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[Experimental study for a combination chemo-immunotherapy using dendritic cells].

This study was designed to seek for the optimal anticancer agents for a combination of chemotherapy and specific immunotherapy using dendritic cells (DC) in gastric cancer. We investigated the immuno-suppressive activity of anticancer agents on human peripheral blood mononuclear cells (PBMC), apoptosis inducing activity on gastric cancer cells and expression of Toll-like receptor (TLR)-4 mRNA on immatureDCs (iDCs) by paclitaxel (TXL) and docetaxel (TXT). We further compared the cytotoxicity of cytotixic T lymphocytes (CTLs) induced by DCs pulsed with tumor cell lysate and apoptotic cells induced by TXT. Although most of the anticancer agents demonstrated the suppression activity on proliferation of PBMC in a dose dependent manner, TXT, doxifluridine and irinotecan did not show the suppressive activity on PBMC even in the highest drug concentration. About 60% of gastric cancer cells demonstrated apoptosis after a 24-48 hour treatment with both TXL and TXT. Expression of TLR-4 mRNA in iDCs was up-regulated by TXT, not by TXL, and peaked at 2 hours after the treatment. CTLs induced by DCs pulsed with tumor cell lysate and apoptotic cells showed a similar killing activity to target cells. These results suggest that TXT appears to be an optimal anticancer agent for a combination therapy with chemotherapy and tumor specific immunotherapy using dendritic cells in gastric cancer.

Adult↗

Specific and effective targeting cancer immunotherapy with a combination of three bispecific antibodies.

For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we previously constructed two kinds of bispecific antibodies (bsAbs), anti-MUC1 x anti-CD3 (M x 3) and anti-MUC1 x anti-CD28 (M x 28), which activate T cells and form bridges between them and MUC1-expressing tumor cells. In our previous studies [Cancer Res. 56 (1996) 4205] specific targeting therapy (STT) consisting of i.v. administration of lymphokine activated killer cells with a T cell phenotype (T-LAK) sensitized with two kinds of bsAbs to human BDC-grafted severe combined immunodeficient (SCID) mice demonstrated remarkable inhibition of tumor growth. However, complete cures could not be obtained. In order to improve antitumor efficacy, we have paid attention to anti-CD2 monoclonal antibodies (mAbs), thought to play an important roles in signal transduction in T cell activation or control of T cell receptor (TCR)-driven activation. Therefore, we developed another bsAb, anti-MUC1 x anti-CD2 (M x 2), in order to examine if this would show synergism with the two previously described bsAbs. The combination of the three bsAbs (M x 3, M x 28 and M x 2 bsAbs) showed highest cytotoxicity against MUC1-expressing BDC cells when given simultaneously with peripheral blood mononuclear cells (PBMCs) or T-LAK cells in vitro. When 2 x 10(7) T-LAK cells sensitized with different combinations of bsAbs were administered four times i.v. to BDC-grafted SCID mice, the best therapeutic result was obtained with a combination of all three bsAbs. These results indicate usefulness of combination of three bsAbs for targeting cancer immunotherapy.

Animals↗

The combined influence of immunotherapy and mite allergen reduction on bronchial hyperresponsiveness in mite-sensitive asthmatic children.

