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Published on: April 21, 2022
Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial
Raffit Hassan1, Marcus Butler2, Roisin E O'Cearbhaill3
1Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. hassanr@mail.nih.gov.
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 .
Insights
Gavocabtagene autoleucel (gavo-cel), a novel T cell receptor fusion construct, shows promising anti-tumor activity in mesothelin-expressing solid tumors. Further study is warranted, but careful monitoring is needed due to a potentially narrow therapeutic window.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Mesothelin is a tumor-associated antigen overexpressed in various solid tumors.
- Treatment-refractory solid tumors present a significant unmet medical need.
- Novel therapeutic strategies targeting mesothelin are under investigation.
Purpose of the Study:
- To evaluate the safety and tolerability of gavocabtagene autoleucel (gavo-cel) in patients with mesothelin-expressing solid tumors.
- To determine the recommended Phase 2 dose (RP2D) of gavo-cel.
- To assess the preliminary efficacy of gavo-cel.
Main Methods:
- Phase 1 results from an ongoing Phase 1/2 trial of gavo-cel.
- Patients received gavo-cel at escalating doses, with or without lymphodepletion (LD).
- Safety endpoints included dose-limiting toxicities (DLTs), pneumonitis, and cytokine release syndrome (CRS). Efficacy endpoints included overall response rate (ORR) and overall survival (OS).
Main Results:
- The RP2D was determined as 1x10^8 cells/m^2 after LD.
- DLTs included grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage.
- At the RP2D, no grade 3+ pneumonitis was observed; grade 3+ CRS occurred in 15% of patients.
- ORR was 20% (13% confirmed) and 6-month OS rate was 70% in evaluable patients.
Conclusions:
- Gavo-cel demonstrated encouraging anti-tumor activity in patients with treatment-refractory mesothelin-expressing solid tumors.
- The therapy may have a narrow therapeutic window, necessitating careful safety monitoring.
- Gavo-cel warrants further investigation in this patient population.
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