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PubMed1998

Combination immunotherapy and antifungal chemotherapy.

Historical clinical observations suggested that cellular immunity is central in the outcome of deep fungal infections, and experimental observations later proved this. Unstimulated effector cells interact synergistically with antifungal drugs. Recombinant cytokines, of which interferon gamma (IFN-gamma) is the most prominent, stimulate several host-effector cells (macrophages, monocytes, neutrophils) for antifungal activity. Effector cells stimulated by such molecules (data with macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor with azoles are presented as examples) also have enhanced synergistic activity with antifungals. A tilt toward a type 1 T-helper (Th1) cell pathway seems essential in antifungal host defenses. Cytokines (and anticytokines) that promote this pathway can be protective in vivo and act cooperatively with antifungal drugs. Observations with interleukin (IL)-12, IFN-gamma, and anti-IL4 illustrate this. The clinical applications of these strategies are just beginning.

Amphotericin B↗
PubMed2002

The pilot experience of immunotherapy-combined photodynamic therapy for advanced gastric cancer in elderly patients.

BACKGROUND: Therapeutic efficacy of endoscopic photodynamic therapy (PDT) for advanced gastric cancer is limited. Recent animal studies have clarified the very important role of host immune cells in PDT. We expected a potential cooperative effect of PDT and immunotherapy, and developed immunotherapycombined PDT (I-PDT) for advanced gastric cancer. METHODS AND MATERIALS: We applied I-PDT for two elderly patients with complicated advanced gastric cancer (92- and 89-yr-old males). Tumor bleeding prevented them from leading an ordinary home life. Initial simple PDT was not effective. Patients received over 109 activated T-lymphocyte-predominant autologous immune cells, mainly intravenously, 5x for one course. PDT was performed endoscopically on the day of the third infusion. RESULTS: Two or three courses of I-PDT safely stopped tumor bleeding, and the initial poor prognoses of a few months of survival seemed to be improved (patient 1, over 32 mo; patient 2, 14 mo). CONCLUSIONS: I-PDT was found to be a safe, feasible treatment that could improve symptoms resulting from advanced gastric cancer.

Age Factors↗
PubMed2004

Combination immunotherapy of B-cell non-Hodgkin's lymphoma with rituximab and interleukin-2: a preclinical and phase I study.

PURPOSE: Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immunodeficient (SCID) mice engrafted with peripheral blood leukocytes (PBLs) from Epstein Barr virus-seropositive donors develop human B-cell non-Hodgkin's lymphomas [B-NHLs (hu-PBL-SCID mouse model)]. We used this hu-PBL-SCID mouse model to study the synergism between interleukin (IL)-2 and rituximab. We also conducted a phase I trial of IL-2 and rituximab in relapsed B-NHL to study whether expansion of natural killer (NK) cells and enhanced cellular cytotoxicity could be safely accomplished in vivo. EXPERIMENTAL DESIGN: Hu-PBL-SCID mice were treated with various schedules of rituximab and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m2 weekly x 4) followed by daily low-dose IL-2 (1 MIU/m2/day x 4 weeks) with pulses of intermediate-dose IL-2 (3-15 MIU/m2). Toxicity, NK cell numbers, and cellular cytotoxicity were measured. RESULTS: In the hu-PBL-SCID mouse, the combination of rituximab and IL-2 showed greater activity against B-NHL than either agent alone. Treatment was most effective when IL-2 was given before rituximab. Twelve patients with heavily pretreated B-NHL entered the phase I trial. Toxicity was manageable, and responses were observed. NK cell expansion and enhanced cellular cytotoxicity against a B-cell lymphoma target were observed but did not correlate with response. CONCLUSIONS: The combination of IL-2 and rituximab is synergistic against B-NHL in the hu-PBL-SCID model. In the phase I trial, a sequential combination of rituximab and IL-2 was well tolerated and achieved biological end points. Responses were observed.

Adult↗
PubMed2000

Phase II study of combined immunotherapy, chemotherapy, and radiotherapy in the postoperative treatment of advanced non-small-cell lung cancer.

The association of adoptive immunotherapy (AI) and radiotherapy has been shown to be effective in the control of residual intrathoracic disease, while having no systemic advantages, in patients operated on for locally advanced non-small-cell lung cancer (NSCLC). The potential synergy of coupling immunotherapy and chemotherapy has been emphasized in several tumors including NSCLC. The aim of this work was to determine the feasibility and activity of a combined therapeutic program, including AI, chemotherapy, and radiotherapy in patients who had undergone incomplete resections for NSCLC. In a phase II trial, 13 patients received the combined treatment. AI was given from week 4 after surgery until week 8. Concurrent chemo-(cisplatin and etoposide)-radiotherapy (60 Gy) was given from week 9 to week 14. Twenty eligible patients received chemoradiotherapy only and were used as a non-randomized concomitant group for merely descriptive purposes. At 9-month follow-up, 10 of the 13 patients had progression of disease and the study was stopped. Progression-free survival and survival were similar to those of the chemoradiotherapy group. The present study showed that the sequence of immunotherapy followed by chemotherapy is not effective as adjuvant treatment in patients operated on for stage III NSCLC, at least when used according to the adopted schedule.

