TY - JOUR
T1 - Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses
T2 - Results from a Phase I/II Trial
AU - Weathers, Shiao Pei
AU - Penas-Prado, Marta
AU - Pei, Be Lian
AU - Ling, Xiaoyang
AU - Kassab, Cynthia
AU - Banerjee, Pinaki
AU - Bdiwi, Mustafa
AU - Shaim, Hila
AU - Alsuliman, Abdullah
AU - Shanley, Mayra
AU - de Groot, John F.
AU - O'Brien, Barbara J.
AU - Harrison, Rebecca
AU - Majd, Nazanin
AU - Kamiya-Matsuoka, Carlos
AU - Fuller, Gregory N.
AU - Huse, Jason T.
AU - Chi, Linda
AU - Rao, Ganesh
AU - Weinberg, Jeffrey S.
AU - Lang, Frederick F.
AU - Sawaya, Raymond
AU - Shpall, Elizabeth J.
AU - Rezvani, Katayoun
AU - Heimberger, Amy B.
N1 - Funding Information:
B.J. O'Brien reports receiving commercial research grants from Monteris. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - 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/m2) treatment. The phase I component used a 3þ3 design, ascending through four dose levels (5 106–1 108 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 CMVþ CD8þ 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.
AB - 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/m2) treatment. The phase I component used a 3þ3 design, ascending through four dose levels (5 106–1 108 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 CMVþ CD8þ 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.
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U2 - 10.1158/1078-0432.CCR-20-0176
DO - 10.1158/1078-0432.CCR-20-0176
M3 - Article
C2 - 32299815
AN - SCOPUS:85088252920
SN - 1078-0432
VL - 26
SP - 3565
EP - 3577
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -
