Therapy‐induced antitumor vaccination by targeting tumor necrosis factor‐α to tumor vessels in combination with melphalan

Abstract

Treatment of tumor-bearing mice with mouse (m)TNF-a, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4 + T cells and consequent activation and maturation of CD8 + CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4 + and CD8 + T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-a and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4 + CD25 + regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and longlasting antitumor adaptive immune response.

Vandetanib Improves Anti-Tumor Effects of L19mTNFα in Xenograft Models of Esophageal Cancer

“…In this study, the use of murine TNFa was mandatory, in view of the lower biological activity of human TNF in the mouse setting, and the therapeutic properties of L19-mTNFa have previously been documented (11)(12)(13). L19mTNFa is not a canonical VDA (20), but its effects on blood vessels and tumor morphology indicate that it behaves as such in esophageal tumor xenografts, in line with previous observations (11).…”

“…Conjugation of L19 to certain cytokines allows their selective accumulation within the tumor microenvironment and enhances their anti-cancer properties; in particular, the fusion protein L19mTNFa, consisting of mouse (mTNFa) conjugated to L19, accumulates around the tumor vasculature and behaves as a vascular disrupting agent (VDA) (11). Moreover, when injected with melphalan in immunocompetent tumorbearing mice, L19mTNFa induces complete and longlasting tumor eradication, triggering the generation of a specific T-cell-dependent immune response to tumor antigens (12,13). Clearly, L19mTNFa exerts complex therapeutic activities in immunocompetent syngeneic mouse tumor models, involving vascular effects, direct cytotoxic effects, and immune-mediated mechanisms.…”

The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth

“…Although it can promote tumor growth, TNF-␣ 48 is essential for the activation and maturation of CD8 ϩ cytotoxic T lymphocyte effectors. 49 Tregs were significantly increased in the tumor-draining LNs from post septic mice, whereas the percentage of CD8 ϩ perforin ϩ T cells and the ratio between CD8 ϩ -producing IFN-␥ and Tregs were significantly lower in these animals compared with sham controls. The decreased frequency of perforin ϩ CD8 ϩ T cells in post septic mice was not a direct consequence of severe sepsis, because LNs from sham and post septic mice without tumor contained the same percentage of perforin ϩ CD8 ϩ T cells.…”

The antibody‐based targeted delivery of interleukin‐4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer

“…3,7,[35][36][37] We first performed combination experiments in F9 tumor-bearing mice using F8-IL4 plus F8-IL2, 5 in consideration of the fact that IL2-based products are the most frequently investigated immunocytokines in clinical trials. which led to complete tumor eradications in 2=5 mice.…”