Adult↗
PubMed2000

Host immune reactivity determines the efficacy of combination immunotherapy and antifungal chemotherapy in candidiasis.

In immunocompetent mice with candidiasis, successful therapy with amphotericin B and fluconazole relies on the induction of protective, T helper (Th) type 1 responses, an effect potentiated by concomitant interleukin (IL)-4 neutralization. To assess the therapeutic efficacy of combined treatments with antifungals and immunomodulators in conditions of immunosuppression, leukopenic or neutropenic mice with disseminated candidiasis were treated with amphotericin B or fluconazole alone or in combination with soluble IL-4 receptor (sIL-4R) or recombinant (r) IL-12 or IL-10 neutralizing monoclonal antibodies. We found that (1) the synergistic effect of sIL-4R and antifungals is retained in immunocompromised mice; (2) synergism with amphotericin B was superior to that with fluconazole, particularly in leukopenic mice; (3) rIL-12 synergized with fluconazole in neutropenic mice; and (4) IL-10 neutralization was always of limited efficacy. This study indicates that the therapeutic efficacy of antifungals is differentially potentiated by cytokines or cytokine antagonists and is influenced by host immune reactivity.

Amphotericin B↗
PubMed1996

Combination immunotherapy with OK-432, recombinant granulocyte-colony-stimulating factor and recombinant interleukin-2 for human hepatocellular carcinoma.

The antitumor effects of immunotherapy using streptococcal preparations (OK-432), recombinant granulocyte-colony-stimulating factor (rG-CSF) and recombinant interleukin-2 (rIL-2) were examined for human hepatocellular carcinoma (HCC). Following subcutaneous injection of OK-432 (2 KE) and rG-CSF (50-60 microg), low-dose intratumoral administration of OK-432 (3-12 KE) was performed. Thereafter, 2 x 10(5) JRU of rIL-2 was subcutaneously injected. This therapeutic regimen was repeated twice. Serum alpha-fetoprotein levels were markedly decreased in three of seven patients with HCC by this treatment. Post-therapeutic histological examination revealed that trabecular cords or pseudoglandular arrangements of tumor cells were completely disordered in all cases and that extensive infiltration of lymphocytes into the tumor stroma was present in five cases. The number of CD4- and CD57-positive cells among tumor-infiltrating lymphocytes after immunotherapy was significantly higher than that in patients without immunotherapy (P <0.01). These findings suggest that even a small intratumoral injection of OK-432 can induce extensive infiltration of helper/inducer and natural killer cells into the tumor stroma when combined with subcutaneous injection of OK-432, rG-CSF and rIL-2 and that these cells might play important roles in tumor cytotoxicity.

Aged↗
PubMed1982

Interim results of EORTC protocol 08742: comparison, after irradiation of locally advanced squamous cell bronchial carcinoma, of abstention, immunotherapy, combination chemotherapy, or chemoimmunotherapy.

After irradiation of locally unresectable epidermoid bronchial carcinoma, 1 year of chemotherapy is significantly superior in delaying both local recurrences and distant metastases and prolonging the disease-free interval. However, BCG immunotherapy alone seems to be superior in terms of survival to no therapy, chemotherapy, and immunochemotherapy. This could be due to a better tolerance to secondary treatments given at time of recurrence.

Carcinoma, Squamous Cell↗
PubMed2003

Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma.

Immunotherapy (IT) has become an accepted therapeutic modality. We previously reported that intracellular hyperthermia (IH) using magnetic nanoparticles induces antitumor immunity. We undertook these studies in order to study the combined effects of IT and IH on melanoma. Magnetite cationic liposomes (MCLs) have a positive surface charge and generate heat in an alternating magnetic field (AMF) due to hysteresis loss. MCLs were injected into a B16 melanoma nodule in C57BL/6 mice, which were subjected to AMF for 30 min. The temperature at the tumor reached 43 degrees C and was maintained by controlling the magnetic field intensity. At 24 h after IH, interleukin-2 (IL-2) or granulocyte macrophage-colony stimulating factor (GM-CSF) was injected directly into the melanoma. Mice were divided into six groups: group I (control), group II (IH), group III (IL-2), group IV (GM-CSF), group V (IH + IL-2), and group VI (IH + GM-CSF). Complete regression of tumors was observed in mice of groups V and VI (75% (6/8) and 40% (4/10) of the mice, respectively), while no tumor regression was observed in mice of the other groups. This study supports the combined use of IT and IH using MCLs in patients with advanced malignancies.

