Utilizing Immunocytokines for Cancer Therapy.
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ABSTRACT:
SUBMITTER: Runbeck E
PROVIDER: S-EPMC8006145 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abstract BACKGROUND Glioblastoma is the most common malignant primary brain tumor in adults with an urgent need for novel treatment options. The administration of pro-inflammatory cytokines could be a potent immunotherapeutic approach to shift the balance between tumor-associated immunosuppression and immune activation. However, the systemic administration of therapeutically active doses of pro-inflammatory cytokines is not feasible due to toxic side effects and there is a need for strategies that enable a targeted delivery of pro-inflammatory cytokines to the tumor site. METHODS We investigated different antibody-cytokine fusion products that enable a targeted delivery of interleukin (IL)-2, IL-12 or tumor necrosis factor (TNF)-α to the tumor site by binding to a tumor-specific epitope of fibronectin. We investigated the expression of this tumor-specific epitope ex vivo in tumor-bearing mouse brains and human glioblastoma samples. Subsequently, we assessed the anti-tumor activity of IL-2, IL-12 or TNF-α fused to an antibody targeting this tumor-specific epitope in orthotopic syngeneic mouse glioma models. RESULTS The tumor-specfic extra domain B of fibronectin is expressed in murine glioma models and human glioblastoma samples. A fluorochrome-labeled antibody targeting this tumor-specific epitope accumulated at the tumor site in the brain in vivo upon systemic administration. IL-2, IL-12, or TNF-α fused to this antibody conferred a survival benefit in orthotopic tumor-bearing mice and cured a fraction of tumor-bearing mice. Mechanistically, antibody-fused TNF-α induced tumor necrosis and increased the activation of tumor-infiltrating natural killer (NK) cells, whereas antibody-fused IL-12 mainly boosted an anti-tumor immune response mediated by NK cells and T cells. CONCLUSION We demonstrate the expression of a tumor-specific epitope of fibronectin in glioblastoma and exploit this for the targeted delivery of IL-2, IL-12 or TNF-α to the tumor site. Our preclinical assessments indicate potent anti-tumor activity in orthotopic, syngneic glioma mouse models and reveal the mode of action for the different immunocytokines. Based on these findings, we initiated a phase I/II clinical trial in patients with recurrent glioma to investigate the targeted delivery of TNF-α (ClinicalTrials.gov identifier NCT03779230).
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Project description:Cytokine therapies are potent immunotherapy agents but exhibit severe dose-limiting toxicities. One strategy to overcome this involves engineering cytokines for intratumoral retention following local delivery. Here, we develop a localized cytokine therapy that elicits profound anti-tumor immunity by engineered targeting to the ubiquitous leukocyte receptor CD45. We designed CD45-targeted immunocytokines (αCD45-Cyt) that, upon injection, decorated the surface of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. αCD45-Cyt therapy eradicated both directly treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, αCD45-Cyt triggered prolonged pSTAT signaling and reprogrammed tumor-specific CD8+ T cells in the TDLN to exhibit an anti-viral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
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Project description:Systemically-administered cytokines are potent immunotherapy agents but exhibit severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention following local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest abscopal effects at distal untreated tumors. Here we report a localized cytokine therapy that safely elicits potent systemic anti-tumor immunity by engineered targeting of the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines (αCD45-Cyt) exhibit significantly diminished internalization rates relative to their wild-type counterparts; this prolonged surface retention sustains downstream pSTAT induction and enables both cis and trans signaling between lymphocytes. Intratumoral αCD45-Cyt administration led to decoration of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. Therapeutically, a single dose of αCD45-IL12 followed by a single dose of αCD45-IL15 eradicated both treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, prolonged exposure to αCD45-Cyt in the tumor and TDLN reprogrammed CD8+ T cells in the TDLN to exhibit an anti-viral transcriptional signature and expanded tumor-specific effector T cells in both the tumor and TDLN. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
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