Stephen P. Creekmore

The Hemodynamic Effects of Treatment with Interleukin-2 and Lymphokine-Activated Killer Cells

STUDY OBJECTIVE To determine the hemodynamic alterations occurring during therapy with the maximally tolerated doses of interleukin-2 and lymphokine-activated killer cells. DESIGN Case series. SETTING Referal-based inpatient oncology service at a university medical center. PATIENTS A sequential sample of 13 patients with metastatic colon carcinoma, malignant melanoma, or hypernephroma who were receiving treatment with interleukin-2 and lymphokine-activated killer cells in the maximally tolerated doses. MEASUREMENTS AND MAIN RESULTS Pretreatment variables of mean arterial pressure, systemic vascular resistance, heart rate, pulmonary capillary wedge pressure, and cardiac index were compared with the same variables measured either immediately before the eighth dose of interleukin-2 or immediately before the initiation of pressor support with dopamine hydrochloride. When these values were compared with the pretreatment values, patients showed a significant decrease in mean arterial pressure (92 mm Hg compared with 75 mm Hg; P less than 0.0001), and systemic vascular resistance (15.1 compared with 8.5 mm Hg/L . min; P less than 0.0001), but an increase in heart rate (73 compared with 110 beats/min; P less than 0.0001) and cardiac index (3.1 compared with 4.7 L/min . m2 body surface area; P less than 0.0001). No significant change was noted in pulmonary capillary wedge pressure. Low systemic vascular resistance persisted throughout interleukin-2 therapy. Although blood pressure normalized in 24 hours, the systemic vascular resistance remained below baseline levels 6 days after interluekin therapy had been stopped. INTERVENTIONS Blood pressure was successfully supported at greater than 90 mm Hg with dopamine hydrochloride or phenylephrine hydrochloride, or both. CONCLUSIONS Therapy with high doses of interleukin-2 induces hemodynamic changes consistent with a high-output and low-resistance state similar to changes noted during the early phase of septic shock.

A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions.

Recombinant interleukin-2 (rIL-2) (NSC# 600664; Hoffmann-La Roche, Inc., Nutley, NJ) was studied in a phase I clinical trial in 33 patients with advanced, measureable cancer of the colon or malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status O-1, and no prior chemotherapy or radiotherapy. The goal of the study was to identify a dose and schedule of IL-2 to generate maximal immune modulation with tolerable toxicity. Such a regimen might allow the addition of other treatment modalities and/or prolonged treatment duration in later trials. Each patient received IL-2 as a continuous 24-hour infusion once weekly for 4 weeks and then twice weekly for 4 weeks. Five treatment groups received from 10(3) U/m2 to 3 x 10(7) U/m2 per 24-hour infusion. The maximal tolerated dose was 3 x 10(7) U/m2/d twice weekly. Patients treated twice weekly at 1 x 10(7) and 3 x 10(7) U/m2/d had immune modulation in terms of lymphocytosis, eosinophilia, increased natural killer (NK) activity, and elevated numbers of peripheral blood mononuclear cells expressing CD16, OKT10/Leu-17, and Leu-19 surface markers. Endogenous generation of peripheral blood lymphokine-activated killer (LAK) activity was demonstrated by lysis of NK-resistant Daudi targets, in patients treated at 3 x 10(7) U/m2/d. Biochemical and hematological abnormalities were moderate and reversible. Clinical toxicity included hypotension, myalgia, arthralgia, stomatitis, fever, fatigue, nausea, headache, chills, diarrhea, and oliguria at high doses. Cardiovascular toxicity was tolerable for most patients and reversed after IL-2 was stopped. Two of six melanoma patients at 3 x 10(7) U/m2/d achieved partial responses by the end of the eighth week. This IL-2 schedule appears to produce potentially clinically useful immune enhancement with tolerable toxicity.

T cell activation via the disialoganglioside GD3: analysis of signal transduction.

The monoclonal antibody (mAb) R24 is a murine immunoglobulin G3 (IgG3) that reacts with the GD3 disialoganglioside present on melanoma cells as well as a subset of T cells. R24 mAb has induced antitumor responses both alone and in combination with interleukin‐2 (IL‐2) in clinical trials. We have reported T cell activation via GD3 as measured by the induction of tyrosine phosphorylation. In this study a more detailed analysis of signal transduction after ligation of GD3 was performed in an attempt to understand the mechanism of in vivo therapeutic benefits observed. Analysis of subsequent events indicated that GD3 engagement resulted in phospholipase Cγ phosphorylation and calcium flux. When ras‐associated events were examined, GD3 signaling resulted in ras activation as determined by GDP/GTP conversion as well as dose‐and time‐dependent IP3 activation. In addition, the majority of the IPS activation by GD3 was inhibited by herbimycin A pretreatment. Elucidation of the nature and potential role of this moiety in GD3 signal transduction should be useful. Collectively, these data suggest a novel mechanism of T cell activation via a single, non‐protein, surface moiety. This novel form of T cell‐mediated activation may permit the delivery and local activation of effector cells at the tumor resulting in site‐specific activation of the immune system. J. Leukoc. Biol. 60s 533–539; 1996.

CITN11-02 interim trial results: subcutaneous administration of recombinant human IL-15 (rhil-15) is associated with robust expansion of peripheral blood CD56+ NK cells

Meeting abstracts IL-15 activates and induces the proliferation of CD8+ T cells and NK cells. The Cancer Immunotherapy Trials Network (CITN) is conducting a Phase I, open-label, dose-escalation study of subcutaneous (SQ) rhIL-15 in advanced melanoma, renal cell, non-small cell lung and squamous