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Biomedical subjects

C R Franks

Publications and source records attributed to C R Franks.

At least 37 records · Page 2Linked to original sources
PubMed1992

Interleukin-2 and interferon-alpha in the treatment of patients with advanced non-small-cell lung cancer.

The role of combination chemotherapy in the treatment of advanced non-small-cell lung cancer is controversial. At best, a small survival benefit can be achieved. Therefore, other treatment modalities are needed. On the basis of the promising treatment results with interleukin-2 (IL-2) -containing immunotherapy in renal cell cancer and melanoma, we performed a phase I-II study with IL-2 and interferon alpha (IFN-alpha). Eligible patients were treated with IL-2 18 x 10(6) IU/m2/day by continuous intravenous infusion (c.i.v.) for 3 days. On the same days, 5 x 10(6) U/m2/day IFN-alpha was given intramuscularly. After a rest period of 4 days, patients at the first dose level received IL-2 2.4 x 10(6) IU/m2/day c.i.v. for a period of 28 days, followed by 14 days' rest, 14 days' treatment, 7 days' rest, and a final treatment for 14 days. Patients at the second dose level were treated according to the same schedule, in which the dose of IL-2 was increased to 3.6 x 10(6) IU/m2/day. During low-dose IL-2 treatment, patients received IFN-alpha 5 x 10(6) U/m2/day on days 1 and 4 of each week. Eleven patients were admitted to the study, six at the first and five at the second dose level. Median age was 54 years; all patients had a performance status of 0 or 1. The most important adverse effects included anorexia, fatigue, nausea, and headache, which were not dose limiting. In the 11 patients treated, no responses were seen. Nine patients developed progressive disease during the first 5 weeks of treatment. We concluded that this regimen of IL-2 and IFN-alpha is ineffective.

Adult↗
PubMed1992

Intravesical therapy of superficial bladder transitional cell carcinoma with tumor necrosis factor-alpha: preliminary report of a phase I-II study.

A phase I-II trial of intravesical immunotherapy with tumor necrosis factor (TNF)-alpha in 24 patients affected by superficial bladder tumors is herein presented. Of these, 11 patients were submitted, at weekly intervals, after complete TUR, to 8 instillations of TNF-alpha at increasing doses from 50 to 600 micrograms. Tolerability was excellent, even at the highest dose. In a second group of 13 patients with a histologically proved papillary marker lesion, TNF-alpha was instilled at weekly intervals at the dose of 500 micrograms for 8 weeks. Three complete responses (23%) were obtained.

Administration, Intravesical↗
PubMed1992

Effects of escalating doses of recombinant human interleukin-2 in correcting functional T-cell defects following autologous bone marrow transplantation for lymphomas and solid tumors.

High-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) in the treatment of malignancies is often associated with immune deficiency following transplantation, possibly contributing to tumor relapse or fatal infection. Interleukin 2 (IL-2), which enhances major histocompatibility complex (MHC)-unrestricted cytotoxicity in vitro, can be applied in vivo as immunotherapy to reduce these potential complications. Recombinant human IL-2 (rIL-2) was administered by continuous i.v. infusion for four courses in 19 patients following ABMT for lymphomas and solid tumors. The patients were assigned to five groups of escalating doses of rIL-2 ranging from 3 to 30 x 10(6) IU/m2/day. The immunological effects and toxicity were monitored. After a transient reduction of lymphocytes in the peripheral blood, a significant lymphocytosis was observed during the rIL-2 infusion with an augmentation of CD2+, CD25+, and CD8(+)-Ia+ T cells and a dose-related increase of CD56+ lymphocytes. Natural killer (NK) activity appeared enhanced in patients treated with as little as 6 x 10(6) IU/m2/day. No statistically significant increase in lymphokine-activated killer (LAK) activity was seen after rIL-2, when compared to LAK activity following ABMT prior to rIL-2 administration. Administration of exogenous rIL-2 to patients who have undergone ablative chemotherapy and ABMT has a role in restoring defective T-cell function. Further trials defining those patients most likely to benefit from rIL-2 integrated with ablative chemotherapy and ABMT are now warranted.

