Background Large surface area microparticle docetaxel (LSAM-DTX) was developed for local administration to the tumor site where it continuously releases drug without significant systemic toxicity or immunosuppression. Post-administration, LSAM-DTX has been found within tumors for up to 50-days.1 To characterize immunomodulation following LSAM-DTX administration, immunophenotyping was performed in 3 tumor settings: before and after intramural-injection + instillation of LSAM-DTX at the site of transurethral resection of non-muscle invasive bladder cancer (NMIBC),2 after intratumoral administration in subcutaneous implanted syngeneic murine renal tumors (Renca), and after intratumoral administration ± systemic cytotoxic T-lymphocyte antigen blockade (anti-CTLA-4) in implanted syngeneic orthotopic murine metastatic luciferase-enabled breast tumors (4T-1-luc).3
Methods Table 1 describes tumor types and treatments. Fold-change data are reported for mIF. Changes in preclinical immune cell populations are reported if statistically significant (p<0.05).
Results In NMIBC clinical study subjects, LSAM-DTX treated tissues had increased density in populations of CD4+ and CD8+ T cells.2 Increases in Tregs and macrophages, including PD-L1+ and CTLA-4+ were also found. Myeloid and MDSC changes varied. Large infiltrations of NK cells occurred in the tumor microenvironment (TME) of 3/5 subjects. In 2 subjects with complete response at 12-months, mIF data demonstrated anti-tumor immunomodulation.
In the Renca model, compared to intravenous (IV) docetaxel, LSAM-DTX had increased circulating CD4+ T, Treg, M1-macrophages and M-MDSC while CD8+ T, G-MDSC, and M2-macrophages decreased. Changes in CD4+ T cells at early timepoints were similar to those found at 23-days.4 LSAM-DTX-treated TME had reduced CD8+ T cells, M1- and M2-macrophages and dendritic cells while G-MDSC were elevated. Spleen immunophenotyping showed increases in Treg and MDSC, variable CD4+ and CD8+ T cell changes, and decreased M2-macrophages.
In the 4T-1-luc model,3 evaluation of blood from mice administered intratumoral LSAM-DTX ± systemic anti-CTLA-4 found increases in circulating CD3+, CD4+ T and B cells. LSAM-DTX monotreatment increased circulating CD8+ T cells and Treg. LSAM-DTX+anti-CTLA-4 increased CD3+, CD4+, and CD8+ T cells in the TME and the combination was associated with significantly reduced thoracic metastasis.
Conclusions Immunophenotyping in 3 diverse tumor settings found commonalities in anti-tumor immunomodulation following local LSAM-DTX including changes in T cells and MDSC. NMIBC subjects demonstrated infiltrations of NK cells. Mice administered LSAM-DTX into renal tumor xenografts had consistent suppression of M2-macrophage levels in the blood, tumor and spleen when compared to IV docetaxel. Intratumoral LSAM-DTX in a metastatic breast cancer model increased T cells in the TME and reduced thoracic metastasis when combined with systemic immunotherapy.
Acknowledgements The authors would like to thank Dr. Max Wattenberg for assistance with multiplex immunofluorescence data analysis.
Trial Registration NCT03636256
Maulhardt HA, Hylle L, Frost MV, et al. Local Injection of Submicron Particle Docetaxel is Associated with Tumor Eradication, Reduced Systemic Toxicity and an Immunologic Response in Uro-Oncologic Xenografts. Cancers (Basel). 2019;11(4):577.
Kates M, Mansour AM, Lamm DL, et al. Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer. J Urol. 2022;208(4):821–829.
Maulhardt H, Marin A, Hesseltine H, diZerega G. Submicron particle docetaxel intratumoral injection in combination with anti-mCTLA-4 into 4T1-Luc orthotopic implants reduces primary tumor and metastatic pulmonary lesions. Med Oncol. 2021;38(9):106.
Maulhardt HA, Marin AM, diZerega GS. Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood. Invest New Drugs. 2020;38(5):1618–1626.
Ethics Approval The clinical study was approved by HonorHealth IRB; approval number 1374606–1, Johns Hopkins IRB; approval number IRB00198864, WIRB; approval number 1256662, UTHSA IRB; approval number HSC20190312H, and Columbia University IRB; approval number IRB-AAAS3837. The animal studies were reviewed and approved by ethics committees at the institution where the study was performed.
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