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

Abstract

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 × 108 cells per m2 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 .

• Authors: Raffit Hassan, Marcus Butler, Roisin E O'Cearbhaill, David Y Oh, Melissa Johnson, Kevin Zikaras, Munisha Smalley, Michael Ross, Janos L Tanyi, Azam Ghafoor, Nirali N Shah, Babak Saboury, Liang Cao, Alfonso Quintás-Cardama, David Hong
• Journal: Nature medicine (Nat Med) Vol. 29 Issue 8 Pg. 2099-2109 (08 2023) ISSN: 1546-170X [Electronic] United States
• PMID: 37501016 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Chemical References

• Receptors, Antigen, T-Cell

Topics

• Humans
• Neoplasms (therapy, drug therapy)
• Receptors, Antigen, T-Cell (genetics, therapeutic use)
• Cell- and Tissue-Based Therapy