(P 537) TGFβ IMPRINTED, EX VIVO EXPANDED UNIVERSAL DONOR NATURAL KILLER CELLS WITH CHEMOTHERAPY FOR RELAPSED BONE AND SOFT TISSUE SARCOMA - NCT05634369, REPORT FROM THE NATIONAL PEDIATRIC CANCER FOUNDATION

Objective:

Background: Bone and soft tissue sarcomas account for 20% of all solid tumor malignancies diagnosed in childhood. The addition of multi-agent chemotherapy improves survival compared to that observed with aggressive surgical local control alone; however, chemotherapy and surgery are not durable for relapsed or primary refractory (R/R) tumors with generally abysmal outcomes (5-year overall survival for R/R osteosarcoma (OS), Ewing sarcoma (ES), rhabdomyosarcoma (RMS), or synovial sarcoma (SS) between 17 and 26%). These poor outcomes highlight the need to develop novel treatment options for patients with relapsed sarcoma. The primary objective of this ongoing trial is to improve the 6-month progression-free survival for children, adolescents and young adults with bone or soft tissue sarcomas.
Rationale: Natural Killer (NK) cells demonstrate innate anti-tumor cytolytic activity in an MHC independent manner. Pre-clinical studies demonstrate that sarcomas are the most NK sensitive cancer type and chemotherapy can increase NKG2D ligand expression that sensitize sarcoma to cytokine activated NK cells. To address the dire need of durable treatment options, a novel cell therapy derived from universal donor (UD) primary NK cells was developed which are expanded utilizing K562 feeder cells expressing 4-1BBL and membrane-bound IL-21 (FC21) for ex vivo growth and activation. A novel non-genetic method of conferring relative TGFβ-resistance to expanded NK cells was induced by the addition of TGFβ during the 14-day expansion process to address the tumor microenvironment suppression of NK cells through TGFβ signaling. These TGFβ-imprinted (TGFβi) NK cells have higher cytotoxicity and are highly resistant to TGFβ suppression. A preparatory regimen of Gemcitabine/Docetaxel will be utilized due to its ability to augment adoptive NK cell immunotherapy by upregulating NKG2D ligands in solid tumors and known activity across relapsed pediatric sarcomas.

Methods: Study design: This clinical trial, NCT05634369, is currently enrolling at one site for initial safety assessment and will open more broadly at National Pediatric Cancer Foundation’s ‘Sunshine Project’ centers over the course of the next year. Patients ≥12 years up to ≤ 40 years of age with relapsed osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, or other soft tissue sarcoma are eligible. Measurable disease is required. Treatment will include up to 8 cycles, 21 days each of chemotherapy preparatory regimen with gemcitabine, docetaxel followed by UD TGFβi ex vivo expanded NK cells. The safety phase of the clinical trial will include 5 patients in each cohort of osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue tumors. After statistical criteria are met for an individual cohort in the safety phase, patients will be enrolled for assessment of efficacy. Tumor responses will be assessed after every two cycles of treatment. Correlative studies include the functional evaluation of NK cells, determination of NK cell sensitization to chemotherapy and minimal residual disease monitoring. For any patients who undergo surgical local control while on study therapy, the impact of the preparatory regimen on tumor sensitization to the NK cells will be assessed. This trial will help further our understanding of how novel cell therapy approaches can address an unmet need in pediatric solid tumors.

Results: N/A- Trials in Progress

Conclusion: N/A-Trials in Progress