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PubMed2003

Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model.

Immunotherapy could be combined with conventional chemotherapeutic modalities aimed at reducing tumor burden. Such combination therapy may be most useful when "metronomic" doses of antineoplastic drugs are used, thereby potentially avoiding some of the immunosuppressive effects of these drugs. Recent studies have shown that some conventional antineoplastic drugs can be exploited for antiangiogenic capacities, a strategy that requires drugs to be administered at regular intervals. We therefore investigated whether such metronomic therapy with the alkylating agent cyclophosphamide (CTX) could be effectively combined with immunotherapy eliciting tumor-reactive CTLs. An immunization protocol using injection of recombinant DNA followed by injection of recombinant modified vaccinia virus Ankara strain was used to initiate a specific CTL response in mice capable of providing resistance to challenge with the murine melanoma B16.F10. Combining this immunotherapeutic regime with metronomic delivery of CTX resulted in antitumor activity that was dramatically enhanced over either treatment administered alone and was also significantly greater than combining immunotherapy with CTX administered by a maximum tolerated dose regime. Whereas both metronomic and maximum tolerated dose delivery of CTX did cause deletion of proliferating tumor-specific CTLs in the blood, this deletion occurred with slower kinetics with the metronomic schedule. Further analysis showed that metronomic CTX treatment did not delete cells with low expression of CD43, a "memory" phenotype, and that these cells maintained potent restimulatory capacity. The combination of immunotherapy and metronomic CTX therapy may be well suited to clinical management of cancer.

Animals↗
PubMed1994

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.

Animals↗
PubMed1984

[Immunological analysis of chemotherapeutic effects for the effective immunochemotherapy against cancer].

The antitumor effect of a treatment combining immunotherapy and chemotherapy was found to depend on both the timing of the combination and the dose of the chemotherapeutic drug. A synergistic increase of the therapeutic effect was observed after treatment with the appropriate dose of the drug followed by immunotherapy on specified days. This indicates that the effect of chemotherapy on the immune status of the host may play an important role in combination with immunotherapy. It can be said that immunochemotherapy is not simply a combination of immunotherapy and chemotherapy. In immunochemotherapy, the influence of both therapies on the host immune responses to tumor cells needs to be isolated more precisely before the application of combination treatments to clinical cancer.

Animals↗
PubMed1996

Antibody-based immunotherapeutic strategies in colorectal cancer.

Monoclonal antibodies may well be on their way to becoming an integral part of therapy after the most recent success in prolonging overall and recurrence-free survival in patients with stage III colorectal cancer after potentially curative surgery. After a median follow-up of 5 years, antibody treatment reduced the overall death rate by 30% and decreased the recurrence rate by 27%. These results are similar with regard to efficacy but there is less toxicity with those obtained in contemporary and more recent chemotherapy trials. The key to success with high-molecular-weight substances such as immunoglobulines lies in the careful selection of the appropriate target population, i.e., patients with minimal residual disease, where only isolated tumor cells which are readily accessible to therapy are present. An argument for combining immunotherapy with chemotherapy can be made on the basis of the phenotype of individual disseminated tumor cells, which by immunocytochemistry were found to only rarely express proliferation-associated antigens and therefore are independent of the cell cycle. Further efforts to improve immunotherapy have also led to the combined clinical use of antibodies with biologic response modifiers which are known to enhance effector cell-mediated antibody-dependent cytotoxicity. Additional rationally designed clinical trials are ongoing in which specific immunotherapy is directed towards known, readily accessible, and abundant cell target structures, either alone or combined with treatment modalities which employ different action mechanisms.

Animals↗
PubMed1992

Combination therapy with thymosin alpha 1 potentiates the anti-tumor activity of interleukin-2 with cyclophosphamide in the treatment of the Lewis lung carcinoma in mice.