Adult↗
PubMed1992

A phase 2 trial of recombinant interleukin-2 and 5-fluorouracil in patients with metastatic colorectal carcinoma.

The toxicity and efficacy of sequential 5-fluorouracil (5-FU) and recombinant interleukin-2 (IL-2) were evaluated in 12 patients with metastatic colorectal carcinoma. This combination of 5-FU and IL-2 produced a 10% partial response rate with 40% of patients remaining in stable disease while on therapy. No clear improvement in survival was demonstrable. In contrast to the disappointing response rates the overall level of toxicity was very low with no treatment related deaths. It is concluded that modifications in treatment schedules are required before further similar studies are commenced.

Adult↗
PubMed1991

Effect of prolonged subcutaneous administration of interleukin-2 on the circadian rhythms of cortisol and beta-endorphin in advanced small cell lung cancer patients.

Interleukin-2 has been shown to stimulate cortisol secretion in man. Owing to its immunosuppressive properties, an increase in cortisol levels during interleukin-2 cancer immunotherapy could potentially counteract induced activation of the antitumor immune response. Few data are available about cortisol secretion secondary to prolonged interleukin-2 administration. To investigate the problem, we evaluated cortisol circadian rhythms in 7 consecutive metastatic small cell lung cancer patients who received interleukin-2 subcutaneously for 4 weeks (daily dose: 6 x 10(6) x IU/m2). Venous blood samples were drawn at 8.00 a.m., 4.00 p.m. and 12.00 p.m., before interleukin-2, and after each week until the end of the cycle. Beta-endorphin levels were also measured on the same samples. Four patients were evaluated during a second interleukin-2 cycle. Mean cortisol levels increased during interleukin-2 therapy, but were significantly higher than those seen in basal conditions after the first week of treatment. Moreover, cortisol peaks observed during the second cycle of therapy were not significantly different from those seen during the first cycle. Mean beta-endorphin levels increased in response to interleukin-2 administration, but the increase did not reach statistical significance. The early cortisol rise progressively decreased as treatment continued. This suggests that the interleukin-2-induced cortisol rise has no relevant clinical importance in antagonizing the activation of an effective antitumor immune response during cancer immunotherapy with interleukin-2.

Carcinoma, Small Cell↗
PubMed1991

Local activation of immune response in bladder cancer patients treated with intraarterial infusion of recombinant interleukin-2.

Tumor regression induced in cancer patients by i.v. infusion of interleukin-2 (IL-2) is often accompanied by severe side effects. To investigate whether local administration would affect immune response without the side effects, two 5-day cycles of continuous intraarterial [internal iliac artery] infusion of recombinant interleukin-2 (rIL-2) were performed in 12 patients with transitional cell carcinoma (tumor stage 1, node stage 0, metastasis stage 0, and grade 1-2) of the bladder. Four groups of 3 patients were treated at each of 4 escalating doses of rIL-2 (18 x 10(3), 18 x 10(4), 18 x 10(5), and 18 x 10(6) IU/m2/day) throughout the course of the two IL-2 cycles. This treatment was effective in inducing a marked intratumor inflammatory response, consisting mainly of T-lymphocytes and macrophages. A remarkable dose-dependent increase in the levels of soluble CD25 was observed in the urine of all patients, which was associated constantly with an enhanced number of intratumor CD25+ cells. Intratumor macrophages were often immunoreactive for interleukin-1 and/or tumor necrosis factor, suggesting an activated status. Increased levels of soluble CD25 and CD25+ lymphocytes were observed in peripheral blood only at the two highest doses of rIL-2, while increased percentages of circulating HLA-DR+ and CD71+ lymphoid cells and enhancement of CD3+/CD16+ T-lymphocytes were found at lower doses. Peripheral blood eosinophils were augmented in almost all patients but were rarely increased in situ. We provide evidence that continuous intraarterial infusion of rIL-2 activates host immune response, acting preferentially at the tissue level.

