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Engineered TIL Therapy Trial Reopens Enrollment After Voluntary Pause Related to Manufacturing Analysis

Instil Bio, ITIL-306’s developer, expects to present initial data from the phase 1 trial’s dose escalation cohorts this year.

The phase 1 clinical trial (NCT05397093) for Instil Bio’s ITIL-306, an investigational autologous tumor infiltrating lymphocyte (TIL) therapy intended to treat various types of solid tumors, has been resumed following a voluntary pause of enrollment related to a manufacturing analysis.1,2

Instil Bio, which announced the dosing of the first patient in the trial in October 2022, voluntarily made the decision to pause enrollment later that same month.2,3 The company simultaneously paused enrollment in its clinical trial (NCT05050006; DELTA-1) for ITIL-168, an unmodified TIL therapy being evaluated for the treatment of advanced cutaneous melanoma. The decision was made with regard to a diminished rate of successful manufacturing for ITIL-168 seen prior to the pause. A prespecified safety analysis did not reveal any unexpected safety issues for patients who received ITIL-168, however some patients enrolled in the trial were not able to receive treatment due to the manufacturing failures.

No manufacturing failures for patients enrolled in the trial of ITIL-306 had been observed at the time of the pause, but the company made the decision to pause both trials in order perform an overall analysis of its manufacturing processes. Although regulatory authorities in the United States, Canada, and the United Kingdom were notified of the pause, the company stated that no regulatory agencies issued a clinical hold.

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. It is being evaluated in the trial for the treatment of patients with epithelial ovarian cancer, non–small cell lung cancer (NSCLC), and renal cell carcinoma.

“We are committed to advancing TIL therapy for the treatment of patients with cancer,” Bronson Crouch, chief executive officer of Instil Bio, said in a statement at the time the pause was announced.3 “This pause in enrollment provides us an opportunity to refine our processes and enable us to manufacture and deliver TIL therapies to patients with no other treatment options. We have assembled a world-class technical operations organization and leadership team to address the challenges associated with manufacturing these therapies.”

Following the analysis of ITIL-306's manufacturing process, additional quality safeguards were implemented to further strengthen protections against potential contamination.1 The company additionally announced that it now expects to present initial safety, translational, and efficacy data from the trial’s dose escalation cohorts at a conference this year.

The DELTA-1 trial for ITIL-168, on the other hand, will not be resumed.4 In December 2022, Instil Bio announced a reprioritization of its programs, which includes a renewed focus on CoStAR-TIL programs, including ITIL-306, and the discontinuation of the company’s unmodified TIL programs, which includes the DELTA-1 trial and the DELTA-2 trial (NCT05393635), which was evaluating ITIL-168 for the treatment of cervical cancer, head and neck squamous cell carcinoma, and NSCLC.

“From the beginning of Instil, we have been committed to advancing TIL therapy by enhancing the native activity of TILs with innovative strategies designed to improve product efficacy and safety,” Crouch said in a December 2022 statement.4 “Although it was a difficult decision to discontinue the development of ITIL-168, this decision provides us the opportunity to accelerate the development of CoStAR and other novel technologies to enhance TIL therapies for patients. We are excited to resume dosing patients in the Phase 1 ITIL-306 study and anticipate providing initial data readouts next year.”

1. InstilBio announces resumption of clinical trial of CoStAR-TIL candidate ITIL-306 in lung, ovarian, and renal cancer. News release. Instil Bio, Inc. January 9, 2023. https://ir.instilbio.com/news-releases/news-release-details/instil-bio-announces-resumption-clinical-trial-costar-til 
2. 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
3. Instil Bio announces voluntary pause of enrollment in ongoing clinical trials related to manufacturing. News release. Instil Bio, Inc. October 31, 2022. https://ir.instilbio.com/news-releases/news-release-details/instil-bio-announces-voluntary-pause-enrollment-ongoing-clinical
4. Instil Bio announces prioritization of genetically engineered CoStAR-TIL program with ITIL-306 in advanced solid tumors and reduction in workforce. Instil Bio, Inc. December 8, 2022. https://ir.instilbio.com/news-releases/news-release-details/instil-bio-announces-prioritization-genetically-engineered