The first patient has been dosed in a Phase 1/2 clinical trial evaluating KSQ-004EX, a novel CRISPR-engineered tumor infiltrating lymphocyte (eTIL) therapy developed by KSQ Therapeutics for the treatment of advanced solid tumors.
Dr. Rodabe Amaria, professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center and principal investigator of the study, enrolled the first patient with an advanced solid tumor to receive this investigational therapy.
"The promise of TIL therapy remains high, but current approaches fall short of addressing the needs of most patients with solid tumors," said Qasim Rizvi, Chief Executive Officer of KSQ and CEO-Partner at Flagship Pioneering. "Preclinically, the combined inactivation of SOCS1 and Regnase-1 in KSQ-004EX strongly increased anti-tumor functionality. We believe these enhancements give KSQ-004EX the potential to significantly advance TIL therapy for the treatment of solid tumors."
Innovative Mechanism of Action
KSQ-004EX represents a significant advancement in tumor infiltrating lymphocyte therapy through its innovative use of CRISPR/Cas9 gene editing technology. The therapy involves the inactivation of two specific genes—SOCS1 and Regnase-1—which were identified using KSQ's proprietary CRISPRomics platform as key inhibitors of TIL anti-tumor activity.
This dual gene inactivation approach is designed to enhance multiple aspects of TIL functionality, including improved engraftment, expansion, tumor infiltration, and killing capacity. Preclinical studies demonstrated that KSQ-004EX cells are more resistant to exhaustion and show improved long-term persistence and memory formation compared to conventional TIL therapies.
Trial Design and Patient Population
The Phase 1/2 clinical trial is an open-label, dose-escalation study that will evaluate KSQ-004EX in patients with various advanced solid tumors, including:
- Melanoma
- Non-small cell lung cancer (NSCLC)
- Head and neck squamous cell carcinoma (HNSCC)
- Colorectal cancer
- Pancreatic cancer
- Cervical cancer
The study is structured in multiple parts. The Phase 1 safety lead-in (cohort 1) will enroll approximately six patients with melanoma, NSCLC, or HNSCC to receive KSQ-004EX. Cohort 2 will involve approximately six patients receiving IL-2 at a dose of 600,000 IU/kg every 8 to 12 hours, up to 6 doses as tolerated. The Phase 2 expansion (arm 3) will enroll around 20 patients in separate cohorts for each of the three primary indications.
Eligible patients must have progressed on prior standard therapies, including:
- For melanoma: progression after anti-PD-1/PD-L1 therapy, with or without anti-CTLA-4/LAG-3
- For NSCLC: progression after platinum-based chemotherapy and checkpoint inhibitor, plus targeted therapy if applicable
- For HNSCC: treatment with 1 to 3 prior lines, including platinum and anti-PD-1/PD-L1
Additional eligibility criteria include age between 18 and 70 years, ECOG performance status of 0 or 1, adequate organ function, and having both a resectable lesion for manufacturing and at least one measurable lesion post-resection according to RECIST v1.1.
Study Endpoints and Objectives
The primary objective of the Phase 1 portion is to evaluate the safety and tolerability of KSQ-004EX. For the Phase 2 expansion, the primary objective shifts to evaluating antitumor activity in indication-specific cohorts.
"This trial represents an important step forward in the development of next-generation cell therapies for solid tumors," noted Dr. Amaria. "By addressing key limitations of current TIL approaches through precise genetic engineering, we hope to offer new treatment options for patients with advanced cancers who have limited therapeutic alternatives."
Addressing Unmet Medical Needs
Despite advances in cancer treatment, patients with advanced solid tumors often exhaust standard treatment options and face poor prognoses. Current TIL therapies have shown promise in certain indications like melanoma but have demonstrated limited efficacy in other solid tumors.
KSQ-004EX aims to address these limitations by enhancing the fundamental properties of TILs through targeted genetic modifications. The therapy represents a potential breakthrough in solid tumor treatment, particularly for patients who have progressed on existing therapies including checkpoint inhibitors and targeted agents.
The development of KSQ-004EX highlights the growing importance of precision engineering in cell therapies and the potential of CRISPR technology to overcome biological barriers that have historically limited the effectiveness of immunotherapies in solid tumors.
KSQ Therapeutics expects to report initial data from the Phase 1 portion of the trial in the coming months as patient enrollment continues across multiple clinical sites.