Antigens, CD↗
PubMed1991

The development of neutralizing antibodies in a patient receiving subcutaneous recombinant and natural interleukin-2.

Systemic administration of interleukin-2 (IL-2) in humans may induce antibodies specific to IL-2. The case is reported of a patient with metastatic rectal carcinoma who was treated with long-term subcutaneous IL-2 and a combination of subcutaneous IL-2 and interferon-alpha 2b (IFN-alpha 2b). This patient developed nonneutralizing and neutralizing anti-IL-2 antibodies recognizing both the recombinant and natural cytokine. Detectable serum levels of neutralizing antibodies were accompanied by the inhibition of immune responsiveness to systemic IL-2 in vivo.

Antibodies↗
PubMed1991

Treatment of leptomeningeal carcinomatosis with continuous intraventricular infusion of recombinant interleukin-2.

A 42-year-old man developed leptomeningeal carcinomatosis 6 years after treatment of a malignant melanoma. He was treated with two courses of recombinant interleukin-2, administered as a continuous intraventricular infusion (6 X 10E5 U/24 h) during 5 days. During the first day of the first course he also received 5 X 10E9 lymphokine-activated killer cells intraventricularly. This gave rise to a severe elevation of intracranial pressure, with headaches and meningismus. During the second course no LAK cells were administered. This course was tolerated much better. The neurological status did not change during the treatment. Recombinant interleukin-2 levels were maintained at about 300 U/mL during both courses.

Adult↗
PubMed1991

Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study.

Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2(IL2), 18 x 10(6) IU/m2/d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC), 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2, 18 x 10(6) IU/m2/d for 5 days alternating with DTIC, 850 mg/m2 IV every 3 weeks, for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventricular tachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with IL2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone.

Adult↗
PubMed1990

Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies.

The safety, tolerance, and clinical effects of a home therapy regimen of recombinant human interleukin-2 (rIL-2) and interferon-alpha 2b (IFN-alpha 2b) self injected subcutaneously have been assessed in 35 patients with advanced cancer refractory to standard therapy. 52 treatment cycles were given, each consisting of a 2-day rIL-2 pulse of 9.0 million IU/m2 every 12 h, followed by 6 weeks of rIL-2 1.8 million IU/m2 twice daily for 5 days per week and of IFN-alpha 2b 5.0 million U/m2 thrice a week. The main adverse effects were fever, chills, nausea, anorexia, and hypotension and were limited to WHO grades of severity I and II in 29 of 35 patients. No treatment-related deaths occurred. The response rates among patients with renal-cell carcinoma were similar to those reported for high-dose intravenous regimens of interleukin-2 that are toxic and have to be given in hospital.

Adult↗
PubMed1990

Hypothyroidism and goiter in a patient during treatment with interleukin-2.

The development of transient hypothyroidism and goiter in a patient with a metastasized malignant melanoma during treatment with recombinant interleukin-2 (rIL-2) and dacarbazine is reported. Signs of autoimmune thyroiditis became apparent 2 weeks after the start of treatment and disappeared after treatment stopped. It is likely that rIL-2 was responsible by interfering with preexisting autoimmune thyroid disease. The possible mechanisms are discussed here. Patients with positive antithyroid microsomal antibody titers are prime candidates for rIL-2-induced thyroiditis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Correlation between clinical response to interleukin 2 therapy and sustained production of tumor necrosis factor.

