瘤内免疫刺激 LOAd703 基因治疗联合化疗在晚期癌症患者中的安全性

LOAd703 is a tumor microenvironment (TME) gene-engineering adenovirus encoding the immunostimulatory transgenes trimerized membrane-bound CD40 ligand (CD40L) and 4-1BB ligand (4-1BBL). Upon administration in the TME, the transgenes are expressed in various cell types to engage both the tumor and its stroma to activate antitumor immunity. CD40-CD40L interaction causes dendritic cell maturation and stimulates T helper 1-type immune responses, whereas 4-1BB-4-1BBL signaling protects T cells and natural killer cells from activation-induced cell death and promotes lymphocyte proliferation. LOAd703 replication with subsequent oncolysis is restricted to cancer cells.

In the dose-escalating part of this clinical study (NCT03225989), LOAd703 was increased according to a standard 3 + 3 design in patients with advanced solid malignancies. LOAd703 was administered every 2 weeks by ultrasound-guided intratumoral injections, combined with a standard-of-care or immune-conditioning gemcitabine-based chemotherapy regimen. The primary endpoint was tolerability.

Three dose levels of LOAd703 were evaluated in 10 patients. Treatment was overall safe and well tolerated. The most common side-effects assessed as secondary to LOAd703 were pyrexia, fatigue and headache. All LOAd703-attributed adverse events were of grade 1-2, and the majority were transient and emerged shortly after administration. One patient developed cytokine release syndrome grade 2. The maximum tolerated dose was not reached. Median overall survival was 8.4 months, and the overall response rate was 20%. A trend of higher interferon-gamma (IFN-γ) plasma levels in the highest LOAd703 dose cohort was observed.

The acceptable toxicity associated with LOAd703 and chemotherapy, combined with signs of clinical benefit in poor prognostic cancer patients, warrant further studies.