Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer

Abstract

IL-15 has potential as an immunotherapeutic agent for cancer treatment because it is a critical factor for the proliferation and activation of natural killer (NK) and CD8 ؉ T cells. Administration of anti-CD40 antibodies has shown anti-tumor effects in vivo through a variety of mechanisms. Furthermore, activation of CD40 led to increased expression of IL-15 receptor-␣ by dendritic cells, an action that is critical for trans-presentation of IL-15 to NK and CD8 ؉ T cells. In this study, we investigated the therapeutic efficacy of the combination regimen of murine IL-15 (mIL-15) with an agonistic anti-CD40 antibody (FGK4.5) in murine lung metastasis models involving CT26 and MC38, which are murine colon cancer cell lines syngeneic to BALB/c and C57BL/6 mice, respectively. Treatment with mIL-15 or the anti-CD40 antibody alone significantly prolonged survival of both CT26 and MC38 tumor-bearing mice compared with the mice in the PBS solution control group (P < 0.01). Furthermore, combination therapy with both mIL-15 and the anti-CD40 antibody provided greater therapeutic efficacy as demonstrated by prolonged survival of the mice compared with either mIL-15 or the anti-CD40 antibody-alone groups (P < 0.001). We found that NK cells isolated from the mice that received the combination regimen expressed increased levels of intracellular granzyme B and showed stronger cytotoxic activity on the target cells. The findings from this study provide the scientific basis for clinical trials using the combination regimen of IL-15 with an anti-CD40 antibody for the treatment of patients with cancer.animal model ͉ cancer immunotherapy ͉ IL-15 receptor-␣

Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques

“…[6][7][8][9][10] Attempts to prevent or treat syngeneic tumors in mice by administration of IL-15 have proven effective. [28][29][30][31][32][33][34][35] In the present study, we evaluated the pharmacokinetics of rhIL-15 in rhesus macaques as part of an effort to define a rational dosing strategy. Previously, we described a unique feature of IL-15 in that it forms stable complexes with IL-15R␣ on cell surfaces (predominantly activated dendritic cells but also on nonhematopoietic cells of lungs and small intestine) that present IL-15 in trans to neighboring NK and CD8 cells that express IL-2/IL-15R␤ (CD122) and the common ␥c (CD132) but not the private IL-15R␣.…”

“…[6][7][8][9][10] Attempts to treat tumor models in mice by administration of IL-15 have proven effective. [28][29][30][31][32][33][34][35] Whereas wild-type C57Bl/6 mice died by 40 days after IV injection of MC38 colon carcinoma cells, IL-15 transgenic mice did not develop metastases and survived. 28 Furthermore, therapy with IL-15 prolonged survival of mice that received syngeneic CT26, MC38 colon carcinoma cells, or B16 melanoma cells.…”

“…When IL-15 was administered with an anti-CD40 antibody that increased IL-15R␣ expression, most of the mice were cured. 35 As part of the preclinical evaluation in the present study, recombinant human IL-15 (rhIL-15) was administered to 18 rhesus macaques divided into groups that received 10, 20, and 50 g/kg/d of rhIL-15, with an additional 6 animals receiving vehicle control daily for 12 days. There were no animal deaths, evidence of autoimmune diseases, or infections.…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…109 Two preclinical studies involving murine models have shown that administration of IL-15 is effective against colon carcinoma with both studies observing prolonged survival of mice with the cancer. 117,118 A study investigating the effects of IL-15 in rhesus macaques showed the cytokine to be generally well tolerated. 115 The development of GMP grade IL-15 in recent years 119 has enabled the initiation of Phase I clinical trials on patients with metastatic melanoma and metastatic renal cell carcinomaalthough results for these are yet to be reported.…”

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

“…28 Second, CD40L pos T cells are one of the main non-malignant cell partners for FL B cells, and CD40 triggering increases IL-15Ra expression on myeloid cells. 43 Finally, TNF is also upregulated within FL cell niche 21 and initiates an interferon-mediated autocrine loop in primary macrophages associated to the expression of interferon-response genes, including STAT1. 44 Altogether, the promoters of both IL-15 and IL-15Ra were shown to contain binding sites for IFN-response factors and NF-kB, and corresponding stimuli were strongly expressed within chronically inflamed lymphoid organs and FL biopsies.…”