[Observation of the effects of LAK/IL-2 therapy combining with Lycium barbarum polysaccharides in the treatment of 75 cancer patients].

Seventy nine advanced cancer patients in a clinical trial were treated with LAK/IL-2 combining with Lycium Barbarum polysaccharides (LBP). Initial results of the treatment from 75 evaluable patients indicated that objective regression of cancer was achieved in patients with malignant melanoma, renal cell carcinoma, colorectal carcinoma, lung cancer, nasopharyngeal carcinoma, malignant hydrothorax. The response rate of patients treated with LAK/IL-2 plus LBP was 40.9% while that of patients treated with LAK/IL-2 was 16.1% (P < 0.05). The mean remission in patients treated with LAK/IL-2 plus LBP also lasted significantly longer. LAK/IL-2 plus LBP treatment led to more marked increase in NK and LAK cell activity than LAK/IL-2 without LBP. The results indicate that LBP can be used as an adjuvant in the biotherapy of cancer.

Phase Ib trial of pentoxifylline and ciprofloxacin in patients treated with interleukin-2 and lymphokine-activated killer cell therapy for metastatic renal cell carcinoma.

The dose of interleukin 2 (IL-2) which can be administered to cancer patients is limited largely by a capillary leak syndrome. Pentoxifylline (PTX) is a methylxanthine which reduces IL-2 toxicity in animals. Ciprofloxacin (Cipro) modifies the metabolism of methylxanthines and, when coadministered with PTX, increases levels of PTX and certain of its metabolites. We conducted a phase Ib trial in patients receiving IL-2 and lymphokine-activated killer cell (LAK) cell therapy for metastatic renal cell carcinoma to identify the maximum tolerated dose of PTX which could be coadministered with Cipro in this setting. Eighteen patients received IL-2 (Roche) by continuous infusion at 6 x 10(6) units/m2/day on days 1-5 and underwent leukapheresis on days 7-9. LAK cells were infused on days 12-14. IL-2 was administered at 2 x 10(6) units/m2/day on days 10-20. Cohorts of patients received PTX at 2.5 (n = 3), 3.1 (n = 6), 3.9 (n = 6), and 4.9 (n = 3) mg/kg by 30 min i.v. infusion every 4 h on days 0-5 and 10-20 and Cipro (500 mg p.o. every 12 h) on days 1-5 and 10-20. Toxicity was compared with that observed in 33 historical control patients who received 37 cycles of an identical regimen of IL-2/LAK without PTX/Cipro. PTX at 2.5-3.9 mg/kg and Cipro were well tolerated. The maximum tolerated dose of PTX was 3.9 mg/kg. Dose-limiting emesis (n = 1) and atrial fibrillation (n = 2) occurred at 4.9 mg/kg and were reversible. Two complete, one partial and one minor, responses were observed. Patients treated with 3.9 mg/kg PTX received 95.0% of the planned dose of IL-2 as compared to 72.8% in the control patients (P < 0.025), primarily due to a lower incidence of azotemia and metabolic acidosis in PTX/Cipro recipients than had been seen in the historical control patients. The results of this study demonstrate that PTX/Cipro can be administered to patients receiving IL-2/LAK without apparent loss of therapeutic efficacy. Moreover, PTX/Cipro recipients exhibited less toxicity than historical controls. Therefore, treatment with PTX/Cipro may allow delivery of higher doses of IL-2, which might induce more responses in IL-2-responsive tumors and regression of tumors unresponsive to conventional doses of IL-2.

Combined hyperthermia and immunotherapy treatment of multiple pulmonary metastases in mice.

The combination of immunotherapy and hyperthermia results in a greater reduction in tumour growth compared to either therapy used alone in a murine subcutaneous tumour model. To evaluate this combination further we tested it in a murine pulmonary metastasis model. Mice were given 5 x 10(5) MCA-105 sarcoma cells on day 0 intravenously resulting in the formation of pulmonary metastases. Mice were treated with local hyperthermia to the left hemithorax with a transcutaneous microwave applicator or with whole-body hyperthermia to 41 degrees C for 30 min on days 3 and 6. Immunotherapy included 5 x 10(7) syngeneic LAK cells administered on days 3 and 6 and interleukin-2 given intraperitoneally three times daily on days 3-7. Animals were killed on day 12 and pulmonary nodules enumerated. While the addition of whole-body hyperthermia to immunotherapy had no significant effect on tumour growth, the combination of local hyperthermia and immunotherapy significantly decreased the number of pulmonary nodules by 94% compared to controls in combined experiments. The mechanism of this beneficial effect may be related to increased trafficking of immune active cells to the tumour-bearing site, an increase in the sensitivity of tumour cells to lysis, or perhaps a local release of cytokines induced by hyperthermia. This study established the efficacy of combined immunotherapy and hyperthermia for the treatment of visceral metastases and provides impetus for the initiation of clinical trials.

Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment.

