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PubMed1990

[Methodological aspects of the optimal use of combined chemo- and immunotherapy].

Methodical aspects of developing rational schemes of combined use of antibiotics and immunomodulators are discussed. Chemotherapeutic drugs are synergists of the factors of nonspecific resistance i. e. enzymes, cationic proteins, etc. However, prediction of the effect of both etiotropic agents and immunomodulators on resistance and immunity is rather complicated. A system for estimating efficacy of combined chemo- and immunotherapy based on multifactorial analysis is described. The main steps of the system are the following: choice of the quality criteria, determination of the experimental factors and levels, choice of the experimental design, performance of the experiment, computer processing of the results, construction of a polynomial statistic model and solution of the therapy problems. The method is universal and applicable to any combination of chemotherapeutics and immunomodulators.

Adjuvants, Immunologic↗
PubMedDate not supplied

High doses of thymosin alpha 1 enhance the anti-tumor efficacy of combination chemo-immunotherapy for murine B16 melanoma.

BACKGROUND: We have reported previously that combined chemo-immunotherapy with cyclophosphamide (CY), thymosin alpha 1 (T alpha 1) and low dose interferon alpha,beta (IFN alpha beta) has significant anti-tumour effects. Here, using mouse B16 melanoma as a model, we tested whether increasing the dose of T alpha 1 could increase the anti-tumour activity of triple combination chemo-immunotherapy. MATERIALS AND METHODS: C57BL/6 mice were challenged subcutaneously with B16 melanoma cells and injected intraperitoneally with saline, CY (200 mg/kg, day 7), or CY with T alpha 1 (200, 600 or 6000 micrograms/kg/day, days 10-13) and IFN alpha beta (30,000 I.U., day 13). RESULTS: Chemo-immunotherapy with high dose (HD)-T alpha 1 caused complete tumour regression for 27.5 days after tumour cell injection (3.9 times longer than untreated controls) and delayed tumour relapse compared to all other groups. Moreover, it significantly increased the median survival time of treated mice, and cured an average of 23% of animals, while none was cured in any other group. Splenocytes from HD-T alpha 1-treated mice showed markedly increased cytotoxic activities against both YAC-l and autologous B16 tumour cells. HD-T alpha 1 treatment reversed the tumour-induced reduction in percentages of CD3 and CD4-positive splenocytes to non-tumour levels, and it increased percentages of CD8, B220 and IL-2R beta-positive cells to well beyond non-tumour controls. CONCLUSIONS: High doses of T alpha 1 improve anti-tumour efficacy of tnple chemo-immunotherapy against B16 melanoma. These effects appear to be mediated by stimulation of the host immune response.

Adjuvants, Immunologic↗
PubMed1998

Prolongation of cardiac graft survival with anti-CD4Ig plus hCTLA4Ig in primates.

BACKGROUND: The aim of this study was to determine whether the use of combined immunotherapy with a brief course of humanized anti-CD4Ig and hCTLA4Ig would prolong heterotopic cardiac allograft survival in primates (rhesus monkeys). This model was based on work in "high responder" rats where a brief course of depletive anti-CD4mAb plus hCTLA4Ig was successful in inducing transplantation tolerance. METHODS: Heterotopic cardiac transplants were performed in rhesus recipients. Donor/recipient pairs between groups were confirmed to be reactive prior to transplantation by MLR matching. Humanized anti-CD4Ig, a recently developed anti-CD4mAb, was given at a dose of 20 mg/kg i.v. on days -3, -2, -1, and 0. hCTLA4Ig was administered at 6 mg/kg/dose i.v. on days 0 and 2 for the first recipient and days 0, 2, 4, and 6 for the second recipient. No further immunosuppression was administered. The treated (n = 2) or untreated (n = 5) recipients were followed for graft function by daily palpitation. RESULTS: Treatment with anti-CD4Ig plus hCTLA4Ig resulted in a significant prolongation of heart graft survival (42 days for the first recipient and 52 days for the second recipient) compared to untreated recipients (7 days x 4, 11 days x 1). FACS analysis demonstrated CD4 depletion of anti-CD4 treated animals to <2% on posttransplant day 1. The CD4+ T cells gradually repopulated to 50-70% pretransplant levels just prior to rejection. No adverse responses (fever, tachypnea, tachycardia, infections) were observed. CONCLUSIONS: These are the first results demonstrating that a brief course of combined specific induction immunotherapy with humanized anti-CD4Ig plus hCTLA4Ig, in the absence of adjuvant posttransplant immunosuppression, was well tolerated and resulted in marked prolongation of cardiac allograft survival in primates.

