In:
Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 4 ( 2019-04-01), p. 572-583
Abstract:
Recombinant human IL2 is being considered as a combination partner for immune checkpoint inhibitors in cancer therapy, but the product only has a narrow therapeutic window. Therefore, we used F8-IL2, an antibody–IL2 fusion protein capable of selective localization to the tumor site, in combination with antibodies against murine CTLA-4, PD-1, and PD-L1. In immunocompetent mice bearing CT26 tumors, the combination of F8-IL2 with CTLA-4 blockade was efficacious, leading to increased progression-free survival and protective immunity against subsequent tumor rechallenges. The combination with anti–PD-1 induced substantial tumor growth retardation, but tumor clearance was rare, whereas the combination with anti–PD-L1 exhibited the lowest activity. A detailed high-parametric single-cell analysis of the tumor leukocyte composition revealed that F8-IL2 had a strong impact on NK-cell activity without collateral immune activation in the systemic immune compartment, whereas CTLA-4 blockade led to significant changes in the T-cell compartment. Leukocyte depletion studies revealed that CD8+ T and NK cells were the main drivers of the therapeutic activity. We extended the experimental observations to a second model, treating MC38 tumor-bearing mice with F8-IL2 and/or CTLA-4 blockade. Only the combination treatment displayed potent anticancer activity, characterized by an increase in cytolytic CD8+ T and NK cells in tumors and draining lymph nodes. A decrease in the regulatory T cell frequency, within the tumors, was also observed. The results provide a rationale for the combined use of engineered IL2 therapeutics with immune checkpoint inhibitors for cancer therapy.
Type of Medium:
Online Resource
ISSN:
2326-6066
,
2326-6074
DOI:
10.1158/2326-6066.CIR-18-0566
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2732517-9