PURPOSE: We investigated whether the association of interleukin-2 (IL-2) with hypothyroidism is related to the presence of thyroid autoantibodies, dose of IL-2, and clinical effectiveness of treatment, and reviewed the literature. PATIENTS AND METHODS: Sixteen cancer patients were treated with high-dose recombinant, continuous infusion IL-2 (18 x 10(6) IU/m2/d) and lymphokine-activated killer (LAK) cells. One patient previously treated for a toxic goiter with radioactive iodine was analyzed separately. Thyroid function and levels of thyroid antibodies were determined regularly. RESULTS: Seven of 15 patients (47%) became hypothyroid with high serum thyrotropin (TSH) levels within 60 to 120 days after the start of treatment; five responded favorably to treatment (one complete remission [CR], four partial remissions [PRs]), compared with none of the other eight patients. Two hypothyroid patients developed antimicrosomal antibodies (AMAs), one showed a further increase of antithyroglobulin antibodies (TgAbs), and six developed TgAbs. Only one of eight euthyroid patients developed slightly elevated TgAb levels. Development of hypothyroidism correlated significantly with a favorable response to treatment (r = .76, P = .001). The patient, treated with radioactive iodine, also became hypothyroid with high levels of TSH and development of AMAs and TgAbs. No difference was found between the hypothyroid and euthyroid patients in mean cumulative dose of IL-2 administered within the first 60 days or total treatment period, or with the relative dose-intensity. No other autoantibodies were found and patients had normal corticotropin (ACTH) stimulation tests. CONCLUSION: The likelihood of developing (transient) hypothyroidism is higher in patients who respond to IL-2 treatment. The development of antithyroid antibodies suggests that IL-2 treatment triggers autoreactive B-cell clones or that cellular and/or cytokine-mediated thyroid destruction leads to activation of autoreactive B-cell clones.

Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission.

Records of 399 patients with metastatic renal cell carcinoma treated with interleukin 2 with or without lymphokine-activated killer cell immunotherapy enrolled in 14 separate clinical trials from multiple institutions were reviewed to determine whether patients with a partial response to interleukin 2 therapy would benefit from surgical resection of residual tumor. Sixty-two patients demonstrated objective responses (15.5%), 18 (4.5%) complete and 44 (11.0%) partial. Eleven patients underwent resection of residual tumor in the lung, kidney, retroperitoneum, or pelvis so that they had "surgically no evidence of disease" (SNED). Of these, 10 had partial responses, and one patient with progressive disease had a complete response. Comparison of response duration showed no difference between the complete response and SNED groups, but there was a significant difference between each of these groups and the partial response group. At this writing, all 11 patients in the SNED group remained alive without evidence of disease (median follow-up, 21 months). In contrast, only 14 patients (76%) with complete responses and 15 patients (35%) with partial responses remained free of disease progression. Enhanced survival of the complete response and SNED groups compared with the partial response group borders on significance and awaits longer follow-up. These data suggest that surgical resection, if technically feasible, may benefit patients who show a partial response to interleukin 2 treatment for metastatic renal cell carcinoma.

Hypovitaminosis C in patients treated with high-dose interleukin 2 and lymphokine-activated killer cells.

Patients (n = 15) with metastatic malignant melanoma, hypernephroma, and colon carcinoma received a three-phase adoptive immunotherapy protocol: phase 1, 10(5) units (high-dose) interleukin-2 (IL-2) iv every 8 h or 1 mg/m2 continuous intravenous infusion; phase 2, 6.5 d rest + leukapheresis; phase 3, 4 d of high-dose IL-2 plus three infusions of autologous lymphokine-activated killer cells. Toxicities of treatment included fever, chills, tachycardia, hypotension, vomiting, diarrhea, and fluid retention. Patients entering the trial were not malnourished, and mean plasma ascorbic acid concentrations before therapy were normal (36.3 +/- 14.2 mumol/L). Mean concentrations dropped by 80% after the first phase of treatment with high-dose IL-2 alone (to 7.4 +/- 4.5 mumol/L). Mean plasma ascorbic acid concentrations remained severely depleted (between 4.5 and 7.4 mumol/L) throughout the remainder of the 15-d treatment. Ascorbic acid concentrations became undetectable (less than 2.8 mumol/L) in 12/15 patients during this time. Blood pantothenate and plasma vitamin E concentrations remained within normal limits in all patients tested throughout the phases of therapy.

Current status of hemapheresis in the United States.

The face of automated hemapheresis in the United States is changing. No longer is it appropriate to view hemapheresis primarily in terms of therapeutic plasma exchange. For many centers, the bulk of day-to-day activities revolves around donor cytapheresis to satisfy the ever-increasing need for units of platelet concentrates. Indications of therapeutic plasma exchange are becoming better focused, with neurological patients being among those most frequently managed. New and innovative applications of automated hemapheresis technology will continue to be developed. Current examples include the production of lymphocyte-activated leukocytes for cancer therapy, use of extracorporeal photoactivation of leukocytes for immune modulation, and the collection of hematopoietic progenitors from peripheral blood for autologous transplantation. As we enter the 1990s, it is important to be aware of new technology and applications and to have the vision to apply them in innovative ways. However, it is also critical to demand rigorous scientific review before broadly adopting any new idea as a standard of practice.