Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial

Abstract

Purpose: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets.Patients and Methods: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m 2 ) treatment. The phase I component used a 3þ3 design, ascending through four dose levels (5 Â 10 6 -1 Â 10 8 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment.Results: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0-8.3 months]; 6-month PFS was 19% (95% CI, 7%-52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV þ CD8 þ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas.Conclusions: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Opening of the Blood–Brain Barrier Using Low-Intensity Pulsed Ultrasound Enhances Responses to Immunotherapy in Preclinical Glioma Models

“…The challenges of evaluating and monitoring immunotherapy in glioma patients will also be the case for their combination with LIPU but does provide further justification for the use of imaging tagged adoptive cellular therapies (71)(72)(73)(74)(75). Immune functional assessment and distribution could be done in the context of window-ofopportunity studies (76,77). In future clinical trials, further studies are needed to confirm the optimal order of sonication and drug administration for a given therapy.…”

Clinical Trials with Biologic Primary Endpoints in Immuno-oncology: Concepts and Usage

“…This contrasts with previous work that had shown feasibility and cytotoxic function of CMV specific T cells expanded from healthy donors. 28…”

Glioma Stem Cells as Immunotherapeutic Targets: Advancements and Challenges

“…Another group at MD Anderson is investigating autologous pp65-specific CTLs following lymphodepleting doses of TMZ and found that the therapy was well tolerated in a pilot trial of 12 patients ( 104 ). Unfortunately, the group recently released results of their phase I/II trial which demonstrated attenuated T cell functionality and poor PFS (NCT02661282) ( 105 ).…”