Central Nervous System

PD 03 - CNS 1 - Poster Discussion - Toxicity and Quality of Life

1021 - Impact of Corticosteroids on the Efficacy of Anti-PD-1 Therapy for Tumors Located Within or Outside the Central Nervous System

Sunday, October 21
5:03 PM - 5:09 PM
Location: Room 217 A/B

Impact of Corticosteroids on the Efficacy of Anti-PD-1 Therapy for Tumors Located Within or Outside the Central Nervous System
R. Maxwell1, A. Luksik1, T. Garzon-Muvdi1, A. L. Hung1, E. S. Kim1, A. Wu1, Y. Xia2, Z. Belcaid3, N. Gorelick1, D. Theodros3, C. Jackson1, X. Ye1, P. T. Tran4, K. J. Redmond4, H. Brem1, D. M. Pardoll1, L. R. Kleinberg4, and M. Lim4; 1Johns Hopkins University School of Medicine, Baltimore, MD, 2Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 3Johns Hopkins University, Baltimore, MD, 4Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD

Purpose/Objective(s): Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery vs. central nervous system (CNS), which may have a more limiting immune environment.

Materials/Methods: This study utilized well-established murine tumor models that are responsive to anti-PD-1 therapy. Wild-type C57BL/6J mice were either subcutaneously (n = 64) or intracranially (n = 80) injected with syngeneic murine-derived colon adenocarcinoma (MC38) or glioma (GL261-Luc) cells, respectively. Mice were then treated with anti-PD-1 therapy (10 mg/kg) with or without dexamethasone (10 mg/kg). Tumor size and survival were monitored. Immune cell populations were analyzed using flow cytometry in peripheral blood and tumor-draining lymph nodes. All animal handling and procedures were conducted in accordance with approved protocols by the Institutional Animal Care and Use Committee (IACUC) at a large research institution.

Results: In both tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8+ T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the survival benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. Immunologic memory against CNS tumors was also preserved in mice treated with combination anti-PD-1 and corticosteroid therapy upon tumor rechallenge.

Conclusion: These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade. Strategies and selection criteria may be developed to guide appropriate use of corticosteroid therapy without limiting the effectiveness of anti-PD-1 therapy, especially for patients with tumors residing within the CNS.

Author Disclosure: R. Maxwell: Research Grant; Dean's and Federal Work Study Funding. A. Luksik: None. T. Garzon-Muvdi: None. E.S. Kim: None. A. Wu: None. Y. Xia: None. Z. Belcaid: None. N. Gorelick: None. P.T. Tran: Research Grant; NIH-NCI, ACS, Kimmel Foundation, Astellas-Medivation, American Lung Association, Movember-PCF, PCORI. Honoraria; Dendreon. Consultant; RefleXion Medical. Advisory Board; Astellas-Medivation, Dendreon. Travel Expenses; Dendreon, RefleXion Medical. Patent/License Fees/Copyright; Compounds and Methods of Use in Ablative RT, Natsar Pharmaceuticals. Chair of Radiation Oncology Study Section; RSNA R&E Foundation. Senior Editor; Cancer Research. K.J. Redmond: Research Grant; Elekta AB, Accuray. Honoraria; AstraZeneca, Accuray. Travel Expenses; Elekta AB, Accuray. H. Brem: None. D.M. Pardoll: Independent Contractor; Astra Zeneca. Patent/License Fees/Copyright; Bristol Myers Squibb. Scientifc Advisor/consultant; Compugen, Potenza. L.R. Kleinberg: Research Grant; Novocure, Accuray. Honoraria; Accuray. Advisory Board; Novocure.

Russell Maxwell, MD

Disclosure:
Employment
Johns Hopkins University: Summer Research Assistant: Employee

Compensation
Dean's and Federal Work Study Funding: Research Grants

Presentation(s):

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