UNLABELLED: Encasings for mattresses, blankets and pillows in combination with mite allergen reduction on the floor have proved effective in reducing bronchial hyperreactivity of mite-allergic children. We studied the effect of combining the use of encasings with specific immunotherapy in comparison to the use of encasings alone (control group). Twenty mite-allergic children (Skin Prick Test, RAST, mean age 10 years) with asthma and high domestic mite allergen exposure ( > 2 microg Der p 1 + f 1/g mattress dust) were included in our study. The concentration of these major allergens as well as specific and nonspecific bronchial hyperreactivity (PC20 FEV1 histamine) were assessed before, 6 months after and 1 year after start of treatment. All children received elongated polytetrafluorethylene (ePTFE; Goretex/Intervent Allergy Bedding System) encasings. A subgroup of eight children were treated additionally by specific immunotherapy with a partially purified mite extract (ALK Scherax) and a maximum dose of 100000 SQ-U Der p + f. Initially both groups were comparable with respect to the parameters assessed. In 80% of children, encasings reduced Der p 1 and Der f 1 concentrations on the mattress to below 3% of the initial values (P < 0.01). The median reduction was 99%. PC20 FEV1 histamine increased from 0.4 to 1.4 mg/dl (median) in the combined group with immunotherapy and encasings (P < 0.05) and remained essentially unchanged in the control group. PC20 FEV1 Der p did not increase significantly in either group. CONCLUSION: Specific immunotherapy with allergen extracts is an effective adjunct to encasings. Encasings, a key factor for reducing Der p 1 and Der f 1 on the mattress, should be used in combination with other avoidance measures (e.g. removal of carpets) in order to improve allergen-induced bronchial hyperreactivity.

Adolescent↗

Combining radiotherapy and immunotherapy: a revived partnership.

Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. The current rationale for its use is based largely on the ability of RT to kill the cancer cells by a direct cytotoxic effect. Nevertheless, considerable evidence indicates that RT effects extend beyond the mere elimination of the more radiosensitive fraction of cancer cells present within a tumor at the time of radiation exposure. For instance, a large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This might have far-reaching consequences regarding the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective antitumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from preclinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance antitumor effects. Conversely, RT could be a useful tool to combine with immunotherapy. This article will briefly summarize what is known about the impact of RT on tumor immunity, including tumor-associated antigens, antigen-presenting cells, and effector mechanisms. In addition, the experimental evidence supporting the contention that RT can be used as a tool to induce antitumor immunity is discussed, and a new approach to radioimmunotherapy of cancer is proposed.

Animals↗

[A case of advanced gastric cancer with liver and lung metastasis effectively treated by combined chemo-immunotherapy of MMC, 5'-DFUR, OK-432].

A sixty-eight-year-old male patient was diagnosed as having inoperable advanced gastric cancer with liver and lung metastasis. The patient was treated by combined chemo-immunotherapy of MMC 10 mg/M, 5'-DFUR 800 mg/day and OK-432 5 KE/2 W. Six months after commencing chemotherapy, CT-scan and upper GI series revealed that metasized liver tumors and stomach lesion were remarkably decreased in size and no cancer cell was confirmed by endoscopic biopsy. Further, the metastatic lung tumor has disappeared on chest X-ray. The patient had been well without any evidence of tumor re-progression for over one year, but from July the liver tumor began to metastasize again and the patient eventually died of liver metastasis on Jan. 1, 1993.

Adenocarcinoma↗

Treatment of bacilliferous BL/LL cases with combined chemotherapy and immunotherapy.

Thirty-six, untreated borderline lepromatous/lepromatous (BL/LL) leprosy patients with an initial bacterial index (BI) of 4+ to 6+ were serially allocated to three treatment groups. Group I patients received a slightly modified WHO regimen (rifampin once a month, clofazimine and dapsone daily) and BCG intradermally (i.d.) (0.1 mg/per dose). Group II patients were administered the same MDT and Mycobacterium w (2 x 10(8)) killed bacilli/dose i.d., and Group III received the same MDT with 0.1 ml of distilled water i.d. Vaccination was repeated every 6 months. Biopsies were taken from the local site of vaccination and from a distant site, i.e., the back. The progress was monitored periodically by clinical, histopathological and bacterial (BI, mouse foot pad, ATP) parameters. Twenty-five patients had completed a follow up of more than 2 years. These included: 7 in Group I, 10 in Group II, and 8 in Group III. One patient of the MDT + BCG group who was progressing well dropped out after 28 months. In cases on combined chemotherapy and immunotherapy, no viable bacilli were demonstrable by mouse foot pad and ATP measurement after 6 months (at 12 months or afterward). However, in come of the control cases on MDT alone, viable bacilli could be detected even up to 18 months (by mouse foot pad) and 2 years (by ATP estimation). With 36 months of treatment, the mean BI decreased from 4.64+ to 1.66+ in the group on MDT alone (controls), 4.9+ to 0.08+ in the MDT + BCG group, and 4.75+ to 0 in the MDT+Mycobacterium w group. Compared with the MDT and MDT + BCG groups, the fall in the BI was significantly more in the MDT + Mycobacterium w group at 12, 18, and 24 months. While all of the cases in the Mycobacterium w groups became smear negative by 36 months, it took 42 months for all of the BCG group to achieve negativity. Immunotherapy appears to have a significant effect on the killing and clearance of bacilli and should be considered as an adjunct to chemotherapy, especially in bacilliferous lepromatous cases.

