Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results

• Published in: Nature medicine Vol. 29; no. 8; pp. 2099 - 2109
• Main Authors: Hassan, Raffit, Butler, Marcus, O’Cearbhaill, Roisin E., Oh, David Y., Johnson, Melissa, Zikaras, Kevin, Smalley, Munisha, Ross, Michael, Tanyi, Janos L., Ghafoor, Azam, Shah, Nirali N., Saboury, Babak, Cao, Liang, Quintás-Cardama, Alfonso, Hong, David
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2023; Nature Publishing Group
• Subjects: 631/250/251; 692/308/2779/109/1940; 692/699/67/1059/2325; 692/699/67/1517/1709; 692/699/67/1641; Antibodies; Anticancer properties; Antitumor agents; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell fusion; Cell therapy; Cell- and Tissue-Based Therapy; Disease control; Health services; Hemorrhage; Humans; Infectious Diseases; Lymphocytes; Lymphocytes T; Mesothelioma; Metabolic Diseases; Molecular Medicine; Neoplasms - drug therapy; Neoplasms - therapy; Neurosciences; Ovarian cancer; Patients; Pneumonitis; Receptors; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - therapeutic use; Solid tumors; Survival; T cell receptors; Tumors
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-023-02452-y

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent ( n  = 3) or after lymphodepletion (LD, n  = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 10 8 cells per m 2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852 . T cells containing an anti-mesothelin single-domain antibody fused to a component of the endogenous T cell receptor signaling complex exhibit notable toxicities but encouraging clinical responses in patients with treatment-refractory mesothelioma and ovarian cancer.