) positive solid tumors.

TK-8001 was developed using the MyT Platform, from which TCRs are identified by immunizing transgenic mice that carry the TCRαβ gene loci with human tumor antigens. The process is intended to identify TCRs with durable specificity and greater affinity towards tumor self-antigen targets of interest than TCRs derived from human donors. In preclinical research, a MAGE-A1-directed TCR identified via this process, which is the one utilized in TK-8001, demonstrated high binding affinity and specificity for a MAGE-A1 epitope on HLA-A*02:01. Additionally, T-cells bearing this TCR showed in vitro serial killing activity and better in vivo antitumor activity than T-cells incorporating human donor-derived TCRs.

“We believe our MyT Platform is distinct in its ability to identify TCRs that have been naturally optimized for affinity, specificity, and sustaining long-term T-cell function, making TK-8001 a promising new therapy to target MAGE-A1 positive solid tumors,” Eugen Leo, MD, PhD, chief medical officer, T-knife Therapeutics, said in a statement regarding the news. “Our IMAG1NE trial combines a TCR with best-in-class potential, manufacturing designed to select the most potent T-cells, and biomarker-guided patient selection criteria that seeks to enroll those patients that we believe have the highest likelihood of safe, deep, and durable responses to TK-8001.”

The accelerated dose-titration, open-label, multicenter clinical trial will enroll approximately 48 patients aged 18 years and older with advanced-stage or metastatic solid tumor malignancies. Patients must have no further available approved treatment options or be in a noncurable state, having previously received at least 2 prior lines of systemic therapy. Participants are required to have the HLA-A*02:01 genotype, a MAGE-A1+ tumor, and 1 or more accurately measurable lesions. To be included, patients must also have an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, a life expectancy of more than 3 months, and adequate organ function. Any toxicities or immune-related adverse events (AEs) related to the participants’ previous therapies must have recovered to baseline or grade 1 or lower. Patients with clinical evidence or a history of central nervous system (CNS) primary tumor metastases, a history of CNS diseases within 6 months before screening, and patients with left ventricular ejection fraction less than 45%, pre-existing arrhythmia, uncontrolled angina pectoris, presently uncontrolled heart failure, or any myocardial infarction, coronary event, or thromboembolic event within 6 months before screening will be excluded from the study. Additional exclusion criteria relate to patient health status and treatment history.

The study’s dose escalation stage is expected to enroll between 6 and 18 patients. The dose expansion stage will enroll up to 30 patients. Participants will undergo leukapheresis and conditioning chemotherapy before receiving TK-8001 via a single intravenous infusion. The study’s primary end points include the incidence and grade of treatment-emergent AEs and the antitumoral activity of TK-8001 measured by overall response rate, rate of stable disease, partial response rate, and complete response rate. The study’s secondary end point is the recommended phase 2 dose. The trial is recruiting at locations in Belgium, Germany, and Spain and its estimated primary completion date is June 2024.

“We are excited to bring our first MyT Platform derived product candidate into the clinic,” Thomas M. Soloway, chief executive officer, T-knife, added to the statement. “This is a significant milestone representing the rapid progress at T-knife, and we are thankful for the support and trust we have received from our many collaborators, investigators, and the patient community as we pursue our goal to build a global company focused on bringing the power of TCR-based therapies to cancer patients.”

REFERENCE
T-knife Therapeutics announces dosing of first patient with TK-8001 in the IMAG1NE phase 1/2 clinical trial. News release. T-knife Therapeutics, Inc. October 20, 2022. https://www.t-knife.com/news/press-releases/10-20-22/