Abatacept↗
PubMed2005

Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy.

Adoptive T-cell immunotherapy combined with non-myeloablative lymphodepletion has emerged as the most effective immunotherapy treatment for patients with metastatic melanoma (objective response rates of 50%). The mechanisms underlying this major advance in the field of immunotherapy include the elimination of regulatory elements and increased access to activating cytokines. This results in the activation of low-affinity T cells, enabling them to destroy tumors. We propose that a more complete depletion of the patient's immune system followed by transplantation with hematopoietic stem cells, which can be genetically modified, would be more effective in the treatment of metastatic cancer.

Animals↗
PubMed2002

Biochemotherapy of melanoma.

Despite the evaluation of many different chemotherapy and immunotherapy drugs, the median survival in metastatic melanoma remains in the range of 6 to 9 months. Combination chemotherapy or combination immunotherapy has not produced a significant advantage over single-agent therapy but is associated with greater toxicity. Based on the potential for additive or synergistic activity with the combination of chemotherapy and biotherapy, many investigators have evaluated biochemotherapy in patients with advanced melanoma. Aggregate results suggest that biochemotherapy is tolerable and produces a response rate in the range of 50% with a complete response rate of 10%. Although these phase II results appear superior to previous results with chemotherapy or immunotherapy alone, the true benefits of biochemotherapy can only be determined with the results of randomized phase III trials; therefore, biochemotherapy should be considered an as yet experimental therapy. Many other issues regarding biochemotherapy, such as sequence, outpatient administration, and use in the adjuvant setting, for stage III melanoma are being actively evaluated.

Antineoplastic Agents↗
PubMedDate not supplied

Metastatic liver disease of colorectal origin: the value of locoregional immunochemotherapy combined with systemic chemotherapy following liver resection. Results of a prospective randomized study.

BACKGROUND/AIMS: Liver resection for metastatic liver disease of colorectal origin, although considered as the 'gold standard' of treatment, is associated with limited long-term survival. The aim of this study was to compare overall survival, disease-free survival and the incidence of intra- or extrahepatic recurrence between patients who were randomly assigned to have locoregional chemoimmunotherapy with systemic chemotherapy group A (n = 62 patients) versus those who were treated with systemic immunochemotherapy group B (n = 60 patients). METHODOLOGY: Group A included patients who, after liver resection, received locoregional immunochemotherapy combined with systemic chemotherapy, while group B included patients who had undergone systemic immunotherapy combined with systemic chemotherapy following liver resection. The two groups were matched in terms of sex, age and stage of the disease. Prognostic factors and their impact on disease-free survival were studied in both groups. RESULTS: Two-year survival was 92% for group A versus 75% for group B, 5-year survival was 73% for group A versus 60% for group B. During the two-year period, 34% of the group A patients versus 52% of those of group B developed either intrahepatic or extrahepatic recurrence of the disease (P < 0.00212). CONCLUSIONS: From the analysis of the above results it becomes clear that regional immunochemotherapy combined with systemic chemotherapy leads to a decrease in the incidence of disease recurrence and thus to a significant prolongation of the overall survival and of disease-free survival.

Adult↗
PubMed1994

[Leakadin immunotherapy in the combined therapy of acoustic neurinomas].

The paper specifies the role of leacadin immunotherapy in combined treatment of acoustic nerve neurinomas. The antitumor immunomodulator leacadin contributes to establishment and consolidation of the tumor carrier's immunological adaptation which results in uneventful postoperative developments and recurrent-free survival.