In this study we have investigated the effects of thymosin alpha 1 (T alpha 1) and interleukin-2 (IL-2), singly or in combination with cyclophosphamide (CY), on tumor growth, survival and cytotoxicity in C57Bl/6NCrlBR mice with Lewis lung carcinoma (3LL). Combined administration of T alpha 1 plus IL-2, after CY treatment, was much more effective than use of each biological response modifier (BRM) alone, and induced complete tumor regression in all of the mice studied. Combination immunotherapy alone without CY only slightly reduced the rate of tumor growth, and these results are in accordance with previous studied which showed that the 3LL carcinoma is resistant to cytokines. Combined chemo-immunotherapy also increased the cytotoxicity of spleen cells and markedly enhanced long-term survival in all treated animals. Depletion of immune cells, using either total-body sub-lethal irradiation (400 rads) or antibodies directed against T-cell (anti-CD4 and CD8) or NK-cell (anti-asialo GM1) populations, abolished the positive response to combination therapy. Histological analysis of the tumors obtained from mice treated with combination chemo-immunotherapy revealed a high number of infiltrating lymphoid cells surrounding a well-circumscribed area of necrosis consisting solely of dead cells. Our studies show that T alpha 1 potentiates IL-2-induced cytotoxic activities in vitro as well in vivo, and that these compounds have a powerful anti-tumor action when associated with chemotherapy.

Animals↗
PubMed1996

[Case reports of mucosal melanoma of the head and neck].

Twelve patients with mucosal melanoma in the head and neck were treated at Yokohama city University from 1975 to 1994. The sex distribution was 5 male and 7 female, and the age ranged from 40 to 79 years-old. The highest number of patients were in their sixties. In 10 cases tumors arose in the nasal cavity, in one case in the maxillary sinus and in other case in the oral cavity. The treatment modality for this tumor consisted of various combination therapies including surgery, radiotherapy, chemotherapy and immunotherapy. Combination chemotherapy consisting of dimethyltriazeno imidazole carboxamide (DTIC, Dacarbazine), amino methyl pyrimidinyl methyl chlorethyl nitrorosourea hydrochloride (ACNU) and vincristine (VCR). Cisplatin (CDDP) was recently used for cases where other chemotherapy was not effective. Surgical treatment in the initial therapy was performed in 8 patients. In three of these 8 cases, the surgical margin was positive. One of them was dead after 9 months, another dead with complication after 1 year and the other survived free of any tumor. Immunotherapy using OK-432, interleukin-2, LAK therapy and low dose CPM was effective for some patients. The 5-year survival rate was 44%. Patients with surgical treatments in the initial therapy had longer survival than those without surgical treatments.

Adult↗
PubMed2000

Immunotherapy with vaccines combining MHC class II/CD80+ tumor cells with interleukin-12 reduces established metastatic disease and stimulates immune effectors and monokine induced by interferon gamma.

Because they are difficult to treat, animal models of widespread, established metastatic cancer are rarely used to test novel immunotherapies. Two such mouse models are used in this report to demonstrate the therapeutic efficacy and to probe the mechanisms of a novel combination immunotherapy consisting of the cytokine interleukin-12 (IL-12) combined with a previously described vaccine based on MHC class II, CD80-expressing cells. BALB/c mice with 3-week established primary 4T1 mammary carcinomas up to 6 mm in diameter and with extensive, spontaneous lung metastases show a significant reduction in lung metastases following a 3-week course of immunotherapy consisting of weekly injections of the cell-based vaccine plus injections of IL-12 three times per week. C57BL/6 mice with 7-day established intravenous B16 melF10 lung metastases show a similar response following immunotherapy with IL-12 plus a vaccine based on B16 MHC class II, CD80-expressing cells. In both systems the combination therapy of cells plus IL-12 is more effective than IL-12 or the cellular vaccine alone, although, in the 4T1 system, optimal activity does not require MHC class II and CD80 expression in the vaccine cells. The cell-based vaccines were originally designed to activate tumor-specific CD4+ T lymphocytes specifically and thereby provide helper activity to tumor-cytotoxic CD8+ T cells, and IL-12 was added to the therapy to facilitate T helper type 1 lymphocyte (Th1) differentiation. In vivo depletion experiments for CD4+ and CD8+ T cells and natural killer (NK) cells and tumor challenge experiments in beige/nude/XID immunodeficient mice demonstrate that the therapeutic effect is not exclusively dependent on a single cell population, suggesting that T and NK cells are acting together to optimize the response. IL-12 may also be enhancing the immunotherapy via induction of the chemokine Mig (monokine induced by interferon gamma), because reverse PCR experiments demonstrate that Mig is present in the lungs of mice receiving therapy and is most likely synthesized by the tumor cells. These results demonstrate that the combination therapy of systemic IL-12 and a cell-based vaccine is an effective agent for the treatment of advanced, disseminated metastatic cancers in experimental mouse models and that multiple effector cell populations and anti-angiostatic factors are likely to mediate the effect.