Adenosine Triphosphate↗

Histological changes with combined chemotherapy and immunotherapy in highly bacillated lepromatous leprosy.

Highly bacillated untreated lepromatous cases with an initial BI 4+ of to 6+ were treated with combined multidrug treatment (MDT) and immunotherapy with heat killed Mycobacterium w or BCG. The vaccines were administered intradermally every six months. It was observed that majority of cases on immunotherapy showed increased lymphocytic infiltration (both at local and distant sites) and some cases showed epithelioid cells as well. The lymphocytic infiltration was (slightly) more vigorous in those vaccinated with Mycobacterium w. Such changes were not seen in the patients on MDT alone. Also, the granuloma fraction reduced much faster in cases who were on additional immunotherapy as compared to those on MDT alone. These changes along with evidence of clinical and bacteriological improvements suggest that immunotherapy may have an important supportive role specially in the therapy of anergic lepromatous cases.

Antitubercular Agents↗

Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy.

Most cytotoxic drugs have gross effects on the immune system, such as neutropenia and lymphopenia. However, their effects on tumor-specific immune responses are unknown. Gemcitabine is a nucleoside analogue that is frequently used to treat non-small cell lung cancer. It is also active in other malignancies, either alone or in combination with cisplatin. Here, we investigate its effects on antigen-specific antitumor immunity using a murine tumor cell line transfected to express influenza virus hemagglutinin (HA). CD4(+), CD8(+), and B220(+) lymphocyte numbers all decreased during chemotherapy (120 microg/g, i.p., every third day for five doses), but B cells were selectively depleted. Gemcitabine induced a profound suppression of the IgG antibody response to HA, and this was unrelated to tumor size. In contrast, in vitro T-lymphocyte recall responses to the class I- and class II-restricted dominant peptide epitopes of HA were enhanced in tumor-bearing, gemcitabine-treated mice. We found that gemcitabine was >2-fold more potent in its ability to inhibit B-lymphocyte proliferation compared with T-lymphocyte proliferation. Thus, gemcitabine does not appear to be detrimental to specific antitumor cellular immunity and may be useful in combination chemo-immunotherapy protocols. In contrast, vaccination protocols requiring a humoral immune response for maximal efficacy may be compromised in patients treated with gemcitabine.

Animals↗

[Combination of adoptive immunotherapy and chemotherapy against advanced cancer with peritoneal dissemination].

In a case of advanced gastric cancer with bilateral Krukenberg's tumors and peritonitis carcinomatosa, total gastrectomy, splenectomy and bilateral oophorectomy was performed. Since progressive peritoneal dissemination was recognized, 150 mg of CDDP and 10 mg of MMC which were proved to be effective by chemosensitivity test of anticancer drugs were administered intraperitoneally. After one month, ascites increased. So LAK cells and TIL were transferred intraperitoneally 6 times. With this treatment ascitic collection remarkably decreased, the performance status improved and serum level of IAP and CA125 normalized. Thus, it is clarified that the combination of adoptive immunotherapy and chemotherapy possesses therapeutic efficacy against advanced gastric cancer with peritonitis carcinomatosa.

Adenocarcinoma, Mucinous↗

Splenectomy combined with gastrectomy and immunotherapy for advanced gastric cancer.

