Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease.

Abstract

Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone or in conjunction with other treatment modalities.

Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12

“…The systemic administration of recombinant IL-12 protein has shown profound antitumor effects in animal models, but its clinical application has been associated with significant side effects. [3][4][5] IL-12 is a heterodimeric cytokine produced predominantly by antigen (Ag)-presenting cells in response to infectious agents. IL-12 induces IFN-␥ production from natural killer (NK) and T cells, stimulates the proliferation of activated NK and T cells, and enhances the cytotoxic activity of NK cells.…”

Retroviral-mediated transfer of genes encoding interleukin-2 and interleukin-12 into fibroblasts increases host antitumor responsiveness

“…Moreover, this route of administration of cytokines might be safer than systemic administration. [41][42][43] Because coexpression of the two subunits of mIL-12 is required to obtain an immunologically functional protein, 44 we have constructed a bicistronic MSCV-based retroviral vector 29 by inserting an IRES sequence from EMCV into a transcription unit to obtain the production of active IL-12. 45,46 In mice, an excess of homodimeric p40 can inhibit heterodimeric IL-12.…”

“…Cooperation between B7-1 and IL-12 has been shown to be more effective than immunization with either immunomodulator alone. 19,43,49 Even if no CTL activity could be obtained, a systemic response was induced, as splenocytes from mice injected with IL-2 and IL-12 fibroblasts showed a higher proliferative response and higher IFN-␥ production compared with that observed in B16F1-bearing mice.…”

IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro

“…23 We hypothesized that dysfunctional antitumor Th1-type responses in cancer patients with active disease might be recovered/enhanced by in vitro stimulation (IVS) of patient CD4 þ T cells using vaccines containing autologous dendritic cells (DCs) engineered to secrete IL-12p70 and/or IL-18. This gene therapy approach could not only prove capable of supporting Type-1 immunity, but would have the potential to obviate toxicities previously observed for systemic application IL-12p70 alone [24][25][26] or IL-12p70 combined with IL-18. 27 Indeed, our group has previously shown in murine models that DCs engineered to secrete both IL-12p70 and IL-18 ex vivo, and subsequently injected intratumorally, promote acute tumor rejection in concert with enhanced Th1-type immunity and determinant spreading in the curative antitumor CTL repertoire.…”