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Intrathecal immunotherapy in CNS tumors disseminating via CSF: preliminary evaluation using different treatment schedules.

Eight patients affected by central nervous system tumours disseminating via cerebrospinal fluid received rIL-2 immunotherapy according to three different protocols involving intrathecal administration followed or not by systemic infusion. Immunological monitoring included serial evaluation of CSF leukocytes, CSF and peripheral blood CD3-CD56+ cells, and NK activity. The most marked rise in CSF leukocyte levels was induced by daily intrathecal rIL2 administration, which also induced increased PB NK activity. Systemic rIL2 infusion following intrathecal treatment maintained a high percentage of CSF CD3-CD56+ cells, but not CSF leukocytes at high levels. Clinical conditions improved after treatment in two patients, worsened in one and remained substantially unchanged in the remaining five. The side effects of intrathecal rIL2 treatment included fever, confusion, and seizures, and there were marked interindividual variations in the immunological response.

Adolescent↗

Two phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma.

Preclinical studies have shown that low dose IL-12 can potentiate cytotoxic lymphocyte responses. Since previous trials have demonstrated significant toxicity from high dose recombinant human IL-12 (rhIL-12), we sought to determine an optimal biological dose for rhIL-12 at lower doses when combined with peptide antigens. Two studies were undertaken. The rhIL-12 was administered at doses of 0 (placebo), 10, 30 and 100 ng/kg, subcutaneously in one study and intravenously in the other. Apart from IL-12 dosing, the studies were identical. Subjects had evaluable stage III or IV melanoma which expressed Melan-A by RT-PCR or immunohistochemistry. Melan-A (26-35) (EAAGIGILTV) and influenza matrix (58-66) (GILGFVFTL) peptides were administered intradermally on weeks 1, 2, 3, 4 and 9. Twenty-eight subjects were enrolled, of whom 24 were evaluable for clinical and immunological responses. Therapy was well tolerated, the main adverse event being influenza-like symptoms. Immunological monitoring included the evaluation of cutaneous reactions and assays for antigen-specific T-cells. Clinical responses included a complete response in a subject with small volume subcutaneous disease, a partial response in a subject with hepatic metastases, and mixed responses in pulmonary, pleural and nodal disease. Biopsies of accessible tumors showed infiltration with CD4+ and CD8+ lymphocytes capable of lysing Melan-A peptide-pulsed targets in vitro. No clear dose-dependent effect of rhIL-12 could be determined. The rhIL-12 given either s.c. or i.v. was well tolerated at doses of 10-100 ng/kg. Clinical and immunological activity has been observed in this study where peptides were administered either with or without low dose rhIL-12.

Adjuvants, Immunologic↗

Immune responses in small intestinal transplantation in the rat: correlation of histopathology and monocyte procoagulant activity.

No predictive serologic marker exists for rejection or graft versus host disease (GVHD) reactions in small intestinal transplantation (SIT). SIT was performed in Lewis (Lew) and Lew X Brown Norway Fl hybrid (LBN) rats in the following combinations: group 1, Lew X Lew; group 2 (isolated rejection), LBN X Lew, and group 3 (isolated GVHD), Lew X LBN. Procoagulant activity (PCA), an index of monocyte immune activation, was measured in the peripheral blood mononuclear cells of graft recipients to assess its value as an immunologic monitor. Histologic findings and PCA were evaluated on days 1, 2, and 3 and every 2 to 3 days after SIT. No pathologic findings of graft or host tissue developed in group 1 (n = 14). Histologic rejection (blunted villi and mononuclear cell infiltration) was seen beginning on day 5 in group 2 (n = 19); early GVHD (loss of nodal and splenic architecture) was first noted on days 5 and 6 in group 3 (n = 17). PCA elevation in SIT was seen to precede histologic evidence of rejection or graft versus host disease in this model and may constitute an important marker for these immunologic events.

Animals↗

Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables.

PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture. RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

Aged↗

Short-term immunological effects of induced emotion.

