Abstract CT197: Profiling of tumor infiltrating T cells in malignant pleural/peritoneal mesothelioma (MPM) and ovarian cancer patients as part of a Phase 1 clinical trial of gavo-cel (TC-210)

Abstract

Abstract Gavocabtagene autoleucel (gavo-cel; TC-210) is a T cell receptor fusion construct (TRuC) cell therapy directed against mesothelin. As part of the phase 1 dose-escalation clinical trial (NCT03907852), patients with advanced solid tumors expressing mesothelin were administered a single infusion of gavo-cel. Thirty-two patients with late-stage disease (23 MPM, 8 ovarian and 1 cholangiocarcinoma) received gavo-cel at doses ranging from 5 × 107 - 5 × 108 TRuC cells/m2. The disease control rate (defined as achieving a response by RECISTv1.1 criteria or having stable disease [SD] for at least 12 weeks post-infusion) was 77%. Dose level 3 (1 × 108 TRuC cells/m2 following lymphodepletion with cyclophosphamide and fludarabine) was selected as the Recommended Phase 2 Dose (RP2D) for the ongoing phase 2 portion of the trial. Spatial distribution of immune cells, particularly T cells, in the tumor and stromal regions of tumor biopsies has been shown to identify patients that may respond to immunotherapies. To understand the tumor immune contexture, we profiled the T cell compartment in biopsies from five patients collected prior to and eight weeks post treatment using multiplexed immunofluorescence. We observed that the MPM patient with a partial response (PR) had a greater number of T cells at baseline in tumor biopsies when compared with the other SD patients. Notably, this patient with a PR, had a 3.6-fold increase in CD3+CD8+ T cell infiltrates into the tumor bed. In contrast, 2 SD patients with MPM had a minimal increase of T cells in the tumor compartment at 8 weeks post infusion. The density of TILs 8 weeks post infusion was much lower in the SD patients compared to the PR subject, indicating a potentially insufficient number of infiltrating T cells. Interestingly, 2/2 SD patients with ovarian cancer had a decrease in CD3+CD8+ T cells infiltrating into the tumor, consistent with an immune exclusion phenotype. The PR patient with MPM had minimal increase in PD-L1 and CD155 (a ligand for the inhibitory receptor, TIGIT) from negligible levels at baseline, whereas both SD patients with MPM had marked increases in PD-L1 and CD155, indicating potential resistance mechanisms. In summary, this preliminary data suggests although CD8+ TILs are increased following treatment with gavo-cel, the tumor regions in patients with SD show evidence of immune surveillance escape via PD-L1 and CD155 upregulation, thus acting as putative mechanisms of resistance. However, as seen in the PR patient with MPM there appears to be a critical number of TILs associating with response. We are currently evaluating the tumor immune contexture in phase 2, focusing on differences across tumor types with regards to TIL content, T cell influx, and correlations with response. We will also explore additional markers such as PD-1 and TIGIT, to profile the exhaustion state of immune cells and their spatial relationship with infiltrating gavo-cel T cells. Citation Format: Munisha Smalley, Michael Ross, Samantha F. Fowler, Lauren McLaughlin, Erin Jeter, Kevin Zikaras, Philip D. Bardwell, Alfonso Quintás-Cardama, Robert Tighe. Profiling of tumor infiltrating T cells in malignant pleural/peritoneal mesothelioma (MPM) and ovarian cancer patients as part of a Phase 1 clinical trial of gavo-cel (TC-210) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT197.