We are conducting a single site, investigator-initiated Phase Ib study with TBI-1301 where autologous T cells are genetically engineered to express a high affinity NY-ESO-1-specific T cell receptor (TCR) and adoptively transferred to HLA-A*02:01+ or A*02:06+ patients with NY-ESO-1+ solid tumors. Point-of-care manufacturing was performed where peripheral lymphocytes are transduced with the MS3II-NY-ESO1-SiTCR retroviral vector, which encodes an exogenous NY-ESO-1 specific TCR and siRNAs targeting endogenous TCR.
Patients underwent modest lymphodepletion with cyclophosphamide (750 mg/m2 on day -3 and -2) followed by a planned infusion of 5x10^9 manufactured TBI-1301 cells on day 0. All patients underwent immune assessment of PBMC by flow cytometry analysis to monitor persistence and phenotype changes of the infused T cells using NY-ESO1-specific pentamer and the following antibodies: CD45RA, HLA-DR, CD27, CD57, CCR7, PD-1, 4-1BB, CD28, TIGIT, CTLA-4, CD103, LAG3, Ki-67, CD25, CD127, and FoxP3.
9 patients (1 endometrial cancer, 1 ovarian cancer, 4 synovial sarcoma, 3 melanoma) were infused with TBI-1301 at the target cell dose with the exception of one synovial sarcoma patient who received 2.1x10^9 TBI-1301 cells. TBI-1301 was well tolerated, and there were no dose limiting toxicities. CRS grade 1-2 was experienced by 5 patients, with two patients requiring tocilizumab. RECIST best overall responses to date are as follows: 2 PR, 5 SD, 1 PD, and 1 pending. Three patients showed detectable levels of NY-ESO1-specific T cells in the periphery for greater than 100 days post infusion. Biomarker analysis of persisting NY-ESO-1 pentamer+ TBI-1301 cells in the peripheral blood showed increased expression of CD27, PD-1 and TIGIT. Additionally, patients with a PR showed significantly higher numbers of NY-ESO-1 CD8+ T cells costaining with CD45RA and CCR7.
ACT with TBI-1301 cells is safe and clinically active. Results provided here confirm long-term persistence of gene-engineered T cells with higher frequencies of CD45RA+ CCR7+ CD8+ T cells in responding patients. Detailed biomarker analysis of persisting TBI-1301 cells will be presented.
NCT02869217.
The authors.
Princess Margaret Cancer Foundation, Takara Bio, Inc.
M.O. Butler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GSK; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Adaptimmune; Research grant / Funding (institution): Takara Bio. A.G. Sacher: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca/MedImmune; Advisory / Consultancy: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Gritstone Oncology; Honoraria (self): Merck. S. Takahashi: Full / Part-time employment: Takara Bio, Inc. N. Hirano: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties: Takara Bio, Inc. All other authors have declared no conflicts of interest.