A groundbreaking phase 1 clinical trial has demonstrated the potential of BNT221, a novel personalized T cell therapy approach for patients with advanced melanoma who have exhausted standard treatment options.
The study, conducted at the Netherlands Cancer Institute (NKI), evaluated an innovative treatment strategy that involves harvesting patients' own T cells and engineering them to target multiple tumor-specific mutations, known as neoantigens.
Study Design and Patient Population
The open-label first-in-human trial (NCT04625205) enrolled patients with locally advanced or metastatic melanoma who had either progressed after immune checkpoint blockade therapy or were ineligible for such treatment. Patients with BRAF mutations must have previously received targeted therapy unless deemed inappropriate by investigators.
The trial was structured in two parts:
- Part 1: A dose-finding study testing BNT221 as monotherapy or in combination with PD-1 inhibitors or IL-2
- Part 2: An expansion cohort evaluating BNT221 with PD-1 inhibition with/without CTLA-4 blockade in first-line metastatic disease
Manufacturing Process and Treatment Administration
The manufacturing process began with leukapheresis to collect patients' peripheral blood mononuclear cells. These cells underwent sophisticated processing to generate T cells targeting up to 40 patient-specific tumor neoantigens identified through whole-exome sequencing.
Prior to cell infusion, patients received lymphodepleting chemotherapy consisting of:
- Cyclophosphamide (25 mg/kg/day for 2 days)
- Fludarabine (25 mg/m2/day for 3 days)
BNT221 was then administered intravenously, with patients monitored in-hospital for up to 2 weeks post-infusion. Filgrastim was given until adequate neutrophil recovery.
Safety and Monitoring
The primary objectives focused on safety evaluation and identifying the highest tolerable dose. Patients underwent regular monitoring of:
- Adverse events and serious adverse events
- Laboratory values
- Physical examination findings
- Vital signs
Imaging assessments following RECIST 1.1 criteria were performed at pre-screening and regular intervals post-treatment to evaluate tumor response.
Scientific Innovation
This trial represents a significant advance in personalized cancer immunotherapy by:
- Targeting multiple patient-specific neoantigens simultaneously
- Employing sophisticated bioinformatics to select optimal targets
- Incorporating quality control measures throughout the manufacturing process
- Conducting detailed immune monitoring to understand treatment mechanisms
The study incorporates extensive correlative analyses including:
- T cell receptor sequencing
- Single-cell RNA sequencing
- Multiplex immunofluorescence imaging
- Circulating tumor DNA analysis
Looking Forward
While full results are still pending, this trial establishes an important proof-of-concept for personalized T cell therapy in advanced melanoma. The insights gained will help optimize future cell therapy approaches and potentially expand this treatment modality to other cancer types.
