Document resource
Background Bone and soft tissue sarcomas account for 20% of all solid tumor malignancies. Responses to chemotherapy and surgery are dismal for relapsed or primary refractory (R/R) sarcomas, resulting in abysmal outcomes. 5-year OS for R/R osteosarcoma (OS), Ewing sarcoma (ES), rhabdomyosarcoma (RMS), or synovial sarcoma (SS) between 17 and 26%.Objective is to improve the 6-month PFS for patients with R/R bone or soft tissue sarcomas.Methods Pre-clinical studies show sarcomas are sensitive to NK cells. Chemotherapy increases NKG2D ligand expression to sensitize sarcoma to NK cell recognition.TGFβ is a pleiotropic cytokine which promotes carcinogenesis, suppresses NK cells in the TME. A novel NK cell therapy derived from universal donors (UD) for a reduced-cost, readily available, off-the-shelf cell therapy was developed. NK cells are expanded with feeder cells expressing 4-1BBL and membrane-bound IL-21 (mb21) and in the presence of TGFβ to induce relative TGFβ-resistance. These UD TGFβ-imprinted (TGFβi)NK cells have higher cytotoxicity, resistant to TGFβ suppression, and enhanced homing to solid tumors. Preparative regimen of Gemcitabine/Docetaxel has known activity across relapsed pediatric sarcomas and ability to augment adoptive NK cell immunotherapy by upregulating NKG2D ligands in solid tumors.Multi-site study launched Oct 2022 included 4 cohorts of OS, EWS, RMS and NRSTS for a safety phase in Part 1 and efficacy phase in Part 2.Enrollment on Part 1 was completed in August 2024. Patients 2 to 40 years are eligible with measurable disease.Treatment includes 8 cycles, 21 days each of chemotherapy with gemcitabine, docetaxel followed by UD TGFβi ex vivo expanded NK cells. Toxicities are assessed continuously after 1st infusion of NK cells.Results Twenty patients were enrolled starting October 2022 at 9 unique sites. Patients received 2-4 prior lines of treatment.Common Grade 3 toxicities attributed to NK cells included infusion related reaction, fever, pleural effusion and generalized muscle weakness. Tumor responses were assessed after every two cycles of treatment. 6-month PFS was censored for progression, death, or initiation of alternative therapy, and required at least one response in the Part 1 to proceed to Part 2. 6-month PFS was demonstrated in 0/5 OS, 2/5 EWS, 1/5 RMS and 2/5 NRSTS.Correlative studies including NK persistence, understanding the effect of NK cells on the tumor microenvironment and minimal residual disease monitoring are underway.Conclusions Innovative combination of chemotherapy and UD TGFβiNK cell therapy demonstrates feasibility and safety in pediatric and young adult patients with relapsed sarcoma, and initial efficacy signal in EWS, RMS, and NRSTS.Trial Registration This study is registered with Clinicaltrials.gov, NCT05634369Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal