Submicron particle docetaxel intratumoral injection in combination with anti-mCTLA-4 into 4T1-Luc orthotopic implants reduces primary tumor and metastatic pulmonary lesions

Abstract

We describe here characterization of the response of local and metastatic disease and immunomodulation following intratumoral (IT) injection of submicron particle docetaxel (SPD) administered alone or in combination with systemic antibody anti-mCTLA-4 (anti-mCTLA-4) in the metastatic 4T1-Luc2-1A4 (4T1) murine breast cancer model. In-life assessments of treatment tolerance, tumor volume (TV), and metastasis were performed (n = 10 animals/group). At study end, immune cell populations in tumor-site tissues and peripheral blood were analyzed using flow cytometry. Signs of distress typical of this aggressive tumor model occurred across all animals except for the combination treated which were asymptomatic and gained weight. TV at study end was significantly reduced in the combination group versus untreated [43% reduced (p < 0.05)] and vehicle controls [54% reduced (p < 0.0001)]. No evidence of thoracic metastasis was found in 40% of combination group animals and thoracic bioluminescence imaging (BLI) was reduced vs. untreated controls (p < 0.01). Significant elevations (p < 0.05) in CD4 + T, CD4 + helper T, Treg, and NKT cells were found in tumor and blood in SPD or combination treatment compared to controls or anti-mCTLA-4. Combination treatment increased tumor-associated CD8 + T cells (p < 0.01), peripheral B cells (p < 0.01), and tumor associated and circulating dendritic cells (DC) (p < 0.05). Tumor-associated NK cells were significantly increased in SPD ± anti-mCTLA-4 treatments (p < 0.01). Myeloid-derived suppressor cells (MDSC) were reduced in bloods in SPD ± anti-mCTLA-4 groups (p < 0.05). These data demonstrate that both SPD and anti-mCTLA-4 produce local anti-tumor effects as well as reductions in metastasis which are significantly enhanced when administered in combination.

Local administration of large surface area microparticle docetaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects: preclinical and clinical studies

“…Direct injection and intravesical administration of LSAM-DTX were well tolerated in preclinical and clinical studies [9][10][11][12]. In a model of metastatic breast cancer, the combination of IT LSAM-DTX and a systemic immune checkpoint inhibitor resulted in increased weight gain and lack of negative systemic side effects often associated with chemotherapy or immunotherapy.…”

“…A syngeneic murine model of mouse metastatic stage IV breast cancer (4T1-Luc2-1A4 cell line (ATCC ® CRL-2539™) in BALB/c (BALB/cAnNHsd) female mice) was used to evaluate the anti-tumor and anti-metastatic activity of LSAM-DTX alone and in combination with immune checkpoint inhibitor therapy [ 11 ] (Table 2 ). 4T1 tumors are poorly immunogenic with minimal T cell infiltration that results in immunologically “cold” conditions in the TME where CD11b + myeloid cells and granulocytic myeloid–derived suppressor cells (G-MDSC) are the predominant infiltrating cell types [ 14 ].…”

“…Significance reported as * p < 0.05, ** p < 0.01, **** p < 0.0001. Adapted with permission from [ 11 ] …”

“…Significance reported as * p < 0.05; ** p < 0.01; *** p < 0.001. Adapted with permission from [ 11 ]

Fig. 9 Recurrence free survival (RFS) as a proportion of high-risk non-muscle invasive bladder cancer (NMIBC) subjects in the escalation cohorts 1–3 ( n = 10; dotted line) vs. the high dose and expansion cohorts (solid line).

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“…This paper summarizes recent preclinical results [9][10][11] evaluating IT administration of large surface area microparticle docetaxel (LSAM-DTX) in a variety of tumor types alone and in combination with immunotherapy and the initial clinical trial utilizing local administration of LSAM-DTX to treat high-risk non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) (NCT03636256) [12].…”