Twenty healthy volunteers (half male) recalled and relived maximally disturbing (NEG) and maximally pleasurable (POS) emotional experiences. Forty minutes of silence, then neutral conversation, preceded and followed 40 minutes of emotion elicitation (NEG and POS randomly rotated). They were under video, cardiovascular, and immunological monitoring. Subjects reported appropriate emotions and showed significant cardiovascular activation during the NEG condition. Speech alone had an independent cardiovascular activating effect. Emotion, particularly NEG, led to further activation. NEG emotion promoted significant declines in mitogenic lymphocyte reactivity, followed by return to pre-emotion levels. A similar though less extreme decline was seen in the POS condition. There was a weak trend for elevated natural killer cell activity under the NEG condition, possibly due in part to changed trafficking patterns. Correlational findings confirmed these group effects. The decline in mitogenic reactivity during POS emotion appeared to be due to subtle degrees of tension and excitement triggered by the experimental experience regardless of the exact emotions recalled. Results suggest that immunologic processes are sensitive to influence by arousal of emotion.

Adaptation, Psychological↗

Clinical and epidemiological implications of the Centers for Disease Control/World Health Organization reclassification of AIDS cases.

OBJECTIVE: To establish whether various accepted and proposed AIDS definitions have clinical and biological validity: because the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) reclassifications of AIDS are important not only for describing the epidemiology of HIV disease but also to individual patients. SETTING: Regional Infectious Diseases Unit, City Hospital, Edinburgh, Scotland, UK. PATIENTS: We analysed the disease progression of 532 HIV-seropositive individuals seen at the City Hospital, Edinburgh, up to the end of July 1991. MAIN OUTCOME MEASURES: Annual numbers of potentially reportable cases from the Edinburgh City Hospital Cohort according to three proposed AIDS case definitions based on: (1) first lymphocyte count < or = 1000 x 10(6)/l; (2) first CD4 cell count < or = 200 x 10(6)/l; or (3) first of two consecutive CD4 cell counts < or = 200 x 10(6)/l. Lifetables to death (irrespective of cause) from month of satisfying the above case definitions, and proportion of patients who satisfied each definition in their calendar year of enrollment in the cohort are reported. RESULTS: There is a threefold increase in patients in the Edinburgh City Hospital Cohort defined as having AIDS under the 1987 and the proposed 1992 CDC definitions--a substantial change for patients and epidemiologists alike. That they are describing different immunodeficiency states is clear from lifetable analysis, which reveals median survivals of 20 and 50 months under the 1987 and the proposed 1992 AIDS definitions, respectively. For epidemiological purposes, redefinitions based on the WHO proposed classification of HIV disease using either a lymphocyte count < or = 1000 x 10(6)/l or a CD4 cell count < or = 200 x 10(6)/l are broadly interchangeable. They are not equally effective for monitoring individual progression (CD4 cell count is superior). Both, for different reasons, lack biological plausibility. CONCLUSIONS: We therefore suggest that the stricter, biologically more plausible, case definition used in Scotland of two consecutive CD4 cell counts of < or = 200 x 10(6)/l [CD4(200) (x 2)] should be adopted--not as a new definition of AIDS, but as an additional important state of severe HIV-related immunodeficiency (SHRID). Median survival under the CD4(200) (x 2) case definition was 40 months in the Edinburgh cohort. We have illustrated differences in CD4(200) case ascertainment between injecting drug users and other HIV-infected patients in the Edinburgh City Hospital Cohort. We recommend that surveillance centres should ascertain date of first immunological monitoring as well as date of SHRID diagnosis in order to identify differential case ascertainment.

Acquired Immunodeficiency Syndrome↗

The effect of anaesthesia and surgery for benign disease of the upper urinary tract on circulating leucocyte subpopulations identified with monoclonal antibodies.

Circulating lymphocyte subpopulations were monitored, using monoclonal antibodies and flow cytometry, in six patients undergoing surgery for benign disease of the upper urinary tract. A significant decrease in the total number of circulating lymphocytes was observed. This could be attributed to a significant decrease of T cells of both major subsets--the so-called T "helper" (Th) and T "suppressor/cytotoxic" (Ts) subpopulations. When the results of the T cell subsets were expressed as a ration (leu-3a+/leu-2a+, T "helper/suppressor") no significant change was noted. In contrast neither B cells nor natural killer (NK) and antibody dependent killer (K) cells were significantly affected. This selective loss of T cells from the circulation may be relevant to post operative infection and should be considered in the course of immunological monitoring.