Animals↗
PubMed1991

Enhanced resection and improved survival in murine neuroblastoma (C1300-NB) after preoperative immunotherapy.

Advanced neuroblastoma treated with standard chemotherapy has a poor prognosis. Combination immunotherapy for murine neuroblastoma with retinyl palmitate, low-dose cyclophosphamide, and interleukin-2 resulted in increased survival, impaired tumor growth, easier surgical resection, and increased class I expression or tumor cells. Preoperative immunotherapy may be useful in treatment of advanced human neuroblastoma.

Animals↗
PubMed1999

Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy.

BACKGROUND: Immunotherapy has been shown to reduce allergen sensitivity to allergens such as cat and dust mite. The aim of this study was to investigate the effect of cat or dust mite immunotherapy on bronchial hyperreactivity and the need for inhaled corticosteroids in children with asthma, cat or dust mite allergy, and hay fever. SUBJECTS: Twenty-nine children, 7 to 16 years old, completed the 3-year study. They were randomly allocated to receive cat/dust mite or placebo and birch/timothy immunotherapy. METHODS: Before immunotherapy was begun and then once each year, bronchial histamine challenges were performed. Bronchial allergen challenge with the perennial allergen was done before and after the 3-year study. Pharmacotherapy was given according to a standardized protocol. RESULTS: PC20 allergen increased significantly in both the active immunotherapy group (P <.001) and in the placebo-pollen group (P <.05). PC20 histamine increased continuously in the active immunotherapy group (P <.05 and P =.002 after 1 and 3 years, respectively) and had also increased after 3 years in the placebo-pollen group (P <.05). The difference between the 2 groups was significant for PC20 allergen (P =.001) but not for PC20 histamine. There was no significant change in the dose of inhaled budesonide needed for symptom control in either of the groups. CONCLUSION: Pollen immunotherapy combined with inhaled corticosteroids results in improvement of both cat/dust mite bronchial sensitivity and hyperresponsiveness to histamine. The combination of cat or dust mite, pollen immunotherapy, and inhaled budesonide enhances this improvement. Cat immunotherapy also induces cat allergen tolerance.

Adolescent↗
PubMed2003

Immunotherapy as part of combinations for the treatment of cancer.

Immunotherapy (biological therapy) comprises such things as active specific immunotherapy ("cancer vaccines"), nonspecific immunostimulation with cytokines, and the inhibition of suppressor influences exerted or elicited by the tumor. Just as cancer chemotherapy began with the use of single agents and evolved into combination therapy, so immunotherapeutic agents have been combined with each other and with chemotherapy. The alkylating agent cyclophosphamide (Cytoxan; CY) has been used for many years to inhibit tumor-derived suppressor influences in rodents, and has been exploited for the same use in humans. Combinations of CY and cancer vaccines such as autologous tumor cells, Melacine, large multivalent immunogen (LMI), and Theratope have been tested with some success in humans for more than a decade. In this use, the CY is a biological response modifier rather than an antitumor agent. Delayed treatment with CY in treating mouse plasmacytomas has proved more effective than immediate treatment, probably because it allows immunity to develop in the host. CY and moderate-dose interleukin-2 (IL-2) have also been a useful regimen in treating human melanomas. IL-2 is itself a useful component of combination immunotherapy, such as with melanoma peptide vaccines, or with interferon-alfa-2b, (IFN-a), as a dual combination or part of a biochemotherapy regimen. IL-2 and histamine, to block reactive oxygen species, may be a more useful combination for treatment of liver metastases of melanoma than IL-2 alone. In this combination, the histamine may permit continued, unimpeded activity of cytolytic T lymphocytes. Several different combinations of drugs and biological agents have been used as biochemotherapy for melanoma, but although there are higher immediate response rates, the long-range survival benefits have been marginal, not justifying the severe toxicity. Combinations of 5-fluorouracil (5-FU) and IFN-a or levamisole have had efficacy in colon and head and neck cancers, but here the biological agents acted as biochemical modulators. Trials of antibodies and chemotherapy have been limited. It appears that trastuzumab (Herceptin) potentiates antitumor therapy in breast cancer and also increases the cardiotoxicity of those regimens.

