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.

Engineering self-propelled tumor-infiltrating CAR T cells using synthetic velocity receptors

“…We thus developed a migration strategy to enhance the infiltration of CAR T cells into solid tumors. Mesothelin CARs have the potential to ameliorate outcomes in many different solid tumor cancers, such as ovarian, pancreatic, and lung among others 5,6,31 . Engineering increased infiltration of mesothelin-targeted CARs has been demonstrated to enhance therapeutic outcomes in immune excluded solid tumors 16 .…”

Immunotherapy for Thymomas and Thymic Carcinomas: Current Status and Future Directions

“…Gavocabtagene autoleucel, a mesothelin-targeting T cell receptor fusion construct, was evaluated recently in a phase I/II clinical trial (NCT03907852) in patients with selected refractory solid tumors expressing mesothelin (malignant pleural mesothelioma, ovarian cancer, and cholangiocarcinoma) and has shown clinical activity with an ORR of 20% and a 6-month OS rate of 70%. Grade ≥ 3 pneumonitis and cytokine release syndrome were observed in 16% and 25% of patients, respectively [103]. Similar efforts are underway to develop ACTs targeting CTAs, and these treatments can potentially be considered for evaluation in patients with TETs in the future [104][105][106].…”

Emerging New Targets in Systemic Therapy for Malignant Pleural Mesothelioma

“…TRuCs comprise one T cell receptor (TCR) subunit attached to a costimulatory domain and integrated into native CD3 complexes via transduction. Upon the recognition of the specific tumor antigen, TRuCs facilitate the activation of the entire TCR independent of HLA stimulation [17]. In vitro, anti-mesothelin TRuC T cells have demonstrated effective cytotoxicity against different cancer cell lines with high mesothelin expression including mesothelioma, NSCLC, and ovarian adenocarcinoma tumor cells.…”

“…Interim data from a phase 1/2 study of gavo-cel after lymphodepletion in patients with treatment-refractory MPM showed an ORR of 21%, a median PFS of 5.6, and a median OS of 11.2 months (NCT03907852). Grade 3 or higher pneumonitis and cytokine release syndrome were observed in 0% and 15% of patients at the recommended phase 2 dose (RP2D) [17]. Gavo-cel is the first targeted therapy to demonstrate tumor response in MPM.…”