Adjuvants, Immunologic↗
PubMed1989

[Evaluation of long-term immunotherapy in patients with lupus nephritis].

In 177 patients with lupus nephritis in the course of three decades three methods of immunotherapy were used the effect of which was evaluated retrospectively. When the criterium of the survival period was used, it was revealed that from a group of 66 patients treated only with glucocorticoids (mainly prednisone by the oral route) less than 60% survived five years the onset of lupus nephritis, only 33% survived 10 years. From a group of 81 patients treated with glucocorticoids and cytostatics (mostly cyclophosphamide by the oral route) 80% survived five years and 50% ten years, while in a group of 30 patients treated with glucocorticoids, cyclophosphamide and levamisole 90% survive five years and as many as 70% ten years from the onset of lupus nephritis. From the onset of SLE however as many as 80% survived ten years in all three analyzed groups, which provides evidence that lupus nephritis accounts for the greatest mortality in patients with SLE, as renal failure was the cause of death in one third of the patients. As to complications, secondary infections were recorded in almost 30% of the patients, incl. 9% lethal ones, non-infections complications less than 5%. The authors discuss assumed mechanism of the action of combined immunotherapy, which holds a priority position, as compared with glucocorticoid monotherapy.

Cyclophosphamide↗
PubMed2001

Activated T-cell and bispecific antibody immunotherapy for high-risk breast cancer. Bench to bedside.

Nontoxic approaches are needed to improve overall survival (OS) and progression-free survival (PFS) for high-risk breast cancer. Combination immunotherapy (IT) consisting of activated T cells (ATC), interleukin-2 (IL-2), and CTL (GM-CSF) was given after peripheral blood stem cell transplant (PBSCT). There were no major toxicities and there appear to be improvements in OS and PFS over historical controls. In order to develop specific cytotoxic T lymphocytes (CTL), we combined ATC with the use of bispecific antibody (BiAb). By arming ATC with anti-CD3 x anti-HER2/neu BiAb (HER2BiAb), the approach converts nonspecific ATC into HER2/neu (HER2) specific CTL. ATC remain armed, kill tumor targets for days, and produce cytokines after binding to tumor. Arming ATC with BiAbs may prove to be effective for targeting a variety of tumors with and without high-dose chemotherapy.

Antibodies, Bispecific↗
PubMed1993

Synergetic effect of interleukin-2 and cellular cytotoxicity against a novel tumor-associated carbohydrate antigen Le(a)/Le(a) (dimeric Le(a)) mediated by monoclonal antibody NCC-ST-421 in adoptive immunization using SCID mice.

The murine IgG3 monoclonal antibody NCC-ST-421, raised against a human gastric cancer, shows strong reactivity with dimeric Le(a) (Le(a)/Le(a); V4FucIII4FucLc6Cer) expressed on gastrointestinal cancer cells. ST-421 reacted minimally with non-dimeric or simple Le(a) expressed on normal tissues. ST-421 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) with human peripheral blood lymphocytes, and complement-dependent cytotoxicity with human complement. Interleukin-2 (IL-2) modulates the function of immunocytes, in particular inducing lymphokine-activated killer (LAK) cell activity and enhancing ADCC. We therefore employed combination immunotherapy with IL-2, LAK, and ST-421-induced ADCC in vitro and in mice with severe combined immunodeficiency (SCID), using target tumor cells expressing Le(a)/Le(a) antigen. ADCC against human colon cancer cell lines in vitro was enhanced three to four times after preincubation with IL-2. Addition of IL-2 reduced the amount of ST-421 required for efficient ADCC 10- to 100-fold. ADCC was activated by IL-2 earlier (1 day) than the generation of LAK cells (3-4 days), and at lower concentration of IL-2. These effects were specific for ST-421, as demonstrated by experiments with irrelevant antibody or irrelevant target cells. An anti-(Fc receptor) antibody blocked the ADCC but not the LAK activity in vitro. The enhancement of ADCC by IL-2 may be caused by activation of effector cells expressing Fc receptors. In vivo experiments using SCID mice inoculated with human colon cancer showed a significant tumor-growth-suppressive effect after combined therapy using human peripheral blood lymphocytes, LAK, IL-2, and ST-421. In summary, adoptive immunization with human lymphocytes activated by IL-2 and ST-421 effectively suppressed growth of gastrointestinal cancer cells expressing Le(a)/Le(a).

