In:
The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 71.1-71.1
Abstract:
Checkpoint inhibitors (CI) have greatly impacted the treatment of solid tumors. Success in the liver has been more limited. When intravenously infused, the CI is delivered predominantly to extrahepatic sites, which results in systemic side effects. Previously, we reported on regional delivery of cellular immunotherapy for liver tumors using pressure-enabled drug delivery (PEDD™, TriSalus™ Life Sciences, Inc.). We hypothesized that PEDD of CI would improve the therapeutic index (TI). Methods In a murine model of colorectal liver metastases (CRLM), we infused high (HP) or low pressure (LP) anti-PD-1 antibodies (RMP1-14) via the portal vein and compared to systemic tail vein delivery (SD) at 0, 0.3, 1.0 and 3.0 mg/kg. Tumor bioluminescence (TB), histopathology, and serologic analysis informed treatment effects and toxicity. Results At a dose of 3mg/kg, LP resulted in similar IVIS TB growth kinetics compared to SD 3 mg/kg at 7 days post-treatment (geometric mean, p = 0.94). In animals treated with a 10-fold lower dose (0.3 mg/kg), tumor growth was significantly lower with HP vs. LP (7.5-fold improvement, p = 0.04). Circulating serum anti-PD-1 levels were similar when we compared SD and LP at 1 and 3 mg/kg (Mean 2512.0 vs. 2250.2 ng/mL, p = 0.25). Comparatively, systemic exposure was significantly lower at 0.3 mg/kg LP (Mean 508.1 ng/mL, p & lt; 0.0001). No increases in hepatotoxicity were seen with PEDD (AST p = 0.57, ALT p = 0.43). Conclusion PEDD of anti-PD-1 CI improved liver tumor control while also limiting systemic exposure. These findings support PEDD for anti-PD-1 therapy to improve TI. Phase 1 exploration of anti-PD-1 PEDD for patients with hepatic malignancy is thus warranted.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.202.Supp.71.1
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2019
detail.hit.zdb_id:
1475085-5
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