IMMU-32. RETARGETING IMMUNOEDITED GLIOMA ESCAPE VARIANTS WITH ADOPTIVE CELLULAR THERAPY. (5th November 2018)

• Record Type: Journal Article
• Authors: Wildes, Tyler; Dyson, Kyle; Grippin, Adam; DiVita, Bayli; Flores, Catherine; Mitchell, Duane
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi128
• Page End: vi128
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.535
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Adoptive T cell immunotherapy (ACT) leads to extension of median survival and long-term cures of treatment-resistant models of malignant glioma, medulloblastoma, and pontine gliomas. While very promising, tailored strategies to overcome ACT failure are needed. Therefore, we studied the tumors and adoptively-transferred T cells of KR158B glioma-bearing mice after they escaped ACT. The remaining T cells recognized the original KR158B tumor; however, the escaped tumor displayed marked immunoediting rendering it distinct from original tumor. We anticipated that successful strategies would need to be tailored to the new antigenic signature and therefore studied the HYPOTHESIS: That ex vivo -expanded T cells specific for glioma escape variants could successfully retarget immunoedited gliomas, despite the loss of primary antigens. METHODS: We performed RNAseq on normal brain, primary KR158B and GL261 gliomas, and tumor escape variants from KR158B (TOGA1.1/1.2) to analyze gene expression changes after ACT. We used restimulation co-cultures of T cells with tumor targets and IFN-g ELISAs to determine T cell activation. RESULTS: RNAseq showed parental tumors KR158B and GL261 share many differentially-expressed genes compared to normal brain. The escape variant TOGA1.1 demonstrated loss of ~80% of the genes that were upregulated in the KR158B and GL261 tumors. When we generated TOGA1.1 or TOGA1.2-specific T cells, they efficiently recognized TOGA1.1 or TOGA1.2 tumors but not primary KR158B or the opposite glioma escape variant. Additionally, T cell receptor (TCR)-Vb spectratyping prior to restimulation determined that distinct TCR-Vb families recognized parental tumors and TOGA1.1 and 1.2. CONCLUSIONS: Glioma escape variants are antigenically-distinct from primary tumors and other escape variants but retain expression of immunogenic antigens. Generation of ACT with specificity for escape variants provides exquisite antigen-specific recognition of the immunoedited tumors. These studies suggest feasibility of repeated treatment of tumors that have escaped ACT with generation of new, activated T cells targeting immunoedited gliomas.