Animals↗
PubMed1990

THF-gamma 2, a synthetic thymic hormone, increases effectiveness of combined chemotherapy and immunotherapy against RPC-5 murine plasmacytoma.

The effect of a synthetic thymic hormone, THF-gamma 2, on the anti-tumor activity of spleen cells was studied in mice immunized against the RPC-5 tumor. Following two courses of the THF-gamma 2 treatment, the mean RPC-5 specific cytotoxic response of immune spleen cells was significantly increased when compared to normal cells (P less than 0.001) and to untreated immune spleen cells (P less than 0.04). In addition, THF-gamma 2 treatment improved the competence of immune spleen cells in adoptive immunotherapy (AIT) when performed in combination with chemotherapy by melphalan. Recipients of spleen cells from THF-gamma 2 treated mice showed a 35% increase in survival when compared to AIT with immune cells alone. The results suggest that THF-gamma 2 treatment of donors for AIT might be applicable to cancer therapy in humans.

Animals↗
PubMed2003

[Usefulness of TS-1 and lentinan combination immunochemotherapy in advanced or recurrent gastric cancer--pilot study aiming at a randomized trial].

The quality of life (QOL) of patients with advanced or recurrent gastric cancer is poor and their immunocompetence is low, making it important to conduct chemotherapy while at the same time improving their QOL and maintaining their immunocompetence. To improve QOL and increase compliance by reducing the side effects but not the antitumor effect of TS-1, a 2-week regime with 2-week administration of TS-1, and a 1-week drug-free interval in combination with the immunotherapeutic agent lentinan (LNT) was started in 5 patients with advanced or recurrent gastric cancer. Toxicity, efficacy, QOL, and immunological parameters were investigated preliminarily to examine whether or not usefulness of lentinan could be evaluated. QOL scores for appetite, nausea/vomiting, and abdominal pain/diarrhea showed improvement, although not in statistically significant values. The Th2 (CD4-positive, IL4-positive T cells) response in peripheral blood decreased significantly. TS-1 and lentinan combination immunotherapy was carried out safely with advanced recurrent gastric cancer. In order to examine the usefulness of LNT combined use, it was thought that a randomised trial using toxicity with not only efficacy but QOL and immunological parameters as indicators would be beneficial.

Adult↗
PubMed1997

Health related quality of life outcomes in patients treated for metastatic kidney cancer: a pilot study.

PURPOSE: We assessed health related quality of life in patients with advanced renal cell carcinoma treated with nephrectomy and tumor infiltrating lymphocyte therapy in combination with interleukin-2. MATERIALS AND METHODS: A total of 20 patients with advanced renal cell carcinoma who underwent nephrectomy and combination immunotherapy with tumor infiltrating lymphocytes and interleukin-2 completed a retrospective, cross-sectional health related quality of life instrument. Established reference populations with other chronic medical conditions, or breast, prostate or other cancers were used for comparison of health related quality of life scores. General health related quality of life was measured with a RAND 36-Item Health Survey 1.0. Cancer targeted quality of life was measured with the Cancer Rehabilitation Evaluation System-Short Form. Sociodemographic and co-morbidity variables were also collected. RESULTS: General health related quality of life in patients treated with tumor infiltrating lymphocytes and interleukin-2 was significantly better than that in heart failure patients on 1 of 8 scales but significantly worse than in the general population on 6 of 8 scales. General health related quality of life in the former patients was also significantly worse than in those with hypertension on 5 of 8 scales and significantly worse than in diabetics on 2 scales. Cancer targeted health related quality of life in patients given immunotherapy was significantly better than in men with prostate cancer on 1 of 5 scales, significantly better than in women with breast cancer on 2 of 5 scales and significantly better than patients with other cancers (nonbreast and nonprostate) on 3 of 5 scales. CONCLUSIONS: Patients undergoing nephrectomy and adjuvant tumor infiltrating lymphocytes plus interleukin-2 therapy for advanced renal cell carcinoma report better health related quality of life than those with other malignancies and better physical function than patients with congestive heart failure. However, health related quality of life is worse than in the general population and similar or worse than in patients with hypertension or type II diabetes. This surveyed population is selective and may represent the best responders among survivors of a highly toxic therapy. Nevertheless, quality and quantity of life should be addressed with patients when considering immunotherapy for metastatic kidney cancer.

