Because of its increasingly demonstrative successes, CAR-T therapy has been well recognized as one of the most promising therapies for cancer. We have developed a novel autologous CAR-T, NKR-2, incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain. When expressed in T-cells, the naturally-expressed DAP10 provides the co-stimulatory signals to NKR-2 to be fully activated. NKR-2 selectively target tumor cells upon recognition of up to eight different NKG2D ligands expressed in many distinct cancer indications. In preclinical studies, NKR-2 demonstrated long-term anti-tumor activity towards multiple solid and hematologic tumors deploying multiple mechanisms of action targeting tumor cells and cells from the neo-vasculature and tumor suppressive immune environment, resulting in an adaptive response. In our recently completed Phase 1 study in hematologic cancers, a single administration of autologous NKR-2 was safe with initial signs of clinical benefit. Likewise, to overcome the operational challenges, our trial design incorporates strategies to harmonize multiple clinical and manufacturing processes while also enhancing patient safety and clinical outcomes.
THINK trial (THerapeutic Immunotherapy with NKR-2) is a EU/US open-label Phase I study to assess the safety and clinical activity of NKR-2 therapy administered in three infusions, two weeks apart in five solid tumor indications (CRC, urothelial, TNBC, pancreatic, ovarian) and two hematologic indications (AML/MDS and MM). No lymphodepleting conditioning is required in this study. The study contains two consecutive segments. The dose escalation segment will enroll 18 patients in two separate hematologic and solid malignancy arms, and evaluate 3 dose levels of NKR-2 (3x108, 1x109 and 3x109 cells per injection) following a 3 + 3 design. The expansion segment will then enroll 96 additional patients in 7 separate cohorts for each indication with 3 steps of statistical analysis (overall futility, futility within each cohort and final evaluation). At time of submission, the trial has completed enrollment in its first cohort among solid indications.
Clinical trial identification
Legal entity responsible for the study
B. Verma, U. Santanam, C. Lonez, D.E. Gilham, F. Lehmann: Employment with a pharmaceutical company: Employee of Celyad. A. Awada, P. Aftimos, P. Lewalle, N. Meuleman, J-P. Machiels, G. Catala, E. Vandenneste, J. Brayer, D. Sallman, S. Sahebjam, T. Kerre, S. Rottey, K. Odunsi, E.S. Wang: Corporate-sponsored research: Institute has received research finding from Celyad.