Open-Label Pilot Study of Genetically Engineered NY-ESO-1 Specific T Cells (GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma

Abstract

Introduction NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A2. NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens overexpressed in mutiple myeloma (MM) and linked to poor clinical outcome. Patients (pts) with MM who received GSK3377794 after autologous stem cell transplant (ASCT) showed encouraging clinical activity. PD-1 expression on CD8 T cells can occur in GSK3377794-treated MM pts and may limit adaptive immune response; this is a mechanism of resistance/relapse in CD19 CAR T-cell trials. Combining GSK3377794 with an anti-PD1 inhibitor (pembrolizumab) may have synergistic antitumor activity. Objective Evaluate safety and efficacy of GSK3377794 alone or in combination with pembrolizumab in pts with relapsed MM. Methods This is an open-label, pilot study (NCT03168438) of GSK3377794 in pts who are HLA-A*02:01, 05, ± 06 positive and have NY-ESO-1+/LAGE-1a+ relapsed/refractory MM. Twenty pts who have received ≥3 prior therapies containing ≥1 (separately or combined; including ASCT) of an IMiD, PI, alkylator, CD38 monoclonal antibody, and glucocorticoid, will be assigned to 1 of 2 arms: GSK3377794 as a single infusion (Arm 1, n=10) or GSK3377794 as a single infusion + pembrolizumab 200 mg IV every 3 wk (Arm 2, n=10). Arm 1 enrollment will complete before enrolling Arm 2. Pembrolizumab treatment will start from Wk 3 (Wk 6 if precluded by toxicity). Each patient will undergo leukapheresis to obtain cells for autologous NY-ESO-1-specific T-cell manufacturing, followed by lymphodepleting chemotherapy with fludarabine + cyclophosphamide, then GSK3377794 infusion of 1−8 × 109 transduced T cells. Study objectives are to assess safety and tolerability (primary) and antitumor activity (secondary) of GSK3377794 treatment (± pembrolizumab). At each visit, pts will be monitored for AEs and treatment-limiting toxicities, efficacy (using IMWG criteria), and biomarkers. Arm 2 enrollment will pause for a 3-wk safety review period after the first 3 pts receive their first pembrolizumab dose. Treatment will continue until disease progression or 108 wk after GSK3377794 infusion. After completing treatment, pts will transfer to long-term follow-up (NCT03391778) to continue safety/survival monitoring for up to 15 years. As of Jan 27, 2019, 50 pts have been screened. Half have tested positive for HLA-A*02:01, 05, ± 06; bone marrow samples from 12/21 (57%) tested positive for NY-ESO-1 ± LAGE-1a. To date, 3 pts have received GSK3377794. Further work is ongoing to enhance patient eligibility. These data are presented on behalf of the original authors with their permission. A similar presentation will be presented at the ASH Annual Meeting, Orlando, FL, USA, Dec 7-10, 2019. This study (NCT03168438) is funded by GSK.