Abstract
PurposeIt was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy.MethodsIn vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment.Results[177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls.ConclusionApplication of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.
Highlights
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and, attracted increasing interest of clinicians over the last years [1, 2]
NF9006 and KB cells were cultured using folate-deficient Roswell Park Memorial Institute (RPMI) (FFRPMI) medium supplemented with 10% fetal calf serum, L-glutamine, and antibiotics and 4T1 cells were cultured in supplemented RPMI medium
Coincubation with excess folic acid reduced the uptake of [177Lu]Lu-DOTA-folate to < 1% (p < 0.05), which corresponded to the uptake in folate receptor (FR)-negative 4T1 cells (~ 0.3%) (Fig. 1a)
Summary
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and, attracted increasing interest of clinicians over the last years [1, 2]. ICIs such as anti-CTLA-4 antibodies are used to block these signals and, stimulate the elimination of cancer cells [3, 4]. It was, observed that only a subset of patients responded to ICI monotherapy [2, 5]. In current clinical therapy settings, ICIs are, often combined with immune sensitizers, including chemotherapeutics [5, 8]
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