Carcinoma, Renal Cell↗
PubMed1991

A murine plasmacytoma MOPC 104E resistant to cyclophosphamide is resistant to immunotherapy.

A murine plasmacytoma MOPC 104E (MOPC) is highly sensitive to chemotherapeutic agents such as cyclophosphamide and mitomycin C as well as to immunotherapy (OK-432-combined adoptive immunotherapy using interleukin-2-cultured killer cells). In the present study, we prepared cyclophosphamide-resistant MOPC cells (MOPC-CPA/R) by serial in vivo passage of tumor cells following cyclophosphamide treatment. The in vivo sensitivity of MOPC-CPA/R to mitomycin C or to immunotherapy (OK-432-combined adoptive immunotherapy) was significantly decreased compared to the parent MOPC. In vitro experiments showed that MOPC-CPA/R were more resistant (five-fold) to lysis by cultured immune spleen cells than MOPC. Inhibition of the lytic activity of cultured immune spleen cells against MOPC was significantly increased (P less than 0.05) by the addition of unlabeled MOPC compared to unlabeled MOPC-CPA/R. These results suggest that MOPC-CPA/R express weaker antigenicity than MOPC. However, the transfer of immune spleen cells cultured with tumor extract derived from MOPC-CPA/R significantly prolonged the survival of MOPC-CPA/R-inoculated mice. Thus, by repeated cyclophosphamide treatment, tumor cells with low-antigenicity were selected. These tumor cells had lower sensitivity to another chemotherapeutic agent and immunotherapy. Such an immunological response may play an important role in cancer therapy.

Animals↗
PubMed1998

Central neurological paraneoplastic syndromes. Part 1. Clinical features, pathophysiology and immunopharmacology.

Neurological paraneoplastic syndromes, sometimes called remote effects of cancer on the nervous system, are rare but important and often devastating complications of cancer. The immunological theory of causation is supported by many different lines of evidence and reasoning which implicate abnormalities of both humoral and cellular immunity. The targets of immunologically mediated injury, although remote from the tumor, may be hard hit and irreversibly damaged, giving rise to discrete syndromes of motor or cognitive impairment. In the CNS, they are neuronal nuclei, cerebellar Purkinjie cells and cell surface glutamate receptors. Although central paraneoplastic neurological syndromes may occur in children or adults, the clinical syndromes and response to treatment differ substantially between the two groups. The current therapeutic armamentarium provides a broad spectrum of nonselective immunotherapies including noncytotoxic and cytotoxic drugs, intravenous immunoglobulins and plasma exchange, some selected for induction and others for maintenance. Combination immunotherapies allow steroid sparing and targeting of more than one immunologic effector pathway, and deploy an advantageous mixture of early- and late-acting drugs. More selective and efficacious immunotherapies are needed.

Journal Article↗
PubMed1989

[Changes of T lymphocyte subsets in BERH-2 hepatoma-bearing rats and effect of different immunotherapies on the tumor].