Twenty-five previously untreated patients with metastatic renal cell carcinoma were treated with 5-day cycles of continuous infusion of interleukin 2 (IL2) and lymphokine-activated killer cell reinfusion. Five achieved a partial response. Three patients were found to have detectable tumor necrosis factor (TNF) in serum before initiation of therapy. On the fifth day of therapy, 24 patients had circulating TNF with immunoradiometric assay whereas 13 had detectable biological activity. Two days after the end of IL2 therapy, TNF concentration (immunoradiometric assay) decreased in most cases but was still detectable in 17 patients. Thirteen patients had still circulating TNF bioactivity. Although there was no significant difference between TNF levels observed on the fifth day of therapy in the responder and nonresponder groups, 48 h after the end of IL2 infusion, both the TNF concentration and the biological activity were significantly higher in the group of responder patients. This result suggests that the clinical response to IL2 therapy in patients with metastatic renal cell carcinoma is correlated to a sustained production of TNF after the end of IL2 infusion.

Animals↗
PubMed1990

Recombinant interleukin 2 for acute myeloid leukaemia in first complete remission: a pilot study.

We treated nine patients in first remission from AML with rhIL-2. The toxic effects of rhIL-2 infusion were, malaise, pyrexia, and hypotension, which resolved rapidly on cessation of rhIL-2 infusion. No patient required transfer to an intensive care unit. Following rhIL-2 infusions patients developed eosinophilia, and a modest lymphocytosis, involving both NK cells, and T lymphocytes. Relapse occurred in six patients at a median of 39 weeks from remission. A particular concern was rapid relapse in the two patients with AML FAB type M5. There was no survival advantage from rhIL-2 treatment when compared to a similar group of chemotherapy only treated AML patients from this institution.

Actuarial Analysis↗
PubMed1990

Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-alpha.

We treated 17 patients who had progressive metastatic renal carcinoma with a combination of subcutaneous recombinant human interleukin-2 (administered every 12 hours, at 9.0 million IU/m2 on days one and two, followed by 1.8 million IU/m2, five days per week, over six consecutive weeks) and interferon-alpha 2b (given at 5 million U/m2 three times weekly, for six consecutive weeks). Treatment courses were repeated in patients presenting with stable or regressive disease after the six weeks of combination therapy (11 of 14 evaluable). Two and three of 14 evaluable patients achieved complete and partial remissions, respectively. Toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (WHO) fevers, chills, malaise, nausea/vomiting, and anorexia in more than two-thirds of the patients treated.

Carcinoma, Renal Cell↗
PubMed1990

Increased numbers of circulating haematopoietic progenitor cells after treatment with high-dose interleukin-2 in cancer patients.

Immunotherapy with recombinant interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells has been applied to patients with metastatic cancers for its antitumour activity. In the present study we investigated the effects of in vivo administration of IL-2 (3 x 10(6) U/m2/d, continuously i.v.) on haematopoiesis. Six patients with disseminated renal cell carcinoma, treated with IL-2 and LAK cells, were monitored for the numbers of white blood cells and circulating haematopoietic progenitor cells (HPC). During IL-2 treatment lymphopenia developed, followed by lymphocytosis after discontinuation of IL-2 infusions. IL-2 administration also resulted in neutrophilia and eosinophilia. Absolute numbers of circulating HPC declined markedly during IL-2 treatment. However, after completing IL-2 infusions, the numbers of circulating erythroid (BFU-E), myeloid (CFU-GM) and multipotential progenitor cells (CFU-GEMM) strongly increased, reaching a maximum after 5 d (day 10 from the start of IL-2 treatment). This increase did not result from repeated leucaphereses, since patients treated with IL-2 alone showed a similar response. In comparison with pretreatment levels the pool of circulating HPC expanded about 20-fold. This study illustrates that IL-2 treatment has a biphasic effect on the frequency of circulating BFU-E, CFU-GM and CFU-GEMM, causing a decrease during IL-2 infusion, followed by an increase after IL-2 administration. The total number of progenitor cells harvested by four consecutive leucaphereses is in the range that is commonly used for peripheral blood stem cell autografting.

Carcinoma, Renal Cell↗