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Engineered TIL Therapy Trial Doses First Patient

ITIL-306 utilizes a CoStAR molecule intended to improve cytokine release, cytolytic activity, and proliferation of TILs.

The first patient has been dosed in a phase 1 clinical trial (NCT05397093) of Instil Bio’s ITIL-306, an investigational autologous tumor infiltrating lymphocyte (TIL) therapy intended to treat various types of solid tumors.1

ITIL-306 utilizes a Costimulatory Antigen Receptor (CoStAR) molecule, which when activated by folate receptor alpha (FRα) within the tumor microenvironment, is intended to effect costimulatory signals to improve cytokine release, cytolytic activity, and proliferation of TILs. In a preclinical study, human carcinoembryonic antigen (CEA)‑positive H508 cells engineered to express FRα and anti‑CEA T-cell receptor (TCR) along with CoStAR achieved tumor control and prolonged survival in a mouse model, with improved T-cell proliferation, persistence, and anti-tumor activity compared to control cells expressing anti-CEA TCR without CoStAR.2 Furthermore, the TCR+CoStAR cells were able to sustain proliferation of T-cells without outside IL-2 supplementation, indicating that IL-2 dosing may not be necessary for ITIL-306 to achieve efficacy.

“The successful initiation of the Phase 1 study of ITIL-306 underscores our commitment to evolving TIL therapy, using strategies to enhance product efficacy and safety, with the goal to achieve durable remissions in patients with treatment-refractory solid tumors,” Bronson Crouch, chief executive officer, Instil Bio, said in a statement regarding the news.1

The open-label multicenter clinical trial is expected to recruit approximately 51 patients aged 18 years or older. It will recruit patients with advanced high-grade serous epithelial carcinoma of the ovary, fallopian tube, or peritoneum; adenocarcinoma of the lung; or clear-cell renal cell carcinoma (RCC) for the dose-escalation stage. The dose expansion stage will divide patients into 3 cohorts, with cohort 1 including patients with high grade serous, endometrioid, or clear cell epithelial carcinoma of the ovary, fallopian tube, or peritoneum; cohort 2 including patients with squamous-cell carcinoma or adenocarcinoma of the lung; and cohort 3 including patients with clear cell or papillary RCC. Participants are required to have progressed during or after at least 1 prior line of systemic therapy, according to several specific parameters for each indication. Additionally, participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate bone marrow and organ function, must be medically suitable for tumor tissue resection, and must have at least 1 remaining measurable lesion after tumor resection for TIL harvest. Patients with low-grade, endometrioid, clear cell, mucinous, sarcomatous, or mixed epithelial ovarian cancer; squamous or neuroendocrine differentiation non-small cell lung cancer (NSCLC); and nonclear-cell RCC will be excluded from the dose escalation stage. Patients with mucinous, sarcomatous, and low-grade EOC; small cell lung cancer or NSCLC with neuroendocrine differentiation; and nonclear-cell RCC other than papillary RCC will be excluded from the dose expansion stage. Additional exclusion criteria relate to patient health status, health history, and treatment history.

Participants will undergo 3 days of lymphodepleting chemotherapy with cyclophosphamide and fludarabine and 2 subsequent days of rest before receiving ITIL-306 via a single infusion. Patients in the initial dose cohort will be treated with a dose of 1 billion CoStAR-transduced TILs. Based on the findings of the preclinical research, participants will not be administered exogenous IL2 after infusion. The study’s primary end point is the frequency and severity of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest. Secondary end points include objective response rate, duration of response, progression-free survival, and overall survival. The study is recruiting at Washington University School of Medicine and Memorial Sloan Kettering Cancer Center and has an estimated primary completion date of July 2025. The first patient who was dosed has NSCLC refractory to standard therapies. Instil Bio expects to announce initial clinical data from the dose escalation stage next year.

REFERENCES
1. Instil bio announces first patient dosed with ITIL-306, our first engineered TIL therapy using the costar platform targeting folate receptor alpha (frα), in non-small cell lung cancer. News release. Instil Bio, Inc. October 18, 2022. https://ir.instilbio.com/news-releases/news-release-details/instil-bio-announces-first-patient-dosed-itil-306-our-first 
2. Moon OR, Qu Y, King MG, et al. Antitumor activity of T cells expressing a novel FOLR1 costimulatory antigen receptor (CoStAR) in a human xenograft murine solid tumor model and implications for in‑human studies. Poster presented at: The American Society of Clinical Oncology (ASCO) Annual Meeting, June 3‑7, 2022.