Phase I/IIa Study of Genetically Engineered NY-ESO-1 SPEAR T-Cells Administered Following Autologous Stem Cell Transplant in HLA-a*02+ Patients with Advanced Multiple Myeloma: Long Term Follow-up (NCT01352286)

Abstract Background: NY-ESO-1 and LAGE-1a are cancer-testis antigens that are overexpressed in patients with multiple myeloma (MM), and the incidence of these antigens correlates with tumor proliferation and other high-risk features. Genetically engineered NY-ESO-1 SPEAR (specific peptide enhanced affinity receptor) T-cells (NY-ESO-1c259T cells) recognize the peptide sequence SLLMWITQC expressed by NY-ESO-1 or LAGE-1a in the context of HLA-A*02 presentation. This study evaluated treatment with NY-ESO-1SPEAR T-cells post-autologous stem cell transplant (ASCT) in patients with advanced MM. Methods: Eligible patients were HLA-A*02:01, 02:05 or 02:06 positive, with refractory, relapsed or high risk MM associated with one or more adverse cytogenetic abnormalities. Eligible patients' tumors also expressed NY-ESO-1 and/or LAGE-1a by qPCR. The primary study endpoint was safety. Secondary objectives included overall response rate (ORR) (sCR+CR+VGPR+PR) evaluated with the International Myeloma Working Group Criteria (Rajkumar S.V. et al., Blood 2011), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), as well as gene-marked cell persistence. Lymphocytes were obtained by leukapheresis, isolated, activated, transduced to express NY-ESO-1c259T cell receptor, and expanded using anti-CD3/anti-CD28 immunomagnetic beads. While the SPEAR T-cells were being manufactured, stem cell mobilization was conducted using 1.5 g/m2 of cyclophosphamide plus G-CSF, and stem cells were collected (minimum: 2 × 106 CD34+ progenitors/kg). Once the manufactured product was ready, high-dose melphalan (140-200 mg/m2) was given 2 days before stem cell infusion. Two days after the stem cell infusion, the SPEAR T-cells were infused (median dose 3.1 × 109 of transduced T-cells, range 0.5-5.1 × 109). Disease was assessed at days 42, 100, 180, 270 and 360 post-T-cell infusion, and then every 3 months. Patients meeting the criteria for lenalidomide maintenance therapy received 10 mg/day starting around day 100 post-ASCT. Results: Twenty-five patients were enrolled, and all have been treated. Median age at enrollment was 61 yr (range 45 - 72); 60% were male. Based on analyses through July 2017, ORR at day 100 was 76% (1 sCR; 12 VGPR; 6PR), and at year 1, 13 patients were progression free (52%) of which 11 were responders (1 sCR; 1 CR; 8 VGPR; 1 PR). Three patients remain disease progression-free at 39, 56 and 61 months post T-cell infusion. Median PFS was ~13 months (range 3-61 months). Eleven of 25 patients (44%) are alive, and median survival was ~35 months (range 6-68 months). The most common adverse events (experienced by >70%) were diarrhea (100%), nausea (100%), anemia (96%), decreased appetite (92%), thrombocytopenia (92%), fatigue (88%), pyrexia (84%), rash (84%), hypokalemia (76%), febrile neutropenia (72%) and vomiting (72%). Autologous GVHD (24%) was reported in 6 patients (3 G3, 3 ≤G2); all resolved with corticosteroids and supportive therapy. No fatal adverse events have been reported. Conclusions: NY-ESO-1 SPEAR T-cell therapy in the setting of autologous stem cell transplant has promising efficacy and acceptable safety. GVHD, which manifests in a similar way as reported in prior transplant studies and is more frequent with adoptive T cell transfer (engineered or not engineered), appears manageable with appropriate supportive care. Analyses of transduced cell persistence, T-cell clonality, and minimal residual disease (MRD) genetic studies are ongoing and will be presented along with the efficacy and safety data for all 25 patients. Disclosures Chagin: Adaptimmune: Employment. Faitg: Adaptimmune: Employment. Iyengar: Adaptimmune: Employment. Trivedi: Adaptimmune: Employment. Norry: Adaptimmune: Employment. Holdich: Adaptimmune: Employment. Binder-Scholl: Adaptimmune: Employment. Amado: Adaptimmune: Employment. Fang: Adaptimmune: Employment.