Abstract CT105: Preliminary safety and efficacy of gavocabtagene autoleucel (gavo-cel, TC-210), a T cell receptor fusion construct (TRuC™), in patients with treatment refractory mesothelin overexpressing solid tumors
Authors: Hong David S. , Johnson Melissa , Tanyi Janos L. , MacMullen Lauren , Tighe Robert , Jalbert Lizzy , Muzithras Viera P. , Zikaras Kevin , Cardama Alfonso Quintas , Hassan Raffit 
Published: July 2021

Abstract
Background: Mesothelin overexpression is present in over 80,000 patients/year with either malignant mesothelioma (MPM), ovarian cancer, cholangiocarcinoma, or non-small cell lung cancer (NSCLC) in the U.S. alone. We are testing a novel genetically engineered anti-mesothelin TRuC™ T cell therapy called gavo-cel (TC-210) in a Phase 1 study in treatment refractory patients with any of the four aforementioned cancers (NCT03907852).
Methods: Gavo-cel was engineered by transducing T cells with a lentiviral vector encoding for an anti-mesothelin llama-derived single domain antibody fused to the CD3epsilon subunit using a flexible glycine serine sequence. Upon translation, gavo-cel TRuCs integrate and reprogram intact TCR complexes to recognize tumor surface mesothelin in an HLA-independent manner. Eligibility criteria required demonstration of mesothelin overexpression on tumors (≥50% of tumor cells expressing 2+ or 3+ staining by IHC) at a central laboratory. Gavo-cel dose escalation proceeded following a modified 3+3 schema. TC-210 expansion and serum cytokine levels were serially measured.
Results: Seven patients (6 MPM, 1 ovarian) received a single gavo-cel intravenous infusion at the initial dose of 5x107/m2 either alone (dose level [DL] 0, n=1) or following lymphodepletion (LD) (DL1, n=6) with fludarabine (30mg/m2/day x4) and cyclophosphamide (600mg/m2/day x3). The median age was 69 years (range, 36-84) and the median number of prior therapies was 5 (range, 2-9). Four patients had received ≥4 lines of therapy, including immune checkpoint inhibitors (n=5), the anti-mesothelin ADC anetumab ravtansine (n=1), and anti-mesothelin mRNA CAR-T (n=1). Four patients required bridging therapy. No on-target/off-tumor toxicities or neurotoxicity events of any grade were observed. Grade (gr) ≥3 treatment emergent AEs occurred in 2 (29%) patients with MPM treated at DL1: 1 with gr3 CRS, and 1 with gr3 CRS, gr3 pneumonitis and gr5 fungal sepsis (unrelated to gavo-cel). CRS and pneumonitis events resolved with tocilizumab and corticosteroids. Grade 3 pneumonitis was considered a DLT, resulting in DL1 cohort expansion to 6 patients. At data cut-off date (November 8, 2020), 6 patients have been followed for &gt;3 months, including 4 followed through month 6. The disease control rate was 100%. All patients experienced target lesion regression by CT: median 61% (range, 5-75%). Three (43%) patients (2 with mesothelioma and 1 with ovarian cancer) had a partial response by RECIST v1.1 criteria, including 1 achieving a complete metabolic response. After a median follow-up of 6.5 months, the median OS at 6 months was (86%). The addition of LD increased TC-210 peak expansion and persistence, with cells being detected up to 30 days post infusion in peripheral blood.
Conclusion: Intravenous systemic administration of gavo-cel was generally safe and resulted in three of seven patients having objective partial response. Dose escalation is ongoing at 1x108/m2. Updated clinical and translational data will be presented.
Citation Format: David S. Hong, Melissa Johnson, Janos L. Tanyi, Lauren MacMullen, Robert Tighe, Lizzy Jalbert, Viera P. Muzithras, Kevin Zikaras, Alfonso Quintas Cardama, Raffit Hassan. Preliminary safety and efficacy of gavocabtagene autoleucel (gavo-cel, TC-210), a T cell receptor fusion construct (TRuC™), in patients with treatment refractory mesothelin overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT105.