Abstract IA008: Altering the T cell receptor repertoire in the sarcoma tumor immune microenvironment

Abstract

Abstract Our lab has been interested in characterizing the T cell receptor (TCR) repertoire of sarcoma subtypes as well as characterizing their immune infiltrates and studying the changes that occur on experimental immunotherapies. In this trial, 15 patients with metastatic soft tissue sarcoma STS patients with a superficial injectable lesion were treated weekly with an intratumoral (IT) toll like receptor 4 (TLR4) agonist Glucopyranosyl Lipid Adjuvant (GLA) for 8-12 weeks plus concurrent radiotherapy. Core biopsies and blood were collected pre and post treatment, and immune analysis was performed by T cell receptor (TCR) sequencing and multiplex IHC. RECIST v1.1 and CTCAE guidelines were used to monitor clinical outcomes. No grade 3 or higher treatment-related toxicity was observed, and local tumor control was achieved in 93% (14/15). 6 (40%) had overall stable disease after IT GLA, and one had complete regression of injected tumor. 3 other patients had long term control of injected tumor past 250 days, during which the uninjected STS had progression despite radiation. In patients with durable local control after IT GLA, multiplex IHC demonstrated increased CD4 and CD8 T cell infiltration, as well as decrease in regulatory T cells. In patient #5-6, TCR sequencing revealed 5-fold increase in PBMC clonality, with selective clonal expansion of T cells present in pre-treatment biopsy. In patient #10-6 (local control to 370 days), there was clonal expansion of T cells within TME which were also found in post treatment PBMC; matched single cell sequencing revealed these clones to be CD4 T cells with Th1 gene signatures. In this trial we found that GLA with radiation induced effective local control of superficial, metastatic STS lesion, inducing a shift in the TME towards an inflammatory state with strong infiltration of T cells. There was selective expansion of clones present in pre-treatment TME in circulating PBMC post IT GLA, isolated to be Th1 cells in one patient. This suggests induction of adaptive anti-tumor response, which may further be enhanced by combination with other immunomodulators. Citation Format: Seth M. Pollack, Y. Dave Seo. Altering the T cell receptor repertoire in the sarcoma tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA008.