Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM

Dimitrios Mathios, Jennifer E. Kim, Antonella Mangraviti, Jillian Phallen, Chul Kee Park, Christopher M. Jackson, Tomas Garzon-Muvdi, Eileen Kim, Debebe Theodros, Magdalena Polanczyk, Allison M. Martin, Ian Suk, Xiaobu Ye, Betty Tyler, Chetan Bettegowda, Henry Brem, Drew M. Pardoll, Michael Lim

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immuneresponse.We showthat LC combinedwith anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo-and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of thiswork could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

Original languageEnglish (US)
Article number370ra180
JournalScience translational medicine
Volume8
Issue number370
DOIs
StatePublished - Dec 21 2016
Externally publishedYes

Fingerprint

Immunity
Drug Therapy
Glioblastoma
Immunotherapy
Programmed Cell Death 1 Receptor
Neoplasms
Adoptive Transfer
Viral Tumor Antigens
Immunosuppressive Agents
Dendritic Cells
Survivors
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mathios, D., Kim, J. E., Mangraviti, A., Phallen, J., Park, C. K., Jackson, C. M., ... Lim, M. (2016). Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Science translational medicine, 8(370), [370ra180]. https://doi.org/10.1126/scitranslmed.aag2942

Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. / Mathios, Dimitrios; Kim, Jennifer E.; Mangraviti, Antonella; Phallen, Jillian; Park, Chul Kee; Jackson, Christopher M.; Garzon-Muvdi, Tomas; Kim, Eileen; Theodros, Debebe; Polanczyk, Magdalena; Martin, Allison M.; Suk, Ian; Ye, Xiaobu; Tyler, Betty; Bettegowda, Chetan; Brem, Henry; Pardoll, Drew M.; Lim, Michael.

In: Science translational medicine, Vol. 8, No. 370, 370ra180, 21.12.2016.

Research output: Contribution to journalArticle

Mathios, D, Kim, JE, Mangraviti, A, Phallen, J, Park, CK, Jackson, CM, Garzon-Muvdi, T, Kim, E, Theodros, D, Polanczyk, M, Martin, AM, Suk, I, Ye, X, Tyler, B, Bettegowda, C, Brem, H, Pardoll, DM & Lim, M 2016, 'Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM', Science translational medicine, vol. 8, no. 370, 370ra180. https://doi.org/10.1126/scitranslmed.aag2942
Mathios, Dimitrios ; Kim, Jennifer E. ; Mangraviti, Antonella ; Phallen, Jillian ; Park, Chul Kee ; Jackson, Christopher M. ; Garzon-Muvdi, Tomas ; Kim, Eileen ; Theodros, Debebe ; Polanczyk, Magdalena ; Martin, Allison M. ; Suk, Ian ; Ye, Xiaobu ; Tyler, Betty ; Bettegowda, Chetan ; Brem, Henry ; Pardoll, Drew M. ; Lim, Michael. / Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. In: Science translational medicine. 2016 ; Vol. 8, No. 370.
@article{1d1254b1ab22485793dacf51f1e25fea,
title = "Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM",
abstract = "The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immuneresponse.We showthat LC combinedwith anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo-and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of thiswork could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.",
author = "Dimitrios Mathios and Kim, {Jennifer E.} and Antonella Mangraviti and Jillian Phallen and Park, {Chul Kee} and Jackson, {Christopher M.} and Tomas Garzon-Muvdi and Eileen Kim and Debebe Theodros and Magdalena Polanczyk and Martin, {Allison M.} and Ian Suk and Xiaobu Ye and Betty Tyler and Chetan Bettegowda and Henry Brem and Pardoll, {Drew M.} and Michael Lim",
year = "2016",
month = "12",
day = "21",
doi = "10.1126/scitranslmed.aag2942",
language = "English (US)",
volume = "8",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "370",

}

TY - JOUR

T1 - Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM

AU - Mathios, Dimitrios

AU - Kim, Jennifer E.

AU - Mangraviti, Antonella

AU - Phallen, Jillian

AU - Park, Chul Kee

AU - Jackson, Christopher M.

AU - Garzon-Muvdi, Tomas

AU - Kim, Eileen

AU - Theodros, Debebe

AU - Polanczyk, Magdalena

AU - Martin, Allison M.

AU - Suk, Ian

AU - Ye, Xiaobu

AU - Tyler, Betty

AU - Bettegowda, Chetan

AU - Brem, Henry

AU - Pardoll, Drew M.

AU - Lim, Michael

PY - 2016/12/21

Y1 - 2016/12/21

N2 - The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immuneresponse.We showthat LC combinedwith anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo-and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of thiswork could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

AB - The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immuneresponse.We showthat LC combinedwith anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo-and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of thiswork could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

UR - http://www.scopus.com/inward/record.url?scp=85006987606&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006987606&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aag2942

DO - 10.1126/scitranslmed.aag2942

M3 - Article

C2 - 28003545

AN - SCOPUS:85006987606

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 370

M1 - 370ra180

ER -