Sunitinib facilitates the activation and recruitment of therapeutic anti‐tumor immunity in concert with specific vaccination

Abstract

The multikinase inhibitor sunitinib malate (SUT) has been reported to reduce levels of myeloid suppressor cells and Treg cells in cancer patients, hypothetically diminishing intrinsic impediments for active immunization against tumor-associated antigens in such individuals. The goal of this study was to identify longitudinal immune molecular and cellular changes associated with tumor regression and disease-free status after the treatment of established day 7 s.c. MO5 (B16.OVA) melanomas with SUT alone (1 mg/day via oral gavage for 7 days), vaccination using ovalbumin (OVA) peptide-pulsed dendritic cell [vaccine (VAC)] alone, or the combination of SUT and VAC (SUT/VAC). We observed superior anti-tumor efficacy for SUT/VAC combination approaches, particularly when SUT was applied at the time of the initial vaccination or the VAC boost. Treatment effectiveness was associated with the acute loss of (and/or failure to recruit) cells bearing myeloid-derived suppressor cells or Treg phenotypes within the tumor microenvironment (TME) and the corollary, prolonged enhancement of Type-1 anti-OVA CD8 1 T cell responses in the tumor-draining lymph node and the TME. Enhanced Type-1 T cell infiltration of tumors was associated with treatment-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and CXCR3 ligand chemokines in vascular/peri-vascular cells within the TME, with SUT/VAC therapy benefits conditionally negated upon adminsitration of CXCR3 or VCAM-1 blocking antibodies. These data support the ability of a short 7 day course of SUT to (re)condition the TME to become more receptive to the recruitment and prolonged therapeutic action of (VAC-induced) anti-tumor Tc1 cells.

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

“…44 This situation may be remedied by combined administration of anti-angiogenic agents (such as the TKIs axitinib, dasatinib or sunitinib) along with a tumor-specific vaccine. [45][46][47] Our DLK1/DLK2-targeted vaccine has an advantage over conventional TAA-targeted vaccine due to the proximal accessibility of circulating T effector cells to tumor-associated vascular pericyte targets in contrast to tumor cells that require T cells to enter, transmigrate and functionally persist within the TME to mediate meaningful therapeutic action. Furthermore, our vaccine promotes sustainable immune-mediated VN that would be envisioned to improve the deliverability of codelivered chemotherapies or adoptively-transferred (TCR-or CAR-engineered) T cells, theoretically without invoking the development of drug resistance or the adverse side-effects associated with anti-VEGF monoclonal antibodies and TKIs.…”

Combination Strategies to Enhance the Potency of Monocyte-Derived Dendritic Cell-Based Cancer Vaccines

“…Combination therapy utilizing dasatinib and DC-based vaccination against tumor blood vessel-associated antigens is currently being explored in the clinic, generating promising preliminary results in a pilot Phase II trial for HLA-A2+ patients with advanced-stage melanoma (NCT01876212). Combinational therapies employing other TKI, such as axitinib (Inlyta ® ) and sunitinib (SUTENT ® ), with dendritic cell vaccinations are also being studied in preclinical models of melanoma [44,45], as well as in a Phase II clinical trial of metastatic renal cell carcinoma (NCT02432846). In a Phase III clinical trial (NCT01582672), sunitinib enhanced the therapeutic efficacy of a novel autologous DC/peptide-based vaccine for patients with metastatic renal cell carcinoma [46].…”

Studies on Anti-Hepatoma Effect of Gan-Ai-Xiao Decoction

“…Western blot assay was used to study the effects of GAXD on apoptotic proteins, which were immediately related to apoptosis of cells. The apoptotic proteins were a research hotspot in the aspect of anti-tumor mechanism [22,23]. Bcl-2 protein inhibits apoptosis of tumor cells, and Bax and caspase-3 proteins induce apoptosis of tumor cells [24].…”