Animals↗
PubMed1993

Phenotypic and functional profile of peripheral blood mononuclear cells isolated from melanoma patients undergoing combined immunotherapy and chemotherapy.

In the present study we tested the phenotypic profile as well as several immunological responses of peripheral blood mononuclear cells (PBMC) isolated from melanoma patients. These patients underwent chemotherapy with dacarbazine and carboplatin from day 1 to day 22, followed by immunotherapy of low-dose recombinant interleukin-2 and recombinant interferon alpha administered subcutaneously from day 36 to day 75. The PBMC from 14 patients were isolated on day 0 before chemotherapy, on day 36 after chemotherapy and on day 76 after immunotherapy. After chemotherapy, a decrease in CD16+ cells and increase in CD3+ and CD4+ cells correlated with a significant decrease in the generation of lymphokine-activated killer (LAK) activity. After immunotherapy, an increase in CD16+ cells correlated with an increase in the induction of LAK activity. A comparison between responding and non-responding patients revealed statistically significant differences in LAK activity of PBMC and response to concanavalin A following chemotherapy, and in the percentage of CD8+ cells following immunotherapy. Our results point toward the value of continuing such a study on a larger population of cancer patients in order to select the appropriate bioassays for monitoring and predicting the clinical responsiveness to combined therapies.

Adult↗
PubMed1991

Clinical and immunomodulatory effects of combination immunotherapy with low-dose interleukin 2 and tumor necrosis factor alpha in patients with advanced non-small cell lung cancer: a phase I trial.

Sixteen patients with metastatic non-small cell lung cancer were treated with a combination of simultaneous low-dose interleukin 2 (IL-2) and tumor necrosis factor alpha. The purpose of this phase I dose escalation trial was to assess the clinical toxicities, immunomodulatory effects, and antitumor efficacy of this combination. Patients received a continuous daily i.v. infusion of 6 x 10(6) IU/m2 of IL-2 for 5 days and a concomitant daily i.m. dose of tumor necrosis factor alpha on each day of IL-2 administration. Tumor necrosis factor alpha administration started at a dose of 25 micrograms/m2/day (level I) for seven patients, 50 micrograms/m2/day (level II) for seven patients, and 100 micrograms/m2/day (level III) for two patients. Treatment was given at 3-week intervals. Only one patient required monitoring by an intensive care unit during therapy. Major toxic effects included fever, local skin reaction at the i.m. injection site, pancytopenia, and general malaise, all of which were reversible within 48 h of cessation of therapy. Dose level II was determined to be the maximum tolerated dose, with the dose-limiting toxicity being thrombocytopenia (less than 50,000/microliters). In 12 evaluable patients, one partial and three minor tumor regressions were observed. Seven patients with progressive disease before entry into this study had radiographic stabilization of their disease (median, 12 weeks) before termination of therapy due to progression. All patients exhibited biological responses including augmented lymphokine-activated killer and natural killer cell activities while receiving therapy, as assessed by the cytolysis of Raji- and K562 targets in vitro. Enhanced lysis of autologous tumor during therapy was demonstrated for four patients with available tumor samples. Serum levels of IL-2 were detected by enzyme-linked immunosorbent assay 2 weeks after cessation of therapy. This serum IL-2 had biological activity, which was evident from the ability to induce proliferation of NK-8 cells (an IL-2-dependent cell line) which was abrogated by anti-IL-2 antibody.

Adolescent↗
PubMed2000

Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a.

Rituximab and IFN have each demonstrated single-agent activity in patients with low-grade non-Hodgkin's lymphoma (NHL). A single-arm, multicenter, Phase II trial was conducted to assess the safety and efficacy of combination therapy with rituximab and IFN-alpha-2a in 38 patients with relapsed or refractory, low-grade or follicular, B-cell NHL. IFN-alpha-2a [2.5 or 5 million units (MIU)] was administered s.c., three times weekly for 12 weeks. Starting on the fifth week of treatment, rituximab was administered by i.v. infusion (375 mg/m2) weekly for 4 doses. All 38 patients received four complete infusions of rituximab and were evaluable for efficacy, although 11 patients (29%) did not-receive all 36 injections of IFN. The mean number of IFN-alpha-2a injections was 31 doses; the mean total units received were 141 MIU (maximum, 180 MIU). The study treatment was reasonably well tolerated with no unexpected toxicities stemming from the combination therapy. No grade 4 events were reported. Frequent adverse events during the treatment period included asthenia (35 of 38 patients), chills (31 of 38), fever (30 of 38), headache (28 of 38), nausea (23 of 38), and myalgia (22 of 38). The overall response rate was 45% (17 of 38 patients); 11% had a complete response, and 34% had a partial response. The Kaplan-Meier estimates for the median response duration and the median time to progression in responders are 22.3 and 25.2 months, respectively. Further follow-up is needed to determine whether this treatment combination leads to a significantly longer time to progression than single-agent treatment with rituximab.

Adult↗