Abstract A019: Phase II trial evaluating the association of peripheral blood immunologic response and therapeutic response to immune checkpoint inhibition in patients with newly diagnosed glioblastoma and gliosarcoma
Authors: Watowich Matthew , Huguely Caitlin , Haynes Tuesday , Liu Seiya , Yaghi Nasser , Briceno Nicole , Anderson Brita , Ahn Susie , Wall Kathleen , Polskin Lily , Komlodi-Pasztor Edina , Sahebjam Solmaz , Watanabe Masashi , Gilbert Mark R. 
Published: March 2024

Background: Glioblastoma and gliosarcoma are highly aggressive, Grade IV CNS malignancies with notoriously immunosuppressive tumor microenvironments. Current standard of care involves maximal safe surgical resection, followed by radiation therapy and chemotherapy. Despite success in other cancer types, immune checkpoint inhibition (ICI) has failed to demonstrate significant efficacy in glioblastoma and gliosarcoma. We hypothesize that the generation of peripheral immune response is necessary for patients’ treatment response to ICI therapy. To test this hypothesis, we are actively enrolling patients with newly diagnosed glioblastoma or gliosarcoma on a Phase 2 clinical trial where all patients receive combinatorial ICI immunotherapy (NCI-21-C-0015). Extensive monitoring of systemic immune response will allow for comparison of overall survival and outcome between patients with a peripheral blood immune response and those without. Methods: A total of 48 patients will receive combinatorial ipilimumab and nivolumab ICI therapy with adjuvant chemotherapy. Peripheral blood samples will be collected at baseline and during the course of treatment for isolation of peripheral blood mononuclear cells (PBMCs) and plasma. Patient tumor tissue will be collected as available from diagnosis and recurrence. Patients’ peripheral immune response will be analyzed through immunophenotyping via high-dimensional spectral flow cytometry, multiplex cytokine and chemokine profiling of patient plasma, single cell RNA- and TCR-sequencing, and functional assays of patient T cells that include ELISpot and responsiveness to in vitro stimulation. Predictive responsiveness of patients’ T cell to ICI will be evaluated with in vitro stimulation utilizing anti-CD3 Ab and CD80-Ig coupled microbeads with and without anti-CTLA-4 blocking Ab. Results of these serial assays will be compared to patients’ clinical changes and overall survival to identify predictors and correlates of improved patient response and outcome. Results/Discussion: As primary endpoints have not been met for many patients and accrual is ongoing, a full analysis of clinical findings is not yet available. Thirty-two of the 48 planned patients have been enrolled onto this clinical trial. Interim analysis has been conducted and passed. Preliminary patient data analysis has confirmed feasibility of proposed methods. Twelve-plex cytokine profiling has been conducted on plasma samples from twenty-five patients and indicates unique patterns among patients, as well as differed expression compared to healthy donor samples supplied through the NIH Blood Bank. Additional patient findings are currently under analysis and will be reported at time of presentation.

Citation Format: Matthew Watowich, Caitlin Huguely, Tuesday Haynes, Seiya Liu, Nasser Yaghi, Nicole Briceno, Brita Anderson, Susie Ahn, Kathleen Wall, Lily Polskin, Edina Komlodi-Pasztor, Solmaz Sahebjam, Masashi Watanabe, Mark R. Gilbert. Phase II trial evaluating the association of peripheral blood immunologic response and therapeutic response to immune checkpoint inhibition in patients with newly diagnosed glioblastoma and gliosarcoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A019.