摘要:

Summary:Tumor infiltrating lymphocytes (TILs) are derived from solid tumors by culturing single cell suspensions of the tumors in low dose interleukin- 2 (IL-2) and intermittent tumor stimulation. We have investigated the survival of TILs after intravenous injection into tumor-bearing mice. Using several murine transplantable sarcomas, we examined the in vivo survival of TILs derived from B6.PL Thy la/CY mice (Thy-1.1), which were used to treat established experimental metastases in C57BL/6N (Thy-1.2) mice. Donor and host lymphoid cells could be clearly distinguished by fluorescence-activated cell sorting. We found that TILs or TILs + IL-2 could extend the survival of and, in some instances, cure established experimental hepatic and pulmonary metastases. Donor TILs could be recovered from treated animals at all time points tested; in mice cured of pulmonary metastases donor TILs could be detected as late as 119 days after intravenous injection even in the absence of exogenous IL-2. The administration of a relatively low dose of IL-2 in vivo to mice receiving TILs increased the number of donor TILs recovered from the lungs of cured animals 5-10-fold at all time points but did not change the period of time during which donor TILs could be detected in vivo. Additionally, TILs could be recovered from animals cured of established metastases and such cells retained their antitumor activity in vivo. Finally, when mice cured of pulmonary metastases by TILs or TILs + IL-2 were rechallenged with tumor, donor TILs specifically accumulated at the site of tumor rechallenge up to 4 months after adoptive transfer of TILs. The data demonstrate that adoptively transferred TILs survive for prolonged periods in cured mice and that these cells retain functional memory T cell characteristics. The data are relevant to ongoing trials of TIL therapy for patients with cancer.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:This investigation compared the immunomodulating activities of two forms of monophosphoryl lipid A, which are analogues of bacterial lipopolysaccharides with little or no toxicity. Tested were a synthetic compound designated 504 and a purified compound, isolated from bacterial cell walls designated MPL. Both of these clinical adjuvant candidates were effective in mice in exerting strong immunomodulating activity in the following areas: (a) enhancing antibody production in young and aging mice; (b) suppressing antibody formation under different experimental conditions; (c) activating macrophages to secrete interleukin 1, hydrogen peroxide, and superoxide anion; and (d) stimulating proliferation of spleen cells from C3H/HeN mice. Both exhibited considerably reduced toxicity in LD50assays when compared to native lipopolysaccharides (LPS). The LD50for MPL was 225 times and that of compound 504, 40 times that of native LPS in the exquisitely sensitive, galactosamine-loaded C57BL/6 murine strain.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:We set up a culture protocol that consistently allows high-fold expansion of tumor-specific T-lymphocytes from most melanoma-invaded biopsies with low doses of recombinant interleukin-2 (rIL-2). Between 2–60 x 106T-lymphocytes could be obtained and cryopreserved from 12 out of 13 patients, by culturing only 50 mm3tumor tissue with rIL-2. Thawed lymphocytes from 11 of these patients could then be expanded by a median factor of 32,800 by culturing them successively in microplates on irradiated feeder cells with rIL-2 for ˜2 weeks and then in culture bags or flasks with only rIL-2 for 1-2 additional weeks. Dead feeder cells disappeared during the last phase of the lymphocyte culture with rIL-2. Interestingly, each time they were expanded under these conditions, tumor-infiltrating lymphocytes (TIL) or lymph-node lymphocytes developed a lytic activity apparently restricted to the autologous melanoma line. Tumor-specific lysis, which was maximum at around the end of T-lymphocyte expansion, ranged between 31-63% lysis at an effector:target (E:T) ratio of 20:1. This culture method would thus appear to be suitable for reliable production of over 1010T-lymphocytes with good tumor-specific lytic activity from most melanoma-invaded biopsy. It should permit analysis of the immunotherapeutic potential of these populations reinjected into cancer patients.