Adjuvants, Immunologic↗
PubMed2002

[Immunomodulation after keratoplasty by CTL4-Ig and anti-CD154 antibodies].

BACKGROUND: The immunoreaction after corneal transplantation is caused by the T cell receptor interacting with the major histocompatibility complex (MHC) receptor of the antigen-presenting cell. The signal is amplified by the CD4 receptor and the costimulatory signal interactions of CD28-B7 and CD40-CD154. We investigated the influence of costimulatory signal blocking on corneal transplant survival in mice. METHODS: Seven groups of 6 BALB/c mice received an orthotopic corneal transplant from C3H mice differing in minor and major MHC and were postoperatively treated as follows: (1) 80 micrograms of CTLA4 fusion protein intraperitoneally (i.p.) for 6 days; (2) 50 microliters of PBS i.p. for 6 days; (3) 1 mg of Solu-Decortin H i.p. for 5 days + dexamethasone AT 0.1% for 35 days; (4) therapy (3) + 50 micrograms of CTLA4 fusion protein i.p. for 6 days; (5) CTLA4-Ig as in (1) + 15 micrograms of anti-CD154 subconjunctivally (s.c.) on days 0, 2, 4, 6, and 8; (6) CTLA4-Ig as in (1) + 25 micrograms of anti-CD154 s.c. for 9 days; and (7) 25 microliters of PBS s.c. for 9 days. RESULTS: All animals had an immunoreaction on the following days: (1) day 18 +/- 3.1; (2) day 13.6 +/- 1.6; (3) day 48 +/- 6.6; (4) day 65 +/- 41; (5) day 23.5 +/- 8.5; (6) day 16.2 +/- 3.6; (7) day 13.8 +/- 2.7. CONCLUSION: The significant prolongation of transplant survival achieved by corticosteroids alone (P < 0.001) is again significantly increased by combining them with CTLA4-Ig (P < 0.001). Specific immunotherapy combined with nonspecific steroid therapy may also improve clinical corneal transplantation results. Compared to the two control groups, CTLA4-Ig and anti-CD154 only influenced transplant survival at a low dosage (P < 0.001).

Abatacept↗
PubMed2003

Bombesin/gastrin-releasing peptide receptor: a potential target for antibody-mediated therapy of small cell lung cancer.

PURPOSE: Bombesin/gastrin releasing peptide (BN/GRP) is a growth factor for small cell lung cancer (SCLC). The receptor (R) for BN/GRP is overexpressed on SCLC cells and other solid tumors. BN/GRP and its receptor form an autocrine loop to promote tumor growth. We developed a novel immunotherapeutic approach targeting cell surface BN/GRP-R on SCLC cells and an immune trigger molecule on host immune effector cells to direct immune effector cells to SCLC cells and mediate targeted cancer cell destruction. Targeted immunotherapy combined with chemotherapy enhanced cell killing. EXPERIMENTAL DESIGN: We designed a synthetic BN/GRP antagonist (Antag 2) and constructed a bispecific molecule (BsMol), H22xAntag 2 (humanized monoclonal antibody) for FcgammaRI. We tested the binding of the BsMol to several SCLC cell lines, its ability to mediate cytotoxicity of SCLC by IFN-gamma-activated human monocytes with chemotherapy, and BsMol-mediated immunotherapy in an animal model of SCLC human xenograft. RESULTS: Common chemotherapy (cisplatin, etoposide, and paclitaxel) inhibited thymidine uptake into SCLC cells in a dose-dependent pattern. Antibody-dependent cellular cytotoxicity mediated by the BsMol inhibited thymidine uptake into SCLC cells and was largely dependent on E:T cell ratio. When SCLC cells were treated with antibody-dependent cellular cytotoxicity followed by exposure to chemotherapy agents an additional 25-40% inhibition of thymidine uptake into SCLC cells was observed consistently. With BsMol and IFN-gamma-activated human monocytes, tumor burdens were reduced significantly in immunodeficient mice bearing human SCLC xenografts. CONCLUSIONS: Combined chemotherapy and immunotherapy targeting BN/GRP-R with a BsMol significantly enhances targeted SCLC cell killing.

