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PubMed1991

[Enhancement of epidermal growth factor receptor (EGF-R) expression on glioma cells by cytokines].

Recombinant tumor necrosis factor alpha (TNF-alpha) significantly enhanced epidermal growth factor receptor (EGF-R) expression in U373-MG glioma cell line as determined by binding of anti-EGF-R monoclonal antibody (MAb) 425. The optimal dose of TNF-alpha was 1000 U/ml of media. When TNF-alpha was combined with recombinant interferon gamma (IFN-gamma), further upregulation of EGF-R was observed. However, IFN-gamma itself did not show any EGF-R enhancement in this cell line. Scatchard analysis of receptor binding revealed that this enhancement of EGF-R expression was due to an increase in the EGF-R density. TNF-alpha did not affect expression of other brain tumor-associated antigens defined by MAb ASHE2, ASHG4 and ASAY1. Cultured fibroblasts showed no upregulation of EGF-R by TNF-alpha, suggesting a differential effect of TNF-alpha on EGF-R expression on glioma cells and normal cells. We investigated whether TNF-alpha treatment of glioma cells increased the tumoricidal effects of radiolabeled MAb 425 which correlate with MAb density on tumor cell surfaces. Growth inhibition of glioma cells in culture by 125I-labeled MAb 425 was significantly enhanced after treatment of the cells with TNF-alpha. In previous clinical trials, 125I-labeled MAb 425 has shown immunotherapeutic effects in glioma patients. The present study provides the basis for considerations of combined immunotherapy of glioma patients with 125I-labeled MAb 425 and cytokines.

Animals↗
PubMed2026

Exploring New Frontiers in Osteosarcoma Treatment: Clinical Trial Insights.

INTRODUCTION: Osteosarcoma (OS) is a common bone malignancy in adolescents and older adults and typically develops in the long bones. Outcomes in advanced cases remain poor despite the use of chemotherapeutic drugs like doxorubicin, methotrexate, and cisplatin, underscoring the urgent need for safer, more focused treatments. METHODS: A comprehensive review of clinical trials and literature identified emerging OS therapies targeting DNA repair, immune pathways, and tumor-specific markers. The EMA's approval of Mepact for nonmetastatic OS underscores the shift toward precision treatments and the evolving landscape of OS management. Patent protection can influence the pricing and accessibility of innovative medicines for OS by affecting market exclusivity and competition. RESULTS: According to recent research, bone morphogenetic protein (BMP), RB, and TP53 gene alterations both contribute to the development of OS. These results highlight the importance of conducting further proteomic and genomic research in order to develop focused and efficient treatment plans. Furthermore, patent protection stimulates innovative drug development by encouraging research investment and faster launches, but restricts affordability due to exclusivity, posing a policy dilemma. DISCUSSION: Treatment for OS is still challenging, particularly in high-grade and metastatic cases when conventional chemotherapy is frequently harmful and unsuccessful. While new targeted medicines and advances in understanding bone cell dynamics and genetic abnormalities such as TP53, RB, and BMPs offer hope for more accurate, less invasive treatments, the approval of Mapact represents progress. CONCLUSION: The necessity for integrated therapies combining immunotherapy, targeted delivery, and molecular insights to enhance OS treatment results is highlighted by developments in genomics and bone remodeling.

Mepact↗
PubMed1998

Neuroimmunoregulation and cancer (review).

It is certain that neuroimmune mechanisms play a role in host defence against cancer. However, this interaction is highly complex and many variations are possible according to the nature of the neoplasms involved. There are indications that adaptive immunity is present in a significant proportion of tumor bearing hosts, and this defence may be boosted by specially designed vaccines and cytokines. Natural immune mediators are also implicated in resistance against tumor development. Here we review the evidence suggesting that hormonal manipulation of the host can result in the elevation of immune defences against cancer. Such manipulation strengthens both the adaptive and natural immune defences of the host, both of which play significant roles. Natural defence mechanisms are boosted by cytokines and hormones during febrile reactions which are now known as the acute phase response. It is suggested that hormonal stimulation of immune mechanisms coupled with the usual immunostimulants already in use may be employed to good advantage for the combination immunotherapy of cancer. Modern molecular biology approaches permit the development of laboratory monitoring procedures which may be used for the prediction and follow-up of therapeutic success.

Acute-Phase Reaction↗
PubMed2001

Immune rejection of a large sarcoma following cyclophosphamide and IL-12 treatment requires both NK and NK T cells and is associated with the induction of a novel NK T cell population.

Combined immunotherapy with cyclophosphamide (Cy) and IL-12, but not IL-12 alone, stimulates eradication of a large established solid tumor (20 mm), MCA207, a methylcholanthrene-induced murine sarcoma. In these studies we demonstrate that NK1.1(+) cells and CD1d-dependent NK T cells each play important yet distinct roles in regression of a large tumor in response to Cy and IL-12, and we define a novel NK T cell subset, selectively increased by this treatment. Mice depleted of NK1.1(+) cells demonstrated more rapid initial tumor growth and prolonged tumor regression following treatment, but tumors were eventually eradicated. In contrast, initial tumor regression following therapy was unimpaired in CD1d(-/-) mice, which are deficient in most NK T cells, but tumors recurred. No tumor regression occurred following Cy and IL-12 therapy in CD1d(-/-) mice that were depleted of NK1.1(+) cells. We found that Cy and IL-12 induced the selective increase in liver and spleen lymphocytes of a unique NK T subpopulation (DX5(+)NK1.1(-)CD3(+)). These cells were not induced by treatment in CD1d(-/-) mice. Our studies demonstrate a contribution of both NK and NK T cells to the Cy- and IL-12-stimulated anti-tumor response. We describe the selective induction of a distinct NK T cell subset by Cy and IL-12 therapy, not seen following IL-12 therapy alone, which we suggest may contribute to the successful anti-tumor response induced by this immunotherapeutic regimen.

Animals↗
PubMed2005

Analysis of anthrax and plague biowarfare vaccine interactions with human monocyte-derived dendritic cells.

The anti-biowarfare anthrax and plague vaccines require repeated dosing to achieve adequate protection. To test the hypothesis that this limited immunogenicity results from the nature of vaccine interactions with the host innate immune system, we investigated molecular and cellular interactions between vaccines, dendritic cells (DCs), and T cells and explored the potential for adjuvants (pertussis) to boost induction of host immunity. Human monocyte-derived DCs were matured in the presence of vaccines and analyzed for their ability to induce Th1/Th2 development from naive T cells, expression of cell surface maturation/costimulation molecules, and cytokine production. The vaccines showed different behavior patterns. Although the plague vaccine is equivalent to control maturation factors in maturation and stimulation of DCs and induces strong MLR and Th outgrowth, the anthrax vaccine is a poor inducer of DC maturation, as indicated by low levels of HLA-DR, CD86, and CD83 induction and minimal proinflammatory cytokine production. Interestingly, however, anthrax vaccine-treated DCs stimulate Th1 and Th2 outgrowth and a limited MLR response. There was no sustained negative modulatory effects of the anthrax vaccine on DCs, and its limited stimulatory effects could be overridden by coculture with pertussis. These results were supported by analysis of anthrax vaccine recall responses in subjects vaccinated using pertussis as an adjuvant, who demonstrate anthrax-specific effector T cell responses. These data show that the anthrax vaccine is a suboptimal DC stimulus that may in part explain the observation that it requires repeated administration in vivo and offer a rational basis for the use of complementary DC-maturing adjuvants in combined immunotherapy.

Adjuvants, Immunologic↗
PubMed2000

Systemic therapy for renal cell carcinoma.

PURPOSE: We review the status of systemic therapy for patients with advanced renal cell carcinoma. MATERIALS AND METHODS: A literature search was performed on MEDLINE and CANCERLIT to identify results of systemic therapy for patients with renal cell carcinoma published from January 1990 through December 1998. Treatment results of chemotherapy agents, immunotherapy, combination programs and adjuvant therapy were reviewed. RESULTS: No chemotherapy agent has produced response rates that justify its use as a single agent. Interferon-alpha and interleukin (IL)-2 demonstrated low response rates ranging from 10% to 20%. The results of 2 randomized trials suggest that treatment with interferon-alpha compared to vinblastine or medroxyprogesterone achieves a small improvement in survival. Response rates in patients treated with low dose IL-2 are similar to those achieved with a high dose bolus schedule but whether the responses are as durable is being addressed in an ongoing randomized trial. A randomized trial of interferon-alpha plus IL-2 compared to monotherapy with either agent showed increased toxicity but no improvement in survival. In 3 randomized trials no survival benefit was associated with adjuvant interferon-alpha therapy following complete resection of locally advanced renal cell carcinoma. CONCLUSIONS: Despite extensive evaluation of many different treatment modalities, metastatic renal cell carcinoma remains highly resistant to systemic therapy. A few patients exhibit complete or partial responses to interferon and/or IL-2 but most do not respond, and there are few long-term survivors. Preclinical research, and clinical evaluation of new agents and treatment programs to identify improved antitumor activity against metastases remain the highest priorities in this refractory disease.

Carcinoma, Renal Cell↗
PubMed1998

[Influence of MP infection on immunologic function in patients with chronic obstructive pulmonary disease].

The aim of this study was to detect Mycoplasma pneumoniae(MP) in sputum with chronic obstructive pulmonary disease(COPD) by using polymerase chain reaction and measured the level of sIL-2R in chronic pulmonary heart disease(CPHD) patients by Enzyme Linked Immnosorbert Assay(ELISA). At the same time, we also measured the level of the serum total IgE in CPHD patients. We determine the relationship between the sIL-2R and lymphocytes. The results showed that rate of MP infection in COPD patients was 34.59%. The rate of MP infection in CPHD patients and asthmatic patients were significantly higher than that in patients with chronic bronchitis. The level of sIL-2R in patients with CPHD who had MP infection increased significantly higher than that in CPHD patients which didn't have MP infection. There was a linear negative correlation between the level of sIL-2R and lymphocytes. The level of serum total IgE in CPHD patients with MP infection was higher than that in patients with other infection. These data suggest that MP is a common agent in COPD patients, particularly in CPHD and asthma. MP infection can impair the cellular immunity and immunotherapy combined with antibiotics may be more effective.

Adult↗
PubMed1999

Effect of methyl-prednisone and cyclosporine on the lipid pattern and polyunsaturated fatty acid biosynthesis in the rat.

The hyperlipidemia posttransplant has been largely attributed to immunosuppressant agents. In the present work we evaluated the effect of oral administration of cyclosporine (5 mg/kg/day) and/or methyl-prednisone (1 mg/kg/day) on lipid composition and polyunsaturated fatty acid biosynthesis in normal adult male rats. The results obtained showed that both agents produced a delay on the growth together with a significant loss of body weight. In liver microsomal fraction from rats treated with methyl-prednisone, a depression in delta 6 and delta 5 desaturation activities, was observed. This effect was corroborated in the fatty acid pattern through the enhancement of linoleic and dihomo-gamma-linolenic acids, and a depression of arachidonic acid. Similar results were noticed in those rats treated with both drugs when compared to the controls. No changes were observed either in the amount of liver microsomal total lipids or in the fatty acid composition of kidney and testis microsomes, as well as in erythrocyte membranes, among the different groups studied. Cyclosporine alone produced a significant depression in plasma triglycerides and showed no modifications in the other lipid parameters studied compared to the controls. Fluorescence anisotropy measured in the different membranes was not modified by the several treatments used. In view of the aforementioned data, it can be stated that methyl-prednisone would be the responsible for many of the lipid disorders that can be observed in posttransplant patients when they are subjected to the combined immunotherapy with cyclosporine.

Animals↗
PubMed2002

Granulocyte-colony stimulating factor enhances chimeric antibody Nd2 dependent cytotoxicity against pancreatic cancer mediated by polymorphonuclear neutrophils.

Nd2 is a monoclonal antibody against pancreatic cancer. We have previously reported that human/mouse chimeric antibody Nd2 (c-Nd2) can induce antibody-dependent cell-mediated cytotoxicity (ADCC) with peripheral blood mononuclear cells (PBMs) as effectors. In this study, we investigated whether c-Nd2 can induce ADCC with poly-morphonuclear neutrophils (PMNs) as effector cells and the effects of granulocyte-colony stimulating factor (G-CSF) in enhancing this cytotoxicity. Cytotoxicities for pancreatic cancer cell line, SW1990 were dose-dependently increased by c-Nd2 during co-culture with PMNs and these cytotoxicities were significantly suppressed by the addition of neutralizing antibodies against CD16, which is Fcgamma receptor expressed on PMN membranes. PMNs treated with G-CSF significantly enhanced in vitro ADCC activity against SW1990 induced by c-Nd2. The in vivo growth of subcutaneously transplanted SW1990 tumor in nude mouse was significantly inhibited by i.p. administration of c-Nd2 compared to control (non-specific IgG1). In addition, this inhibitory effect was enhanced by the combination of c-Nd2 and G-CSF. Immunohistochemical study with anti-mouse neutrophil elastase antibody demonstrated strong infiltrations of PMNs into and around the transplanted tumor, treated with c-Nd2 and G-CSF. These results suggest that PMNs play an important role in c-Nd2 inducing ADCC and that combination immunotherapy of c-Nd2 with G-CSF may have clinical applications in the treatment of patients with pancreatic cancer by enhancing ADCC.

Animals↗
PubMed2005

[Adjunctive reflections on history of hematopoietic stem cell study--editorial].

The article reviews concisely around the history of hematopoietic stem cell research, basic and clinical, since its very beginning after the nuclear explosions at the end of the Second World War, that explains why the stem cell study in the world began with the hematopoietic stem cells and the existence of non-hematopoietic stem cell in vivo had been left out of account for many decades till 21st century. During 50-60s of the last century, it was known from the animal experiments that there must be hematopoietic stem cells existing in vivo and believed that the effective bone marrow transplant is actually the stem cell transplantation. It is reviewed how the basic studies of stem cell interacted with the clinical stem cell transplantation and how great the contribution was given to strongly push forward the development of contemporary stem cell biology and modern hematology from the basic studies especially in the immunological and molecular biological fields, for instance, the applications of HLA technology and monoclonal antibody produced, flow cytometry, and genetic recombinant cytokines, the novel technique for gene cloning, genomics, proteomics, and iRNA as well as bioinformatics. It has lead to the pluralistic cell therapy as a novel trend in stem cell transplantation as to combine immunotherapy and mesenchymal stem cells with the conventional stem cell transplants. This paper looks back in the past several decades, however, on every achievement of stem cell study that were usually accompanied with some idealistic one-sidedness or even errors in design and conclusion of some experiments. Usually it took a period of 2 or even 4 decades to clarify some basic idea, that seemed normal in the science development, for examples, the dividing line between the hematopoietic stem cell and progenitor cells, possibility to expand or clone the real stem cell ex vivo, and whether the majority of leukemias are originated from stem cell level, etc. Towards the end of 20th century, the greatest discovery was the existence of adult stem cells in adult tissues, which are no doubt the remnants from the embryonic development including all stages of embryonic stem cells, very earlier and later, hematopoietic and nonhematopoietic, and could be induced to differentiate into all kinds of tissue cells by proper ways in vitro. No evidence has really provided for the hypothesis of so called trans-differentiation or de-differentiation, which brought about strong calls in questions in the past 5 years. The problems in developing the clinical gene therapy by using hematopoietic stem cell as carrier of interested gene still remained to be solved so far. Because of the relatively weak base of related basic studies, the clinical application of gene therapy resulted in the failure of clinical practice with lots of lessons towards the end of last century. The whole history of stem cell study in the world was an endless process of continuous redress for theoretical ideas in stem cell biology that had never been consummate.

Hematopoietic Stem Cells↗
PubMed2005

[New insights into cytotoxic effector cells].

Cytotoxic immune cells play a role against infectious or tumour invasion. There are two types of cytotoxic cells : those involved in innate or natural immunity (natural killer cells, Tgammadelta lymphocytes, NKT cells) and those involved in the adaptive or acquired immunity (cytotoxic T lymphocytes). Recent advances in immunology have allowed the characterisation of unconventional cytotoxic populations, to better individualise the real cytotoxic cells within the traditional CD8+ T-cell population, and finally to get more insights into the activation of the cytotoxicity properties, in particular with regard to NK cells. The data recently acquired concerning the effector cytotoxic cells contribute to a better understanding of the interactions between the immune system and tumour cells. This may provide rational basis for combined immunotherapy protocols.

Cytotoxicity, Immunologic↗
PubMed1987

Effect of anti-B16 melanoma monoclonal antibody on established murine B16 melanoma liver metastases.

The administration of anti-B16 monoclonal antibody of the IgG2b isotype to mice bearing established B16 melanoma liver metastases caused a significant and consistent reduction of up to 90% in the number of these metastases. No reduction in the number of metastases was noted when antigenically unrelated tumor or nonspecific immunoglobulin were employed. The antibody-mediated antitumor effect was completely abrogated by total body irradiation of the host. Treatment of the tumor-bearing host with antiserum directed against asialo GM1 prior to anti B16 antibody administration, abrogated the therapeutic effect indicating the involvement of a radiosensitive, ASGM1-positive cell in the tumor regression. The antitumor effect of the antibody treatment could be augmented by the concomitant administration of recombinant interleukin-2. The effect seen may have possible application in the treatment of liver metastases in humans by combined immunotherapy using recombinant interleukin-2 and specific antitumor monoclonal antibodies.

Animals↗
PubMed1982

[Multidisciplinary treatment of malignant melanoma of the nose and paranasal sinuses--with special reference to oral administration of enterosoluble BCG capsules].

In authors' clinic, seven patients with malignant melanoma of the nasal cavity and paranasal sinuses were treated with "per oral BCG" immunotherapy combined with other treatments for 3 years and 7 months from September 1978 to March, 1982. Eighty mg of BCG was enclosed in an enterosoluble capsule and administered to these patients orally once a week. Total doses of BCG administered were ranged from 2,240 mg to 11,860 mg. These treatments were effective for metastasis to the lung, but ineffective against the abdominal metastasis. Immunological parameters of these patients indicated good scores during the treatments. Mean survival time of four cases who died was 3 years and 3 months, and three other cases lived for 5 months, 11 months, and 2 years and 10 months, respectively. On the other hand, mean survival time of six historical control cases was 1 year and 10 months. Multidisciniplinary treatment was thought to be effective to extend their survival time. Three cases complained of arthralgia as a side effect by oral BCG administration.

Adult↗
PubMed1984

[Advantages and limits on the surgical therapy of esophageal cancer].

During a 11-year period, 315 patients of squamous cell carcinoma of the thoracic esophagus were treated. Notwithstanding the great majority of the patients had advanced cancer and operative contra-indications were very limited, the percentage of the operation of total patients was 94% (297/315) and that of operative mortality was 7.0% (20/297). As a standard surgical procedure, subtotal esophagectomies were performed through a right thoracotomy, followed by a laparotomy with simultaneous reconstruction via the posterior mediastinal route. On the 181 cases of the squamous cell carcinoma of the thoracic esophagus resected and reconstructed by this method before 1977, the survival rate of 1-year was 50%, that of 3-years was 19% and that of 5-years was 10%. Post operative T-shaped irradiation was performed in about a half of the total 181 patients. The efficacy of the postoperative irradiation was discernible in patients of each stage. It is expected that a precise schedule of chemotherapy and immunotherapy combined with post-operative irradiation might improve the prognosis of the esophageal cancer.

Adult↗
PubMed1995

Fas/APO-1 gene transfer for human malignant glioma.

Human malignant glioma cells are susceptible to apoptosis induced by antibodies to Fas/APO-1, a cytokine receptor protein of the nerve growth factor/tumor necrosis factor receptor superfamily. Here we show that a critical level of cell surface expression of Fas/APO-1 is a prerequisite for induction of glioma cell apoptosis via Fas/APO-1. Although Fas/APO-1 mRNA was expressed in three Fas/APO-1 antibody-resistant glioma cell lines, these cells expressed either little Fas/APO-1 protein (LN-319 and LN-405) or an abnormal Fas/APO-1 protein that was not translocated to the cell membrane and therefore functionally inactive (LN-308). Although all glioma cell lines expressed mRNA for Fas/APO-1-delta TM, a soluble form of Fas/APO-1 lacking the transmembrane domain, none of the cell lines released detectable amounts of soluble Fas/APO-1, a potential endogenous antagonist of Fas/APO-1-mediated glioma cell apoptosis. Stable transfection of three resistant glioma cell lines with a human Fas/APO-1 cDNA expression vector dramatically enhanced cell surface expression of Fas/APO-1 and induced susceptibility to Fas/APO-1 antibody-mediated apoptosis. These data indicate that malignant glioma cells, unlike other tumor cells, uniformly harbor the intracellular cascade required for Fas/APO-1-mediated apoptosis. Low level of Fas/APO-1 expression results from inefficient transcription and translation of the Fas/APO-1 gene or the synthesis of mutant Fas/APO-1 proteins. gamma-Interferon, tumor necrosis factor-alpha, and interleukin 1 beta augmented Fas/APO-1-mediated apoptosis of Fas/APO-1-transfected glioma cells by acting on the subcellular suicidal cascade triggered by Fas/APO-1 activation. Dexamethasone attenuated Fas/APO-1 antibody-induced apoptosis, not only of constitutively Fas/APO-1-positive glioma cells, but also of Fas/APO-1-transfected glioma cells. The antiapoptotic effect of dexamethasone could be overcome by preexposure of the glioma cells to gamma-interferon or by coexposure to Fas/APO-1 antibodies and cycloheximide. Thus, Fas/APO-1 gene transfer and combined immunotherapy using Fas/APO-1 antibodies and cytokines may overcome Fas/APO-1 antibody resistance of Fas/APO-1-negative human malignant glioma cells, which may represent subpopulations within single gliomas or form a separate subgroup of human malignant gliomas.

