Intratumoral low-dose interleukin-2 induces rejection of distant solid tumour

Abstract

This study shows that local tumor treatment with low-dose recombinant interleukin-2 (IL-2) can mediate rejection of a large distant solid tumour. When SL2 lymphoma cells were injected intraperitoneally (i.p.) in syngeneic DBA/2 mice on day 0.70% of these mice were cured by daily i.p. injections with 20,000 units IL-2 on days 10-14. After injecting mice with SL2 both i.p. and subcutaneously (s.c.) on the flank. 50% of the mice treated i.p. with low-dose IL-2 rejected both the i.p. tumour and the large distant s.c. tumour. In contrast, i.p. IL-2 treatment on days 10-14 cured fewer than 10% of the mice bearing only a s.c. SL2 tumour. The described IL-2 immunotherapy also caused systemic tumour rejection in mice bearing both ascitic and solid P815 mastocytoma. Thus it was shown that low-dose IL-2 can induce systemic tumour rejection, when injected at a site of tumour growth. Interleukin-2-induced rejection of s.c. SL2 tumour was highly specific, as mice that were rejecting i.p. and solid s.c. SL2 lymphoma did not reject solid P815 mastocytoma, which was injected s.c. simultaneously on the other flank. Furthermore, solid s.c. tumours consisting of mixtures of SL2 and P815 were not rejected in mice that rejected i.p. SL2 or P815. We conclude that intratumoral injections of low-dose IL-2 can enhance an ongoing weak immune reaction against the tumour resulting in systemic tumour rejection.

IL-2 Intratumoral Immunotherapy Enhances CD8+ T Cells That Mediate Destruction of Tumor Cells and Tumor-Associated Vasculature: A Novel Mechanism for IL-2

“…IL-2 may induce necrosis, leading to an effective immune response with (16) or without lymphocytes (17). We observed increased necrosis in some of our IL-2-treated mice (data not shown).…”

“…IL-2 has been shown to inhibit (12,13) or induce (14,15) vascularity in different systems. IL-2 has also been reported to cause necrosis or induce an antitumor response that may involve lymphocytes (16,17), neutrophils, macrophages (18,19), NK cells (20,21), and/or T cells (22,23). Therefore, the next series of experiments were designed to determine which mechanism(s) mediated the IL-2 response seen in the data shown above.…”

NK cell-based cancer immunotherapy: from basic biology to clinical application

“…It is well-known that IL-2, a growth factor that induces proliferation and expansion of lymphocytes and plays key roles in immune responses, can activate NK cells and enhance NK cytotoxicity against malignant cells [67]. Many studies using animal models have demonstrated the effectiveness of IL-2 on NK cell activation and anti-tumor responses [68][69][70][71][72][73][74][75][76][77][78][79][80][81]. Robinson and Morstyn [82] has also reported that NK cells from lung cancer patients that fail to kill tumor cells, can regain the cytotoxicity against targets after activation by IL-2.…”

Direct and indirect antitumor effects by human peripheral blood lymphocytes expressing both chimeric immune receptor and interleukin-2 in ovarian cancer xenograft model

“…20 Intratumoral treatment with IL-2 is more effective than peritumoral treatment 17,21 or treatment at a more distant site. 22 Peripheral blood lymphocytes or cytokine-induced killer cells electroporated with RNA encoding anti-Her-2/ neu-specific CIR have been shown to elicit potent immune responses against Her-2/neu-overexpressing SKOV3 tumors. 9,23 The main problem with this approach has been that, due to lack of survival and gradual decrease in cell number, the antitumor effects of PBLs were not maintained long enough to target the tumors.…”