Animals↗
PubMed2000

[Allergen-specific immune therapy in the treatment of asthma].

OBJECTIVES: 1. To identify all published randomised controlled trials of allergen specific immunotherapy in asthma. 2. To estimate the overall efficacy of allergen specific immunotherapy upon asthmatic symptoms, medication requirements, lung function, nonspecific bronchial hyperreactivity (BHR) and allergen specific BHR. SEARCH STRATEGY: A search of the asthma database by the Cochrane Airways Group at St. Georges Hospital Medical School, London identified 660 nonunique citations with the keywords Immunotherapy* or Hyposensitive or Desensiti*. This database included all studies published up to 1997 with the keywords Asthma or Wheez* from the Medline, Embase and Cinahl databases, together with other studies identified by handsearching. SELECTION CRITERIA: The review was restricted to randomised controlled trials (RCT). Only studies which focussed upon asthma were included. Allergen specific immunotherapy was defined as the subcutaneous administration of extracts of house dust mites, pollens, animal danders or moulds, chemically modified allergoids or antigen-antibody complexes. Although placebo controlled trials were methodologically stronger, studies which administered house dust or other relatively antigenically inactive preparations to the control group were also considered. Double blinded trials were preferred, but single blind and open studies were also reviewed for possible inclusion. At least one of the following clinical outcomes had to be reported: asthmatic symptoms, asthma medication requirements, lung function, nonspecific BHR or allergen specific BHR. Inclusion of studies in the review was decided by a simple majority of all three reviewers, who independently read the methods sections of papers identified by the search strategy and applied the stated criteria. Quality assessment was performed by 2 reviewers, who independently assessed the concealment of allocation. DATA COLLECTION AND ANALYSIS: The comparisons were: Allergen immunotherapy v placebo, Allergen immunotherapy v antigenically inactive control, House dust v placebo and Allergen immunotherapy v untreated control. These comparisons were performed separately for each outcome, whenever these results were reported. Outcome data were extracted and entered into RevMan 3.0.1 for statistical analysis. Categorical outcomes were analysed as odds ratios (OR) and 95% confidence intervals (95% CI) calculated by Peto's method. Continuous outcomes were analysed as standardised mean differences (SMD). Fixed effects models were used to obtain summary statistics for the overall efficacy of allergen immunotherapy and x2 tests were performed to assess heterogeneity between studies. MAIN RESULTS: Fifty four randomised controlled trials published between 1954 and 1997 satisfied the inclusion criteria. There were 25 studies reporting immunotherapy for mite allergy, 13 studies of pollen allergy, eight studies of animal dander allergy, two studies of allergy to the mould Cladosporium and six studies which attempted simultaneous immunotherapy for multiple aeroallergens. Concealment of allocation was assessed as clearly adequate in only 11 studies. The adequacy or otherwise of 40 studies could not be determined from the details published in the papers. Only three studies used a clearly inadequate method for concealment of allocation. There was a significant overall improvement in asthma symptom scores following immunotherapy (combined SMD -0.52; 95% -0.70 to -0.35). Patients randomised to immunotherapy were also significantly less likely to report a deterioration in asthma symptoms than those randomised to placebo (OR 0.27; 95% CI 0.21 to 0.35). Asthma medication requirements were significantly reduced (SMD -0.51; 95% CI -0.74 to -0.28). Patients randomized to immunotherapy were also significantly less likely to require medication than those randomised to placebo (OR 0.28; 95% CI 0.19 to 0.42). There was no overall improvement in lung function following immunotherapy and marked hete

Asthma↗