Peripheral blood and tumor-infiltrating T lymphocyte subsets in BERH-2 hepatoma-bearing rats were investigated by indirect immunofluorescence stain and flow cytometry. Based on the above study, comparison of immunoregulatory action and inhibitory effect on the tumor were also done in vivo among several groups which received IFN, IL-2, 5-FU, combined immunotherapy (CI) or immunochemotherapy (IC), respectively. The results indicated that T lymphocyte subsets in hepatoma-bearing rats would undergo changes which were closely related with tumor growth and metastasis. IC had multiple phased advantages against the tumor, such as improving immunity, eliminating immunosuppression and directly killing the tumor cells. It is a valuable therapeutic regime in hepatoma.

Animals↗
PubMed1988

A trial of postoperative adjuvant combination chemo-immunotherapy for stage IV gastric carcinoma.

A chemo-immunotherapy program was designed on the basis of our clinical findings, which revealed that the ability to generate cell-mediated cytotoxicity was remarkably augmented after adriamycin (AM) administration in cancer patients. Twenty patients with stage IV gastric carcinoma who had undergone noncurative resections were treated with the above regimen that consisted of active immunotherapy with autologous tumor cells, in combination with 30 mg of AM, given 7 days before the immunization, followed by long-term tegafur (FT) and immunomodulators. The survival of these patients was compared to that of 3 other groups of patients, namely; 30 patients treated with another chemo-immunotherapy regimen which comprised autologous tumor cells in combination with several anticancer drugs followed by long-term FT and immunomodulators (CCI1), 17 patients treated with mitomycin C followed by long-term FT and immunomodulators (CI), and 24 patients with comparable histories (HC). The first treatment group had significantly improved survival, as compared to the HC group (p less than 0.01) and the survival tended also to be more favorable, when compared to the CCI1 group (p less than 0.2) or the CI group (p less than 0.2). Moreover, the survival rate at 9 months was significantly higher than that of either the CCI1 group (p less than 0.01) or the CI group (p less than 0.01).

Adjuvants, Immunologic↗
PubMed2005

Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo.

BACKGROUND: Epithelial ovarian cancer often develops resistance to standard treatments, which is a major reason for the high mortality associated with the disease. We examined the efficacy of a treatment regimen that combines immunotherapy to block the activity of epidermal growth factor receptor (EGFR), overexpression of which is associated with the development of resistant ovarian cancer, and photodynamic therapy (PDT), a mechanistically distinct photochemistry-based modality that is effective against chemo- and radioresistant ovarian tumors. METHODS: We tested a combination regimen consisting of C225, a monoclonal antibody that inhibits the receptor tyrosine kinase activity of EGFR, and benzoporphyrin derivative monoacid A (BPD)-based PDT in a mouse model of human ovarian cancer. Therapeutic efficacy was evaluated in acute treatment response and survival studies that used 9-19 mice per group. Analysis of variance and Wilcoxon statistics were used to analyze the data. All statistical tests were two-sided. RESULTS: Mice treated with PDT + C225 had the lowest mean tumor burden compared with that in the no-treatment control mice (mean percent tumor burden = 9.8%, 95% confidence interval [CI] = 2.3% to 17.3%, P < .001). Mean percent tumor burden for mice treated with C225 only or PDT only was 66.6% (95% CI = 58.7% to 74.4%, P < .001) and 38.2% (95% CI = 29.3% to 47.0%, P < .001), respectively. When compared with PDT only or C225 only, PDT + C225 produced synergistic reductions in mean tumor burden (P < .001, analysis of variance) and improvements in survival (P = .0269, Wilcoxon test). Median survival was approximately threefold greater for mice in the PDT + C225 group than for mice in the no-treatment control group (80 days versus 28 days), and more mice in the PDT + C225 group were alive at 180 days (3/9; 33% [95% CI = 7% to 70%]) than mice in the C225-only (0/12; 0% [95% CI = 0% to 22%]) or PDT-only (1/10; 10% [95% CI = 0.2% to 44%]) groups. CONCLUSION: A mechanistically nonoverlapping combination modality consisting of receptor tyrosine kinase inhibition with C225 and BPD-PDT is well tolerated, effective, and synergistic in mice.

Analysis of Variance↗