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:High-dose recombinant interleukin-2 (rIL-2) therapy can induce long-term remission in patients with melanoma and renal and colon cancer. More recently, in vivo IL-2 therapy was shown to induce complete or partial remission in some cases of relapsed chemotherapy-resistant acute myeloid leukemia. We have investigated the phenotypic modifications of bone marrow cells obtained from five patients with acute myeloid leukemia in relapse receiving high-dose i.v. rIL-2. We found that, in three of five patients, IL-2 could induce, in vivo, an increase in the expression of CD54/ICAM-1 and to a lesser extent of CD58/LFA-3 on bone marrow leukemic blasts. This demonstrates that rIL-2 modifies directly or indirectly the expression of the cell surface molecules of the tumor cells themselves. Upregulation of such adhesion molecules could account for the enhancement of cell interactions between the tumor and effector cells such as T, natural killer, and phagocytic cells as well as being indicators of differentiation signaling.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:Recombinant interleukin-4 (IL-4) profoundly inhibits the proliferative response of chronic lymphocytic leukemic B cells (B-CLLs) to recombinant interleukin-2 (IL-2). In the present study, we confirmed and extended these data by showing that IL-4 strongly suppresses the [3H]thymidine incorporation by B-CLLs stimulated by recombinant tumor necrosis factor a, recombinant interferon a, IL-2, and low molecular weight B cell growth factor in the absence of costimulant. Recombinant interleukin-4 inhibits spontaneous DNA synthesis suggesting that it also interferes with the autocrine proliferation of these cells. Kinetic studies indicate that IL-4 suppresses rather than shifts the peak of cytokine-induced DNA synthesis. Moreover, IL-4 blocks the progression of B-CLLs in or into Gl stage of the cell cycle as shown by the inhibition of cytokine-induced [3H]uridine incorporation. Finally, IL-4 pretreatment of B-CLLs prevents their subsequent proliferative response to the above cytokines, indicating that IL-4 confers to the B-CLLs a state of resistance to numerous stimulatory cytokines. The antiproliferative effects of IL-4 suggest that this lymphokine may have important therapeutic implications for the B-CLL patients.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:From June 1988 to November 1990 the Southwest Oncology Group initiated nine protocols for the phase II evaluation of recombinant human tumor necrosis factor alpha (rhuTNFα) in cancer patients. Patients with diverse metastatic malignancies including breast, colon, gastric, pancreatic, endometrial, and bladder cancers, as well as multiple myeloma and various sarcomas received 150 µg/m2of rhuTNFa daily for 5 days every other week. Of 147 patients entered in the study, 127 were eligible and were evaluated for toxicity and response. Of 124 patients known to have completed treatment, 92 (74%) went off study for progression, 21 (17%) for toxicity, and 12 (10%) for other causes, mainly that of worsening medical condition. Thirteen percent of patients experienced grade 4 or fatal toxicity. The most serious toxicities were pulmonary failure and coagulopathies. The predominant grade 3 toxicities were symptomatic (chills, fever, malaise, headache, myalgia, and nausea or vomiting). Only one partial remission was seen in a patient with metastatic bladder cancer lasting 4 months (rate 0.8%, exact 95%; confidence interval 0-4%). At the study dose and schedule, rhuTNFαdoes not appear to have significant antitumor activity. The biological basis for this finding is discussed.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:A phase I trial was performed to assess the immunomodulatory activities, maximum tolerated doses, and the toxicity of recombinant interleukin- 2 (rIL-2) administered in combination with doxorubicin to patients with refractory malignancies. Therapy was administered to successive cohorts of four to six patients who were treated at three different dose levels (1A, IB, 2A). Levels 1-2 refer to doxorubicin (40 or 60 mg/m2) given as an intravenous (i.v.) bolus on day 1, and levels A-B refer to rIL-2 (1.0 or 3.0 x 106U/m2) given as a continuous i.v. infusion on days 2-5, 9-12, and 16-19. Cycles were repeated every 28 days. Seventeen patients were entered in the trial. Dose limiting toxicity consisted of neutropenia, and the maximum tolerated dose (MTD) of the combination was doxorubicin 40 mg/m2 and rIL-2 3.0 x 106U/m2. No objective responses were observed. Lymphocytosis related to rIL-2 occurred and flow cytometry demonstrated significant increases in the following subsets: CD3+CD25+HLADr+and CDllb-CD16c+CD8-. Natural killer cell activity and lymphokine-activated killer (LAK) cell precursors were increased in patients treated at dose levels 1A and IB (40 mg/m2doxorubicin), but no consistent changes in LAK activity were noted. No clinical responses were seen and the overall toxicity of this combination was moderate to severe. Administration of doxorubicin prior to rIL-2 does not enhance the immunologic effects of rIL-2.