Abstract CT263: Atezolizumab clinical trial biopsies reveal varied immune landscapes in clear cell sarcoma and chondrosarcoma
Authors: Ferry-Galow Katherine V. , Fino Kristin K. , Coyne Geraldine O'Sullivan , Moore Nancy , Sharon Elad , Burgess Melissa , Chen James , Conley Anthony P. , Davis Elizabeth J. , Merriam Priscilla , Razak Albiruni R. Abdul , Van Tine Brian , Foster Jared C. , Takebe Naoko , Rosenberger Christina L. , Doroshow James H. , Chen Alice P. , Parchment Ralph E. 
Published: April 2024

Abstract
Introduction: Clear cell sarcoma (CCS) constitutes &lt;1% of sarcomas and frequently presents in adolescents and young adults. Chondrosarcoma is one of the most common bone malignancies in adults, occurring as conventional chondrosarcoma (CS) or the more-aggressive dedifferentiated chondrosarcoma (dCS). There is no standard of care therapy approved for these malignancies. The activity of immune checkpoint inhibition (ICI) in alveolar soft part sarcoma, together with case reports of ICI activity in these other sarcoma subtypes, prompted us to conduct a phase 2 clinical trial of atezolizumab (atezo), in patients (pts) with advanced CCS, CS, or dCS (NCT04458922).
Methods: We evaluated the effect of targeting PD-L1 with atezo upon the growth and immune landscape of CCS, CS, and dCS. Pts received intravenous atezo 1200 mg/m2 once every 21 days. Prior ICI therapy was not allowed. Tumor biopsy pairs for immuno-pharmacodynamic (IO-PD) studies were collected at baseline and on Cycle 3 Day 1(C3D1); paraffin sections were analyzed using immunofluorescence (IF) microscopy after staining with two multiplexed antibody panels (CD4/FOXP3 and PD-L1/CD8/CD3ζ pY142). Biomarker-positive cells within the tumor area and margins were quantified using image analysis algorithms. Activated cytotoxic T lymphocytes (CTLs) were defined as CD8+ CD3ζ pY142+ and reported as the percentage of the total CD8+ cell density.
Results: Nine pts were enrolled per disease cohort. No RECIST objective responses were observed; accrual was closed due to futility. Median progression-free survival (PFS) was 2.66 months (range: 1.3 to 11.7) in CCS, 3.22 (range: 1.4 to 8.9) in CS, and 2.04 (range: 0.4 to 11.7) in dCS. IF microscopy of biopsy pairs from five CCS pts revealed varied immune landscapes: 4/5 C3D1 biopsies contained PD-L1+ cells, 4/5 contained CD8+ cells, and 3/5 contained activated CTLs. Immune phenotype did not generally correlate with response; however, the highest percentage of activated CTLs occurred in the CCS pt with the longest PFS and this pt showed an increase in PD-L1+ cells on treatment—consistent with target engagement of the PD-L1/PD-1 immune checkpoint. dCS biopsy pairs (N=3) also contained a range of biomarker densities that did not correlated with PFS. In dCS and CCS, on-treatment increases in the percentage of activated CTLs were accompanied by increased Treg cell density in some pts. In contrast, CS biopsies (N=5) were uniformly devoid of infiltrating immune cells.
Conclusion: The tumor microenvironment of CS is an immune desert, while dCS and CCS tumors contain a range of immune cell compositions. Atezo treatment increased the percentage of activated CTLs and density of PD-L1+ cells in some tumors, but an increase in Treg cells may explain why that pharmacodynamic evidence of ICI activity (the increase in activated CTLs) was not associated with clinical response. Funded NCI Contract No. HHSN261201500003I.
Citation Format: Katherine V. Ferry-Galow, Kristin K. Fino, Geraldine O'Sullivan Coyne, Nancy Moore, Elad Sharon, Melissa Burgess, James Chen, Anthony P. Conley, Elizabeth J. Davis, Priscilla Merriam, Albiruni R. Abdul Razak, Brian Van Tine, Jared C. Foster, Naoko Takebe, Christina L. Rosenberger, James H. Doroshow, Alice P. Chen, Ralph E. Parchment. Atezolizumab clinical trial biopsies reveal varied immune landscapes in clear cell sarcoma and chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT263.