Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: Phase 1/2 trial interim results Journal Article
| Authors: | Hassan, R.; Butler, M.; O’Cearbhaill, R. E.; Oh, D. Y.; Johnson, M.; Zikaras, K.; Smalley, M.; Ross, M.; Tanyi, J. L.; Ghafoor, A.; Shah, N. N.; Saboury, B.; Cao, L.; Quintás-Cardama, A.; Hong, D. |
| Article Title: | 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 . © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. |
| Keywords: | adult; clinical article; controlled study; protein expression; middle aged; overall survival; genetics; clinical trial; neutropenia; ascites; drug efficacy; drug safety; solid tumor; cancer patient; neoplasm; neoplasms; phase 2 clinical trial; bleeding; thrombocytopenia; antineoplastic activity; tumor regression; lymphocytopenia; pneumonia; t lymphocyte receptor; receptors, antigen, t-cell; immunogenicity; cell therapy; maximum tolerated dose; phase 1 clinical trial; biological therapy; disease control; drug dose increase; pericardial effusion; lymphocyte antigen receptor; mesothelin; pericarditis; pleurisy; cell fusion; tumor microenvironment; cytokine release syndrome; peritonitis; overall response rate; therapeutic index; humans; human; male; female; article; cell- and tissue-based therapy; x-ray computed tomography; gavocabtagene autoleucel |
| Journal Title: | Nature Medicine |
| Volume: | 29 |
| Issue: | 8 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-08-01 |
| Start Page: | 2099 |
| End Page: | 2109 |
| Language: | English |
| DOI: | 10.1038/s41591-023-02452-y |
| PUBMED: | 37501016 |
| PROVIDER: | scopus |
| PMCID: | PMC10427427 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
