In vivo traffic of indium-111-oxine labeled human lymphocytes collected by automated apheresis.

The in vivo traffic patterns of autologous lymphocytes were studied in five normal human volunteers using lymphocytes obtained by automated apheresis, separated on Ficoll-Hypaque gradients, and labeled ex vivo with 111In-oxine. Final lymphocyte infusions contained 1.8-3.1 X 10(9) cells and 270-390 microCi (9.99-14.43 MBq) 111In, or 11-17 microCi (0.41-0.63 MBq) per 10(8) lymphocytes. Gamma imaging showed transient lung uptake and significant retention of radioactivity in the liver and spleen. Progressive uptake of activity in normal, nonpalpable axillary and inguinal lymph nodes was seen from 24 to 96 hr. Accumulation of radioactivity also was demonstrated at the forearm skin test site, as well as in its associated epitrochlear and axillary lymph nodes, in a subject who had been tested for delayed hypersensitivity with tetanus toxoid. Indium-111-oxine labeled human lymphocytes may provide a useful tool for future studies of normal and abnormal lymphocyte traffic.

Interleukin-2 induces profound reversible cholestasis: a detailed analysis in treated cancer patients.

Interleukin-2 (IL-2)-based immunotherapy is associated with profound reversible cholestasis and hyperbilirubinemia. We performed a nonrandomized retrospective and prospective analysis to determine the incidence, characteristics, clinical course, and nature of the IL-2-induced liver dysfunction in patients with cancer. Patients received IL-2 at a dose of 20,000 to 100,000 units (U)/kg thrice daily for up to 5 days. Fifty-one patients on adjuvant treatment protocols received a mean of 10.18 +/- 2.38 IL-2 doses and 11.67 +/- 4.16 doses were delivered to 210 patients with advanced disease during this period. Retrospective analysis of all patients receiving this therapy revealed increases in the following liver function tests expressed as median, 25th percentile, and 75th percentile (range): bilirubin (mg/dL) 4.5, 2.6, 6.5 (.4 to 38.5); alkaline phosphatase (U/L) 256, 179, 378 (56-1680); SGOT (U/L) 80, 52, 117 (18 to 483); SGPT (U/L) 91, 64, 132 (20-540); prothrombin time 13.4, 12.8, 14.5 (10.8 to 35.4); and albumin (g/dL) values decreased (trough) slightly 3.0, 2.8, 3.2 (2.3 to 3.8). Multiple regression analysis revealed several factors that were significantly associated with the increase in bilirubin when jointly considered (model P2 less than or equal to .001) including total IL-2 dosage, increase in creatinine, alkaline phosphatase, weight, and SGOT. Similar increases were noted in a prospectively evaluated group of 10 patients. A return to normal levels of bilirubin was noted within 5.6 days of stopping IL-2. Fasting serum cholylglycine increased from a mean of 32.3 +/- 1.6 to a peak of 1556.0 +/- 625.0 mg/mL. Although conventional ultrasound examinations were unrevealing, tissue ultrasound examinations revealed a mean scatterer spacing (MSS) increase compared to baseline of .10 +/- .04 (P less than .02) suggesting hepatic edema or an infiltrative process. Further, computerized hepatobiliary nuclear medicine scans revealed a delay in uptake (2.2 +/- 0.5 fold greater) and excretion (8.0 +/- 5.9 fold greater) of technetium-99m labeled disofenin. These findings support the development of profound reversible cholestasis as the primary basis for the elevated bilirubin in patients undergoing IL-2 treatment and may have implications for understanding the jaundice observed in some patients postoperatively as well as that associated with sepsis and other inflammatory disorders. Specifically, the release of IL-2 or the induction of other factors similarly induced by IL-2 may be responsible for these findings. Tissue ultrasound and computerized hepatobiliary scans provide additional noninvasive assessments of liver function and physiology.

Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma.

Lymphoid cells infiltrating into human tumors can be expanded in vitro in medium containing interleukin-2 (IL-2). Adoptive transfer of these tumor-infiltrating lymphocytes (TIL) mediates potent antitumor effects in murine tumor models. Clinical trials to evaluate the efficacy of these cells in patients with advanced cancer are underway. We have investigated whether infused TIL labeled with indium 111 (111In) oxine can traffic and localize to metastatic deposits of tumor. Six patients with metastatic malignant melanoma who had multiple sites of subcutaneous, nodal, and/or visceral disease were the subjects of the study. The patients received cyclophosphamide 36 hours before receiving the intravenous (IV) infusion of TIL followed by IL-2 IV every eight hours. The distribution and localization of the TIL were evaluated using serial whole body gamma camera imaging, serial blood and urine samplings, and serial biopsies of tumor and normal tissue. 111In-labeled TIL localized to lung, liver, and spleen within two hours after the infusion of activity. Activity in the lung diminished within 24 hours. As early as 24 hours after injection of 111In-labeled TIL, localization of TIL to sites of metastatic deposits was demonstrated in all six patients using either imaging studies or biopsy specimens or both. 111In activity in tumor tissue biopsies ranged from three to 40 times greater than activity in normal tissue. A progressive increase in the radioactive counts at sites of tumor deposit was seen. This study shows that labeled TIL can localize preferentially to tumor, and provides information concerning the possible mechanism of the therapeutic effects of TIL.