Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood

Abstract

Administration of chemotherapeutics as direct injections into tumors offers increased anti-tumor activity and reduced systemic toxicity. In this study, the Renca syngeneic murine xenograft model of renal cancer was used to evaluate the effects of intratumoral (IT) submicron particle docetaxel (NanoDoce®) on tumor growth and immunomodulation. Tumor volume (TV) was compared to controls, including intravenous (IV) chemotherapy. Flow cytometry of peripheral bloods and tumors was used to evaluate immune cell populations. Groups of animals were inoculated with a second Renca tumor at a site distant from the primary tumor. IT NanoDoce significantly reduced primary TV and reduced the growth rates of untreated secondary tumors. CD4+, CD8+ and Treg populations were increased in peripheral bloods from animals administered IT NanoDoce. Additional evaluation of the effect of IT NanoDoce on peripheral and local immune cell populations as well as the impact on sites of distant tumor growth are warranted.

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

“…The relative increase in concentrations of CD4 + T cells and CD4 + helper T cells as well as CD8 + T cells in the tumor and peripheral blood following SPD (Fig. 3 ) is consistent with previous reports of increased concentrations of T cells in SPD-treated Renca xenografts [ 6 ]. These immune cell responses include increased density of CD4 + helper T cells, CD8 + T cells, B cells, NKT cells, and DC in the TME.…”

“…The increase in primary tumor kill as well as reduction in metastasis with the addition of systemic anti-mCTLA-4 therapy suggests that disruption of the TME by SPD in combination with systemic immunotherapy produces a more effective anti-tumor response. The findings of this study, in addition to previous studies of SPD treatment in uro-oncologic xenografts [ 1 ], Renca xenografts [ 6 ] and SPP IT injections in pharmacology and clinical studies [ 5 ] support the hypothesis that submicron taxane particles are directly tumoricidal in the primary tumor and contribute to the innate and adaptive immune system’s therapeutic response by turning the primary “cold” tumor “hot” without creating local or systemic toxicity.…”

“…High levels of docetaxel were retained in SPD-injected sites up to 50 days post-treatment. We also reported that injection of SPD into syngeneic murine xenografts models of renal adenocarcinoma (Renca) significantly reduced or eliminated primary tumor growth compared to IV docetaxel and affected rates of tumor growth in secondary tumor implants [ 6 ]. In addition, CD4 +, CD8 +, and Treg populations were increased in peripheral blood from animals following SPD treatment.…”

“…In addition, CD4 +, CD8 +, and Treg populations were increased in peripheral blood from animals following SPD treatment. Data from preclinical and clinical studies demonstrated that local administration of SPD or submicron particle paclitaxel (SPP) provided increased anti-tumor activity directly at the primary tumor site [ 1 , 6 – 9 ] and indirectly through enhanced immune effector cell response in peripheral blood [ 1 , 5 , 6 ]. Further benefit is seen following submicron particle taxane IT therapy with reduced systemic toxicity compared to IV taxanes therapy [ 1 , 3 , 5 , 6 ].…”

“…Data from preclinical and clinical studies demonstrated that local administration of SPD or submicron particle paclitaxel (SPP) provided increased anti-tumor activity directly at the primary tumor site [ 1 , 6 – 9 ] and indirectly through enhanced immune effector cell response in peripheral blood [ 1 , 5 , 6 ]. Further benefit is seen following submicron particle taxane IT therapy with reduced systemic toxicity compared to IV taxanes therapy [ 1 , 3 , 5 , 6 ]. The cytotoxic T lymphocyte antigen 4 (CTLA-4) is a critical receptor that regulates T cell activation and tolerance.…”