Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo

Abstract

The tumor microenvironment (TME) is established and maintained through complex interactions between tumor cells and host stromal elements. Therefore, therapies that target multiple cellular components of the tumor may be most effective. Sorafenib, a multi-kinase inhibitor, alters signaling pathways in both tumor cells and host stromal cells. Thus, we explored the potential immune-modulating effects of sorafenib in a murine HER-2-(neu) overexpressing breast tumor model alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine (3T3neuGM). In vitro, sorafenib inhibited the growth of HER-2 overexpressing NT2.5 tumor cells, inducing apoptosis. Sorafenib also interfered with ERK MAPK, p38 MAPK, and STAT3 signaling, as well as cyclin D expression, but did not affect HER-2 or AKT signaling. In vivo, single agent sorafenib disrupted the tumor-associated vasculature and induced tumor cell apoptosis, effectively inducing the regression of established NT2.5 tumors in immune competent FVB/N mice. Immune depletion studies demonstrated that both CD4+ and CD8+ T cells were required for tumor regression. Sorafenib treatment did not impact the rate of tumor clearance induced by vaccination with 3T3neuGM in tumor-bearing FVB/N mice relative to either sorafenib treatment or vaccination alone. In vivo studies further demonstrated that sorafenib enhanced the accumulation of both CD4+ and CD8+ T cells into the TME of vaccinated mice. Together, these findings suggest that GM-CSF-secreting cellular immunotherapy may be integrated with sorafenib without impairing vaccine-based immune responses.

Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy

“…In tumor-bearing mice, data suggested that sorafenib decelerated the growth of tumors through inducting of cell apoptosis, inhibiting of cell growth and angiogenesis. These data are consistent with the previous reports of sorafenib for the treatment of cancers with dysregulation of Ras/MEK/ERK pathway 31 - 33 . These may expand its role in a broader spectrum of oncotherapy.…”

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

“…Among the approved MKIs for HCC, the immunomodulatory effects of sorafenib have been studied the most extensively. In vivo and in vitro studies demonstrated that sorafenib may enhance antitumour immunity by increasing the M1 polarisation of TAMs, [86][87][88] enhancing CD4+ and CD8+ T cell infiltration and function, [89][90][91] suppressing Treg numbers, [91][92][93][94] or reversing the function MDSCs in the tumour microenvironment. 88,95,96 Other MKIs (lenvatinib, regorafenib, and cabozantinib) have also demonstrated antitumor immune activity in various pre-clinical models.…”

Targeting tumour microenvironment by tyrosine kinase inhibitor

“…Similar mechanism as dasatinib and imatinib has also been documented by sorafenib treatment, in which sorafenib also impaired T cells activation through LCK inactivation on T cells [ 106 , 107 ]. In this regard, sorafenib treatment increased CD4 (+), CD8 (+) T population while reduced PD1 (+) CD8 (+) T as well as declined the regulatory T cellular function and proliferation [ 108 , 109 ]. In line with these observations, clinical investigation on 45 sorafenib-receiving HCC patients showed reduced Th2 and regulatory T populations after high dose treatment of sorafenib (400 mg and 800 mg/day) with mean plasma concentration of 3-6 mg/L, suggested the immune-modulatory effect of sorafenib [ 110 ].…”