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The toxicity and/or the stimulation of natural killer cell activity that resulted from exposure to a-interferon varied according to circadian dosing time, both in mice and in human beings. Ten patients with advanced renal cell carcinoma or melanoma were treated with recombinant a-interferon-2b using a continuous 21-day intravenous schedule at circadian modulated rate. Patients received 15-20 MU/m2day in an ambulatory care program. The drug was delivered via an external programmable-in-time pump. Thirty-nine courses of therapy were given (2-12 courses per patient). Severe side effects included World Health Organization grade III somnolence (one patient, 1 course) and grade III-IV neutropenia (five patients, 10 courses). Karnofsky performance status decreased by 40% in 3 patients (five courses). Two of these patients were withdrawn from the study because of toxicity. Disease was stabilized in four of the seven patients evaluable for response. Seven of the 10 patients are alive at 15 months' median follow-up. Two have continued with chronotherapy for 9+ and 13+ months, respectively. A large interpatient variability characterized the maximally tolerated dose. Two patients led their usual activities while receiving 20 MU/m2/day for three courses or more. Conversely, two patients exhibited severe side effects with 10 MU/m2/day. As compared with schedules of standard administration or continuous flat infusion, this circadian schedule of infusion allowed a large increment in total daily dose and dose intensity. A starting dose of 15 MU/m2/day was well tolerated by 8 of 10 patients and can be recommended using this circadian modulated schedule.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:We prospectively examined thyroid function during and following chronic, outpatient therapy with recombinant interleukin-2 (rIL-2) and Roferon- A (rIFN-α2a). Twenty-two of 30 patients with advanced renal cell carcinoma treated on a phase II open pilot study of concomitant rIL-2 and rIFN-α2a were included. Serum levels of thyroxine, triiodothyronine, free thyroxine index, thyrotropin, antithyroid antibodies, and thyrotropin (TSH) receptor binding antibodies were measured before therapy and after every other cycle. Selected patients underwent studies after every cycle and following completion of therapy. Twenty patients (91%) developed laboratory evidence of thyroid dysfunction, 11 (50%) developed hypothyroidism, five (23%) had a biphasic pattern, and four (18%) had hyperthyroidism. The incidence of thyroid dysfunction increased with increased number of treatment cycles. Transient hyperthyroidism was noted in six of the 11 patients studied after the first cycle and persisted after cycle three in only two patients. Hypothyroidism was not observed after cycle 1, but became increasingly frequent between cycles 2 (56%) and 6 (90%). Thyroid function normalized following therapy in nine of 12 patients tested. Antithyroid antibodies were identified pretherapy in five patients (23%) and de novo in none; TSH receptor binding antibodies were not detected. This study demonstrates a remarkably high frequency of reversible thyroid dysfunction in patients with advanced renal cell carcinoma treated with repeated cycles of rIL-2 plus rIFN-α2a. We conclude that chronic therapy with rIL-2 and rIFN-α2a produces thyroid dysfunction in virtually all patients most likely secondary to a nonspecific, nonautoimmune, toxic manifestation of prolonged treatment. IL-2 therapy may, therefore, produce thyroid dysfunction by more than one mechanism.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:A recent study reported that a single bolus dose of interleukin-2 (IL-2) decreased blood pressure to normal in adult hypertensive rats and prevented the development of spontaneous hypertension in young rats. The Surgery Branch of the National Cancer Institute has had extensive experience with the administration of IL-2. A review was performed focusing on the experience of IL-2 administration to cancer patients with established preexisting hypertension. Seventeen evaluable patients were identified. Sixteen of the patients experienced a return of their hypertension with the completion of therapy. One patient was able to stop his antihypertensive medications and remain normotensive for 3 months' follow-up. One normotensive patient developed hypertension after initiating IL-2 therapy. Our data do not demonstrate significant reduction in blood pressure in previously hypertensive patients undergoing high-dose IL-2 therapy.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID