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PubMed1991

Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study.

In this pilot study of metastatic melanoma, interleukin-2 (IL-2) and cisplatin (CDDP) chemotherapy were combined using an alternating schedule designed to explore potential synergism between these modalities. Bolus IL-2 was given at a dose of 600,000 IU/kg intravenously (IV) every 8 hours, days 1 to 5 and 15 to 19, followed by high-dose CDDP administered by two different regimens: (A) 135 to 150 mg/m2 IV bolus over 30 minutes with the chemoprotectant WR-2721 910 mg/m2 or (B) 50 mg/m2 IV over 2 hours every day for 3 days. The trial design allowed an assessment of response to each phase of therapy. Among 27 assessable patients, there were 10 (37%) overall responses, including three (11%) complete responses (CRs) with durations of 9, 16, and 30+ months. Tumor regression was noted in seven patients (partial response [PR], four; minor response [MR], three; response rate [RR], four of 27 [15%]) after IL-2 administration and in 14 patients (PR, 12; MR, two; RR, 12 of 27 [44%]) after CDDP treatment, demonstrating noncrossresistance between the components of the regimen. Major PRs (greater than 90% reduction of tumor burden) or CRs were only seen in patients responding to IL-2. Toxicity during IL-2 therapy was typical for high-dose IL-2 protocols and was reversible. Among the first 20 patients treated with CDDP regimen A, there were eight episodes of grade IV nephrotoxicity (creatinine level greater than 5.0 mg/dL), including three of six patients treated with an initial CDDP dose of 135 mg/m2. This side effect was more frequent among patients with liver metastasis (P less than .05, Fisher's exact test). No significant nephrotoxicity was noted in seven patients treated on regimen B. Although ototoxicity was frequent, minimal bone marrow and neurologic toxicity was noted. There were no treatment-related deaths. This combination showed at least additive activity against melanoma, and the more protracted CDDP schedule was well tolerated. This regimen may serve as a model for future combined immunotherapy and chemotherapy trials in metastatic melanoma.

Adult↗
PubMed2006

Immunotherapy options in metastatic renal cell cancer: where we are and where we are going.

The treatment of renal cell carcinoma is rapidly changing as a result of recent evidence concerning the efficacy of biological drugs, antiangiogenetic agents and signal-transduction inhibitors. This paper will provide a critical overview of the use of immunotherapy in renal cell carcinoma and review the available data concerning the efficacy of interferons, interleukin-2 and other forms of immunological treatment, particularly allogenic transplantation and vaccines. Moreover, it will focus on the new mechanisms of regulation of the immune system with a better understanding of the interaction between host and tumor, the role of T regulatory cells, heat-shock proteins and vaccines. The mechanism of action and the results obtained in renal cell carcinoma using the new molecular targeted drugs will be examined, along with the possibility of using immunotherapy combined with the new biological agents. Future research will not only need to make every effort to optimize the use of the new molecules and to define their efficacy precisely, but also to consider how to integrate these drugs with the traditional immunotherapy.

Carcinoma, Renal Cell↗
PubMedDate not supplied

Combined immunopharmaceutical therapy of patients with unresectable pancreatic carcinoma.

BACKGROUND/AIMS: This paper presents the results of a prospective randomized study of targeting locoregional chemotherapy and targeting locoregional immunostimulation therapy implemented in 36, out of 66, patients with a histological diagnosis of pancreatic duct carcinoma seen by our group from 1991 to Sept. 1994. METHOD AND MATERIALS: Sixty-six patients with unresectable pancreatic duct carcinoma were separated into two groups. The first group received laparotomy (n = 30), with palliative gastric bypass (n = 8) or with palliative biliary bypass (n = 18). The second group received laparotomy (n = 36), with palliative gastric bypass (n = 9) or with palliative biliary bypass (n = 20), supplemented with locoregional immunostimulation and locoregional chemotherapy. This therapy consisted of ten days of infusion with Proleukin (IL2) and Imukin (gamma-IFN), emulsified in Lipidiol-Urographin. This infusion was performed five days trans-splenically and five days trans-tumorally. Fifteen days later, targeting locoregional chemotherapy was administered, again emulsified in Lipidiol-Urographin. RESULTS: All the patients in the first group are dead, with a mean survival of 4.5 months, as of November 1995. Presently, 47% (n = 17) of the second group have achieved a positive objective response, with a mean survival of 14.1 months. During re-exploration, eight patients became tumor free after pancreatic resection, which became feasible after our therapy and six are alive and have remained tumor free to date. CONCLUSION: Targeting locoregional immunotherapy, combined with locoregional chemotherapy appears to be a promising therapy, meriting further consideration for clinical application in patients with unresectable pancreatic ductal carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Effectiveness of peanut agglutinin-binding glyco-related antigen and cyclophosphamide on metastasis of Lewis lung carcinoma.

Soluble tumor-associated antigens were isolated from Lewis lung carcinoma (3LL) cells by detergent solubilization and purified by affinity chromatography on peanut agglutinin (PNA)-agarose. Subcutaneous injection of PNA-binding glyco-related antigen into 3LL-bearing male C57BL/6 mice significantly augmented delayed-type hypersensitivity (DTH), and also inhibited the growth of the primary 3LL tumors. The effects of combined immunotherapy and chemotherapy with this antigen and cyclophosphamide (CY) were examined following excision of 3LL by determining the number of pulmonary surface nodules and wet weight of the lungs. Injection of PNA-binding glyco-related antigen and CY significantly inhibited pulmonary metastasis and prolonged the survival of the mice. The spleen cells obtained from mice with combined treatment showed higher neutralizing activity against 3LL cells than other groups. Therefore, combined immuno and chemotherapy may be useful in preventing metastasis.

Animals↗
PubMedDate not supplied

Combination therapy of the H2712 murine mammary carcinoma with cytotoxic T lymphocytes and anti-estrogens.

BACKGROUND: The triphenylethylene antiestrogenic agents, tamoxifen (TX) and toremifene (TO), are currently being used for the therapy of estrogen dependent breast carcinomas and for some other estrogen receptor positive tumors. Some observations indicate that these drugs may have a beneficial effect on estrogen receptor negative tumors as well. MATERIALS AND METHODS: The H2712 mammary carcinoma of C3H/HeJ mice was studied in combination immunotherapy experiments using cytotoxic T lymphocytes (CTL) and TX or TO. The effect of TX and TO on the in vitro lysis of H2712 cells by CTL was also investigated. Finally, the H2712 cells were examined for the presence of estrogen receptors. RESULTS: Both TX and TO potentiated the lysis of H2712 cells by CTL in vitro, and exerted a growth inhibitory and therapeutic effect on H2712 mammary carcinomas in vivo. The therapeutic effect of CTL isolated from tumor bearing mice was improved on H2712 carcinomas when the animals were also treated orally by TX or TO. Using the dextran-coated charcoal assay, H2712 cells were found to be negative for classical estrogen receptors. CONCLUSIONS: These results indicate that the anti-estrogens, TX and TO, have the ability to suppress the growth of the estrogen receptor negative mammary carcinoma and to amplify target cell lysis by tumor-reactive CTL. By this mechanism these drugs enhance host immunity to an estrogen receptor negative tumor.

Animals↗
PubMed2003

Stimulation of T-cell cytokine production and NK-cell function by IL-2, IFN-alpha and histamine treatment during remission of non-Hodgkin's lymphoma.

Limited therapeutic options remain for patients with relapsing lymphoma following chemotherapy and autologous stem cell transplantation (ASCT), hence motivating investigations of complementary treatments. The aim of the present study was to evaluate feasibility and immunological effects of an immunotherapy schedule administered during chemotherapy-induced remission of aggressive non-Hodgkińs lymphoma (NHL). Repeated cycles of rIL-2, rIFN-alpha and histamine were administered to a patient with a grade III follicle center cell lymphoma, following relapse and high-dose chemotherapy with stem cell support. T-cell cytokine production and repertoire alterations were monitored by flow cytometry together with assessment of natural killer (NK) cell-mediated cytotoxicity. The treatment schedule induced significant increases in frequencies of CD4+ T cells expressing intracellular IFN-gamma or IL-4, thus a T helper (Th) 1 and Th 2 type of response were observed. CD8+T cells showed enhancement mainly of TNF-alpha production. Such induction of T-cell effector functions was accompanied by an augmentation of NK-cell cytotoxicity and a pronounced reduction of possibly regulatory CD57 expressing lymphocytes. The results indicate synergistic T- and NK-cell activation by tolerable doses of the combined immunotherapy, administered during remission after chemotherapy and ASCT in NHL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Heat shock enhances the susceptibility of tumor cells to lysis by lymphokine-activated killer cells.

OBJECTIVE: To determine whether heat-treated thyroid cancer cells augment the susceptibility of target cells to lysis by autologous lymphokine-activated killer cells. DESIGN: Peripheral blood lymphocytes from patients with thyroid cancer were incubated with recombinant interleukin 2 (100 U/mL) for 7 days, and thyroid cancer cells obtained from surgical specimens were heated at 44 degrees C for 20 minutes and incubated at 37 degrees C for 18 hours before performing the radioactive chromium Cr 51 release assay. RESULTS: The susceptibility of heat-treated thyroid cancer cells to lysis by autologous and allogeneic lymphokine-activated killer cells was significantly greater than that of untreated tumor cells. The mechanism of enhanced susceptibility was unclear. However, the effect depended on de novo protein synthesis, because inhibition of RNA synthesis by dactinomycin completely abolished the heat-enhanced susceptibility of tumor cells. CONCLUSION: Immunotherapy combined with hyperthermia may be useful in management of thyroid cancer.

Adenocarcinoma, Papillary↗
PubMed1997

[The Churg-Strauss syndrome with cerebral seizures and terminal kidney failure].

HISTORY AND CLINICAL FINDINGS: A 67-year-old man with known bronchial asthma was admitted to hospital because of deteriorating general state of health, fever, progressive renal failure and confusional states. INVESTIGATIONS: Erythrocyte sedimentation rate was 70/95 mm and the concentration of C-reactive protein raised to 30 mg/dl. WBC count was 19,000/microliter with 39% eosinophilia. Anticytoplasmatic antibodies (cANCA) had a high titre (1:160). On admission the creatinine level was 5.6 mg/dl. Renal biopsy indicated marked glomerular and tubulo-interstitial scarring. Chest radiograms showed transient pulmonary infiltrates. Churg-Strauss syndrome (CSS) was diagnosed on the basis of the clinical and biochemical findings. TREATMENT AND COURSE: Haemodialysis was instituted to counteract the renal failure with water retention. Inflammatory parameters and clinical symptoms rapidly responded to administration of corticosteroids (prednisolone, initially 250 mg/d for 3 days, then 150 mg/d for 5 days followed by slowly decreasing doses). Two weeks after starting prednisolone he had secondary generalised seizures. Magnetic resonance imaging (MRI) of the skull demonstrated marked hyperintense focal changes which in their pattern were characteristic of cerebral vasculitis. As a steroid-refractory condition had to be assumed, cyclophosphamide was also given (100 mg/d). Within 6 weeks the clinical symptoms gradually regressed and the MRI changes became practically normal. CONCLUSION: Early combined immunotherapy should be given if CSS runs a complicated course, rather than the usually recommended corticosteroid monotherapy.

Aged↗
PubMed2005

Genes to vaccines for immunotherapy: how the molecular biology revolution has influenced cancer immunology.

Recent advances in our understanding of the complex signaling pathways involved in immune system regulation, along with analyses of genetic differences between tumors and their normal cellular counterparts, have accelerated development of immune-based strategies for cancer treatment and prevention. More clinically relevant animal models have shown that successful immune-based strategies will require the integration of interventions that target specific tumor antigens with regulators of the antitumor immune response. Immunotherapy for cancer is at a critical crossroad, as therapeutics designed to target cancer-associated antigens and regulatory signaling molecules enter clinical trials. We outline here a paradigm for early-stage clinical development of immunotherapy combinations that use vaccines to drive tumor antigen-specific responses while simultaneously targeting immune regulatory pathways.

Antigens, Neoplasm↗
PubMed2003

Rational approaches to human cancer immunotherapy.

Over most of the 20th century, immunotherapy for cancer was based on empiricism. Interesting phenomena were observed in the areas of cancer, infectious diseases, or transplantation. Inferences were made and extrapolated into new approaches for the treatment of cancer. If tumors regressed, the treatment approaches could be refined further. However, until the appropriate tools and reagents were available, investigators were unable to understand the biology underlying these observations. In the early 1990s, the first human tumor T cell antigens were defined and dendritic cells were discovered to play a pivotal role in antigen presentation. The current era of cancer immunotherapy is one of translational research based on known biology and rationally designed interventions and has led to a rapid expansion of the field. The beginning of the 21st century brings the possibility of a new era of effective cancer immunotherapy, combining rational, immunological treatments with conventional therapies to improve the outcome for patients with cancer.

Animals↗
PubMed1991

Acute renal failure with preserved renal plasma flow induced by cancer immunotherapy.

Adoptive immunotherapy in patients with advanced cancer produces significant regression of metastatic disease in selected patients, but it is complicated by severe side effects. Prevention of these complications is still limited because their precise mechanisms remain unknown. For this reason we have investigated renal function and hemodynamic parameters in 16 patients with renal cell carcinoma before and during treatment with a combination of high doses of both recombinant interleukin-2 (rIL2) and recombinant alpha-interferon. After patients had received three injections of combined immunotherapy, there was a decrease in mean blood pressure (-20%), glomerular filtration rate (-25%), urine output (-50%), and fractional sodium excretion (-0.8%). This was associated with an increase in heart rate (+30%), plasma creatinine level (+30%), fractional potassium excretion (+14%) and microalbuminuria (+130%). However, renal plasma flow remained constant. The increment in microalbuminuria may reflect an alteration of glomerular capillary permeability. The reduction in GFR may be accounted either for a decrease in efferent to afferent arteriolar resistance ratio, leading to a decrease in glomerular capillary pressure, or for a decrease in ultrafiltration coefficient, or both. Nonsteroidal antiinflammatory drugs, such as ketoprofen, used to minimize side effects, could considerably worsen renal function and should be avoided in patients treated by rIL2. Our results bring new insights into the pathogenesis of functional acute renal failure and provide a rational basis for the use of vasopressors in the treatment of cytokine-induced acute renal failure.

Acute Kidney Injury↗
PubMed1990

The role of tumor necrosis factor in allograft rejection. II. Evidence that antibody therapy against tumor necrosis factor-alpha and lymphotoxin enhances cardiac allograft survival in rats.

In the previous study we demonstrated that circulating levels of TNF-alpha are elevated during liver allograft rejection and may precede clinical manifestations. The current study was designed to investigate the efficacy of antibody therapy against tumor necrosis factor-alpha and lymphotoxin (LT) in a rat heterotropic cardiac transplant model utilizing Buffalo donors and Lewis recipients. Control animals received no immunotherapy and experienced rejection on postoperative day 11 +/- 0.4 (mean +/- SEM). Experimental animals received immunotherapy either intraperitoneal or intravenous from days 1 to 10. The i.p. administered anti-TNF-alpha prolonged graft survival to 16 +/- 2.7 days (P less than 0.05 vs. controls); the i.v. administration prolonged survival to 15 +/- 1.4 days (P less than 0.004). Animals treated with i.p. anti-LT survived 17 +/- 1.7 days (P less than 0.002 vs. controls). Combination immunotherapy of anti-TNF-alpha and anti-LT increased function to 21 +/- 2.2 days (P less than 0.001 vs controls). Conversely, administration of purified TNF-alpha or LT to graft recipients accelerated the time to rejection. Mean survival for both treatments was 7 days (P less than 0.001 vs. controls). Histologic examination of the transplanted cardiac tissue showed a typical pattern for acute rejection; there was no evidence of hemorrhagic or coagulative necrosis. In contrast, administration of purified TNF-alpha or LT to recipients of a syngeneic heart did not stimulate rejection. These data suggest that TNF-alpha and LT may play a role in the pathogenesis of acute allograft rejection. In addition, the mechanism appears to be distinct from that seen in TNF-alpha or LT-mediated cytotoxicity of tumor cells.

Animals↗
PubMed1991

1990 Sir Henry Wellcome medal and prize winner. Leukoregulin: a new biotherapeutic cytokine in the search for more effective anti-viral pharmacologic agents.

This investigation examines whether cytokines, as exemplified by leukoregulin, with their immense potential for biorecognition and target cell modulation as a result of their complex three-dimensional structure, have the potential to provide new directions for biotherapy of infectious disease. Leukoregulin is a naturally occurring immunologic cytokine, secreted by stimulated lymphocytes, which increases membrane permeability and drug uptake in tumor but not in normal cells. This study demonstrates that leukoregulin also increases the plasma membrane permeability of cells acutely infected with herpes simplex type 1 virus and that the increase in membrane permeability is accompanied by a 10- to 100-fold increase in the ability of acyclovir to inhibit the release of infectious virus when the cells are treated with leukoregulin 3 hours after infection with the virus. This is the first demonstration that a cytokine, alone or in combination with anti-viral chemotherapy, can effectively inhibit virus replication in human cells following acute virus infection, which indicates that combination immunotherapy and chemotherapy have the potential to completely inhibit the production of infectious virus by acutely infected human cells.

Acyclovir↗
PubMed1997

Combination therapy with BRMs in cancer and infectious diseases.

In recent years many studies have stressed the importance of using biological response modifiers (BRMs) in the treatment of different conditions of immune-impairment correlated with ageing, cancer and infectious diseases. In particular, the use of different BRMs in conjunction with conventional therapies has been extensively explored. Our studies have demonstrated that treatment with Thymosin alpha-1 and low doses of IFN or IL-2 exert powerful biological effects both in vitro and in vivo. They are highly effective in restoring cytotoxic activities in immunosuppression induced by tumors and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to induce a dramatic inhibition of tumor growth in both experimental models and in humans. Immunotherapeutic treatment also has an application in controlling infectious diseases, especially those occurring in the immuno-compromised host. The advantage of using the combined immunotherapy treatment with antiviral drugs has been recently demonstrated by our group both in a murine experimental influenza model and in patients infected with HBV, HCV and HIV.

Bacterial Infections↗
PubMed2002

[Likopid in the complex immunomodulating treatment of patients with sarcoidosis of the lung and intrathoracic lymph nodes].

AIM: To examine the functional status of the immune system in patients with lung and intrathoracic lymph nodes sarcoidosis and to evaluate the efficiency of immunomodulation alone and in its inclusion in combined treatment of the disease. MATERIALS AND METHODS: 58 patients with the disease of varying severity were followed up. Comprehensive examination, involving clinical, immunological, X-ray, and physical studies, in patients treated with combined immunotherapy was performed. Initial examination revealed mixed immunodefficiency with impaired T- and phagocytic activity. According to the degree of immunological changes, the patients were given immunotherapy, including polyoxidonium, T-activin (or immunophan) injections, a complex of multivitamins and trace elements, and total adaptogens. After partial or complete normalization of an immunogram, all the patients received licopid (two-three 10-day courses, 10 mg/day). RESULTS: The optimal result (as long as 3-year remission) was achieved in the first time diagnosed sarcoidosis who have not taken glucocorticoidal hormones. CONCLUSION: The follow-up shows that addition of licopid is a compulsory component of immunotherapy in this disease; the efficiency of treatment is determined by its multimodality. The courses of therapy should be repeated when immunological indices deteriorated.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2002

The hematopoietic system-specific minor histocompatibility antigen HA-1 shows aberrant expression in epithelial cancer cells.

Allogeneic stem cell transplantation (SCT) can induce curative graft-versus-tumor reactions in patients with hematological malignancies and solid tumors. The graft-versus-tumor reaction after human histocompatibility leukocyte antigen (HLA)-identical SCT is mediated by alloimmune donor T cells specific for polymorphic minor histocompatibility antigens (mHags). Among these, the mHag HA-1 was found to be restricted to the hematopoietic system. Here, we report on the HA-1 ribonucleic acid expression by microdissected carcinoma tissues and by single disseminated tumor cells isolated from patients with various epithelial tumors. The HA-1 peptide is molecularly defined, as it forms an immunogenic peptide ligand with HLA-A2 on the cell membrane of carcinoma cell lines. HA-1-specific cytotoxic T cells lyse epithelial tumor cell lines in vitro, whereas normal epithelial cells are not recognized. Thus, HA-1-specific immunotherapy combined with HLA-identical allogeneic SCT may now be feasible for patients with HA-1(+) carcinomas.

Hematopoietic Stem Cell Transplantation↗
PubMed2003

Rituxan immunotherapy and zevalin radioimmunotherapy in the treatment of non-Hodgkin's lymphoma.

Immunotherapy with the anti-CD20 monoclonal antibody rituximab has been shown in clinical trials to be effective in the treatment of both indolent and aggressive non-Hodgkin's lymphomas (NHL). Recent studies have demonstrated improved clinical benefit with extended dose and maintenance therapies in patients with indolent lymphomas and chronic lymphocytic leukemia. Rituximab's label was recently expanded to include treatment of bulky disease, retreatment of patients previously treated with rituximab, and an eight-week extended treatment schedule. Rituximab has also been effectively combined with chemotherapy, resulting in higher response rates and longer response durations in randomized trials in patients with aggressive lymphoma. Studies continue to evaluate and expand the role of rituximab in the treatment of NHL, including its use in combined immunotherapy approaches and autologous stem cell transplant as well as in the treatment of autoimmune disorders. Radioimmunotherapy with the rituximab and ibritumomab tiuxetan (Zevalin) regimen was recently approved for the treatment of relapsed or refractory low-grade, follicular or CD20+ transformed NHL, including rituximab refractory follicular NHL. The regimen is delivered on an outpatient basis over the course of a week. Studies are currently exploring sequential dose therapy, radioimmunotherapy with rituximab maintenance, and ibritumomab tiuxetan radioimmunotherapy as part of autologous stem cell transplant. Current understanding of the mechanisms of action of rituximab and the use of rituximab and ibritumomab tiuxetan in patients with indolent and aggressive NHL will be discussed.

Animals↗
PubMed1992

Use of human leukocyte antigen-mismatched allogeneic lymphokine-activated killer cells and interleukin-2 in the adoptive immunotherapy of patients with malignancies.

Clinical effects and side effects were investigated in the adoptive immunotherapy of patients bearing malignant diseases using human leukocyte antigen (HLA)-mismatched allogeneic lymphokine-activated killer (LAK) cells. Allogeneic LAK cells were induced from peripheral blood lymphocytes (PBL) of healthy donors with the same blood types as those of patients. Recently we succeeded in increasing the proliferation rate and enhancing the cytotoxic activity of LAK cells by means of initial stimulation with pokeweed mitogen (PWM, PWM-LAK cells). Five of 12 patients applied in the adoptive immunotherapy showed clinical effects such as partial or complete regression of pulmonary metastases and pleural effusion. All pulmonary metastatic lesions were eliminated in one case by this adoptive immunotherapy combined with chemotherapy. Toxic effects were chillness, fever and general fatigue which were reversible, and no allergic side effects occurred even though allogeneic LAK cells were injected frequently. In the patients who received more than 10(11) of allogeneic LAK cells, anti-HLA class I antibodies appeared without any evidence of autoantibody. However, immunological side effects were never experienced after injection of allogeneic LAK cells even when the anti-HLA class I antibodies existed in the patients; this phenomenon suggests the safety of the adoptive immunotherapy using allogeneic LAK cells. Taken together, allogeneic LAK cells could be considered as alternative therapy for patients with malignancies who could not supply sufficient materials of autologous LAK cells. Recently, LAK cells, particularly PWM-LAK cells were found to obtain significantly potent and prompt lectin-dependent cell-mediated cytotoxicity (LDCC). All tumor cells confluent in microtest plate well could be annihilated by PWM-LAK cells plus PWM less than 8 hours. New immunotherapy using PWM-LAK cells or lectin-stimulated LAK cells with PWM or other lectins is discussed.

Adult↗