As cell therapies for solid tumours have struggled to reach the efficacy bar set in haematologic malignancies, tumour-infiltrating lymphocytes (TILs) have finally found a foothold – but require co-dosing with a risk-riddled systemic cytokine therapy. Obsidian Therapeutics, which raised a $160.5-million series C on Wednesday, is engineering a TIL therapy with the necessary cytokine stimulation already built-in, eliminating the need for an additional, potentially harmful infusion.
The round, led by new investor Wellington Management, will go towards enrolling more patients in Obsidian’s ongoing early-stage studies of its engineered TIL therapy, dubbed OBX-115, in patients with melanoma and non-small-cell lung cancer (NSCLC). The funding will also help scale up the company’s manufacturing capabilities ahead of pivotal trials.
Due to their polyclonal nature, TILs stand to succeed in solid tumours where CAR-T and T-cell receptor (TCR) cell therapies have struggled, Obsidian chief executive Madan Jagasia told FirstWord.
“Compared to haematologic malignancies, solid tumours have fewer clinically-validated tumour-specific neoantigen targets that are shared across patients, which limits the applicability for CAR-Ts and TCR-Ts that are engineered to target a specific tumour antigen,” he explained. TILs, on the other hand, “can naturally recognize multiple neoantigens and therefore overcome single-antigen escape mechanisms.”
In February, the FDA approved lovance's Amtagvi (lifileucel) as the first TIL therapy to treat certain forms of melanoma.
However, to effectively combat cancer, the TIL therapy requires a near-simultaneous administration of the T-cell growth cytokine IL-2 to support the expansion, persistence, and activity of the cells in vivo. According to Jagasia, systemic IL-2 can lead to severe toxicities including capillary leak syndrome (CLS), myocardial infarction, acute renal failure and immune-mediated neuropathy. Indeed, Amtagvi carries a boxed warning for treatment-related mortality.
Using its cytoDRiVE platform, Obsidian packages and inserts a gene cassette encoding IL-15 tagged with a drug-responsive domain (DRD) into the patient-derived cells. After infusion, the cells then produce IL-15 fused to the DRD, which can only be stabilised for membrane-bound expression in the presence of acetazolamide, an FDA-approved small molecule commonly used as a diuretic
Once patients receive acetazolamide, TIL expansion is triggered – all without requiring IL-2. Additionally, Jagasia said that the engineered therapy are less exhausted cells with enrichment for CD8+ T-cells.