Antibodies↗
PubMed1993

Immune events in skin. II. Inhibition of dendritic (veiled) cells function and traffic with anti-lymph dendritic cell sera.

The migrating dendritic cells (DC) from the canine skin-draining afferent lymph are the most potent stimulators of the allogeneic MLR of all other lymph cell subpopulations. The MLR could be inhibited by addition of xenogeneic (rabbit), polyclonal anti-lymph dendritic cell serum (ADCS) to the cultures. ADCS blocked the presentation of Ia and CD1 antigens on the surface of DC. Studies using mouse anti-human monoclonal antibodies, cross-reactive with canine cells, indicate that blocking of Ia, but not of CD1 antigen, is responsible for inhibition of MLR. ADCS abrogated also the accessory function of DC in the lymph lymphocytes response to PHA. The inhibition reached 73%, when the serum was added for the whole period of the culture, and 23% after preincubation of DC with ADCS (anti-dendritic cell serum). ADCS administered subcutaneously into the dorsal area of hind paws caused a selective, transient disappearance of DC from the afferent lymph of normal dogs, which lasted for 2 h after the injection. We conclude, that the functional and physical elimination of migrating skin DC mediated by ADCS in vitro and in vivo, justify the possible use of this serum in the combined immunotherapy directed at the prolongation of skin graft survival.

Animals↗
PubMed2000

Unresectable advanced gastric cancer effectively treated by combined chemo-immunotherapy: a report of two cases.

We have experienced two cases of unresectable advanced gastric cancer effectively treated by chemo-immunotherapy. One case was of a 68-year-old male patient diagnosed as having inoperable advanced gastric cancer with liver and lung metastasis. This patient was treated by combined chemo-immunotherapy of MMC 10 mg/M, 5'-DFUR 800 mg/day and OK-432 5 KE/2W. At 6 months later, a computed tomography (CT) scan and upper gastrointestinal (GI) series revealed that the metastatic liver tumors and stomach lesion were remarkably decreased in size, and endoscopic biopsy confirmed no cancer cells in the stomach lesion. Moreover, the metastatic lung tumor had disappeared on chest X-ray. The other case was of a 68-year-old female patient with unresectable advanced gastric cancer treated by combined administration of MMC 10 mg/M, 5-FU 200 mg/day and OK-432 5 KE/2W. At 2 months after commencing the treatment, there was a reduction in the serum carcinoembryonal antigen (CEA) level. At 6 months later, the CEA had decreased to normal, the primary and metastatic sites had completely disappeared on CT, and endoscopic biopsy confirmed no cancer cells in the stomach lesion. This patient has survived to date for 5 years and 6 months after commencing the treatment. These results suggested that combined chemo-immunotherapy of MMC, antimetabolite, and OK-432 was an effective treatment for unresectable advanced gastric cancer.

Aged↗
PubMed2001

Potentiatied antitumor effectiveness of combined chemo-immunotherapy with interleukin-12 and 5-fluorouracil of L1210 leukemia in vivo.

In this study we investigated the efficacy of a combination of IL-12 and 5-FU, a chemotherapeutic exerting several immunomodulatory effects, in murine L1210 leukemia. Mice inoculated with 1 x 10(5) leukemia cells were treated with a single dose of 5-FU (50 mg/kg) and seven daily doses of IL-12 (100 ng/dose), and were observed for survival. Treatment with IL-12 or 5-FU given alone produced moderate anti-leukemic effects. However, combination of both drugs resulted in a significant prolongation of mouse survival time. Importantly, there were 70% of long-term (>60 days) survivors among mice treated with both agents simultaneously. Moreover, we observed 100% of long-term survivors when mice were treated with a minimally increased dose of IL-12 (170 ng) in combination with 5-FU (50 mg/kg). The antileukemic effects were completely abrogated in scid/scid mice and in mice depleted of peritoneal macrophages and significantly decreased after administration of anti-CD3+, anti-CD4+ or anti-CD8+ monoclonal antibodies. Administration of anti-NK1.1 antibodies did not decrease the antileukemic effects indicating that NK cells are not important effectors of this treatment regimen. Collectively, these results indicate that the combination of IL-12 and 5-FU is inducing strong antileukemic responses that are dependent on the presence and activity of macrophages and T lymphocytes and warrant further studies of combined chemo-immunotherapy with IL-12.

Animals↗