Combination therapy with a synthetic peptide of C-reactive protein and interleukin 2: augmented survival and eradication of pulmonary metastases

Abstract

A synthetic peptide (RS-83277) derived from the structure of human C-reactive protein (CRP) was previously shown to have antitumor activity in three different murine tumor models when administered in multilamellar vesicles (MLV). The therapeutic effects were comparable to those seen with MLV-encapsulated native CRP. The present study evaluated the therapeutic and immunomodulatory effects of administering CRP peptide RS-83277 MLV simultaneously with low-dose recombinant interleukin-2 (IL-2) to C57Bl/6 mice bearing established pulmonary metastases of fibrosarcoma T241. Results demonstrated that the capacity of RS-83277 MLV to inhibit tumor metastases and prolong survival was significantly augmented by combination with 10,000 U/day IL-2 i.p. Treated animals showed no evidence of toxicity. By immunohistochemistry, increased Thy 1.2+ cells were detectable in lungs of RS-83277 MLV/IL-2-treated animals compared to those receiving RS-83277 MLV alone. Circulating tumor necrosis factor alpha (TNF) and interferon (IFN) were not detectable in animals receiving RS-83277 MLV alone, but TNF was significantly elevated in animals receiving IL-2. In the presence of combination therapy, however, circulating TNF was not detectable. Results suggest that the combination of synthetic CRP peptide RS-83277 MLV and low-dose IL-2 offers a therapeutic advantage over either agent alone.

Inhibition of Mouse Mammary Adenocarcinoma (EMT6) Growth and Metastases in Mice by a Modified Form of C-Reactive Protein

“…Two-thirds of the animals in the control groups and those treated with native-CRP in LUVETs showed lung metastatic growths at day 29, whereas 7 of 31 (23%) of mCRP-or mCRP-LUVETtreated animals had observable lung metastases. These results support those studies which showed that active forms of CRP could significantly improve survival and decrease the number of metastatic lesions in mouse models of cancer disease [25,26].…”

“…Administration of IL-2 could exacerbate complications caused by weakened vascular tissues, thus limiting the delivery of a therapeutically effective amount of IL-2. Therapeutic administration of mCRP, specifically prior to IL-2 therapy, may reduce the toxic side effect of IL-2 therapy and allow for more effective use of IL-2 similar to the effects of the combination of CRP and IL-2 as reported [26] and described above.…”

“…The most notable measured effects required CRP to be encapsulated in liposomes [24,28], and native, pentameric CRP was not significantly active in any in vitro or in vivo assay [24,[28][29][30]. Synthetic peptides derived from the CRP sequence also exhibited therapeutic effects for a number of tumor model systems [25,26]. As with the intact molecule, the therapeutic effect of the CRP peptide required liposome encapsulation [25].…”

“…In mouse model systems, preparations of CRP in liposomes, or certain CRP peptides in liposomes, significantly improved the survival and decreased the number of metastatic lesions in both a pulmonary fibrosarcoma and a liver colon adenocarcinoma [24,25]. Further, when active forms of CRP were used in combination with IL-2, essentially all metastatic lesions were eliminated and more than 50% of treated animals were long-term survivors [26].…”