We studied the effects of a splenectomy in combination with immunotherapy on the survival of patients who had undergone a total gastrectomy. It was found that a splenectomy was not effective against advanced gastric cancer at stage III, and that the spleen should be retained for immunotherapy. Splenectomy for gastric cancer at terminal stage IV, particularly in combination with immunotherapy, produced not only augmentation of cellular immunity, but also increased survival.

Gastrectomy↗

[Development of cancer immunotherapy by a combination of biological response modifiers on the basis of their mechanism of action].

The enhancement of antitumor effects by combination of biological response modifiers (BRM) was investigated on the basis of their action mechanisms. Experimentally, significant inhibition of tumor growth by combination treatment with BRM, which eliminated immune suppressive mechanisms and in turn enhanced immune responses, was observed. Furthermore, inhibition of tumor growth was observed under conditions of uniform biorhythm in mice and the effect of modification of biorhythm was enhanced by combination with BRM. Clinically, combination treatment of plasma exchange and LAK-cell adoptive immunotherapy was discussed.

Animals↗

[The role of adoptive immunotherapy in the combined treatment of neglected forms of colorectal cancer (a preliminary report)].

Results of treatment of 24 patients with neglected colorectal tumors in the period from 1988 till 1994 are presented. Six patients had stage C and 18 patients had stage D after Dukes. Methods of combined action on the tumor including dissection of the tumor and its metastases, using immunoadoptive therapy as extracorporal connection with the donor porcine spleen, intravenous infusions of interleukin-2 and chemotherapy were employed. All the patients with stage C according to Dukes are alive: the average period of observations was 1143 +/- 206 days with intervals within the limits of 4,5-1,5 years. Seven patients of 18 with stage D after Dukes are alive with the average period of observations 1331 +/- 216 days and an interval of observations within the limits from 6 to 2 years. Dead patients with stage D after Dukes lived 525 +/-98 days on the average, i.e. about 1,4 year. The employed method of combined treatment of colorectal tumors improves survival, prolongs the lifetime of patients with neglected forms of the disease.

Adult↗

Combination of levamisole immunotherapy and polychemotherapy in advanced breast cancer.

In a randomized double-blind study, 101 female patients with breast cancer treated with Adriamycin chemotherapy in combination with vincristine and cyclophosphamide received either levamisole immunotherapy or placebo. The investigation was preceded by a pilot study involving 44 patients, of whom 25 received levamisole; the intermittent four-drug schedule of cyclophosphamide, vinblastine, methotrexate, and 5-fluorouracil, however, formed the basis of chemotherapy. In both studies, levamisole increased the response rates (P = 0.03), and in the present controlled trial it also significantly lengthened survival (P = 0.05). The results correlated with initial and levamisole-induced improvement of cell-mediated immunity.

Adult↗

Analysis of electrophoretic mobility histograms of mouse splenocytes and thymocytes during tumor growth and after combined chemotherapy and immunotherapy.

Changes in electrophoretic mobility histograms of splenocytes and thymocytes were studied in plasmacytoma X5563-bearing mice as an indicator of response to treatment with mitomycin C (MMC) alone or combined with the immunomodulator Krestin (PSK). Tumor growth was inhibited by 80-90% in the MMC-treated and was further inhibited in the MMC and PSK-treated group. Electrophoretic mobility histograms of splenocytes were used to determine the fraction of cells having intermediate mobility between high mobility (T cells) and low mobility (B cells). This fraction of intermediate-mobility cells increased in tumor-bearing mice, but a normal electrophoretic mobility pattern was obtained following successful antitumor treatment. In the electrophoretic mobility histogram of thymocytes, on the other hand, the low-mobility cells (cortical thymocytes) decreased in number during tumor growth and were further reduced in the MMC-treated group. This reduction was less in the MMC and PSK-treated group. These results suggest that combined therapy with MMC and PSK prevents damage of the host defence mechanism and allows more efficient antitumor treatment. Analysis of electrophoretic mobility histograms of splenocytes and thymocytes using a fully automated cell electrophoretic instrument makes possible the rapid evaluation of the immunological effects of drug therapy of tumor-bearing mice.

Animals↗