Adolescent↗

Combined-modality treatment of inoperable lung cancer (i.v. immunotherapy, chemotherapy, and radiotherapy).

Patients with inoperable non-small cell carcinoma of the bronchus were treated by iv methanol extraction residue of bacillus Calmette-Guérin (MER) followed by combination chemotherapy with methotrexate, doxorubicin, cyclophosphamide, and lomustine (MACC). Radiotherapy was added in patients with localized disease. MER was given iv in four weekly courses. The dose ranged between 0.1 and 0.8 mg/m2/course and was determined according to the skin reactivity to MER. None of the 19 patients treated with iv MER had an objective tumor response during immunotherapy. Five of 16 evaluable patients receiving MACC (31%) achieved partial response. The overall median survival for all 17 patients treated was 11 months according to the protocol. During immunotherapy the following side effects were observed: all patients had fever and chills and most had malaise, nausea and/or vomiting, and headache. Transient abnormalities of liver function tests were found in six patients, and in one patient roentgenographic changes suggestive of lung granulomas were seen. The side effects were more severe during the first course than in the further treatments. Side effects of the MACC combination were comparable to those observed in previously reported studies. Immunological monitoring performed during immunotherapy revealed that iv MER had an unfavorable effect on the immune system. Following four courses there was a decrease in the in vivo skin reactivity to MER and to five recall antigens. Twenty-four hours after the initiation of iv MER there was a tendency for decrease in the lymphoproliferation to phytohemagglutinin, an increase in the indices of the adherent cell suppressor system and the prostaglandin-related suppressor system, and an increase in the percentage of adherent mononuclear cells. No consistent changes in serum lysozyme were found. A transient increase in the total number of peripheral blood leukocytes and a decrease in the number of lymphocytes were noticed 24 hours after iv MER. Taking into account the results of the immunological studies and the overall therapeutic results, we do not feel justified in continuing to use this combined modality treatment.

Adenocarcinoma↗

Donor specific suppressor cells in association with rejection of a renal allograft.

Details are presented of three aspects of immunological monitoring in a single instance of severe irreversible rejection of a renal allograft. Rejection is associated with strong evidence of lymphocyte mediated cytotoxicity (LMC). During this period reduced responsiveness of recipient cells to stimulation in vitro by donor cells is observed; this is more reduced than is responsiveness to random cells. Donor-specific suppressor cells also develop, as detected in two systems. It is postulated that the data are evidence that competition exists between different agressive and suppressive subpopulation of recipient lymphocytes.

Analgesics↗

Clinical and experimental immunobiology of medulloblastomas.

A wide pre- and postoperative immunological monitoring of B- and T-cell markers in children with medulloblastomas is presented. Preoperative investigations showed a noticeable failure of T-cell-dependent immunity, currently identified by "active" E-rosette forming cells (Ea-RFC) and blastogenesis tests, with a significant increase of spontaneous cell-mediated cytotoxicity (SCMC). In postoperative long-term controls, a slight recovery of Ea-RFC and blastogenesis tests was observed. The main findings concerning cytotoxicity kinetics are discussed.

Adolescent↗

Immunobiology of primary neoplasms of the C.N.S. Preliminary results.

A preliminary report on the immunological monitoring of primary intracranial neoplasms is presented. The most important findings concerning B-cells and T-cells mediated immunity and delayed hypersensitivity reactions in this kind of patients, are discussed. Among the fairly significant immunobiological pictures, the Authors stress the "normal behaviour" of the B-cells dependent pool, the undebatable depression of the delayed hypersensitivity reactions, and the noticeable failure of the T-cell dependent pool, particularly marked in malignant gliomas, which are also characterized by the presence of cells with natural cytotoxic activity.

Brain Neoplasms↗

A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer.

PURPOSE: The objectives of this study were to assess the toxicity and immunological response induced by the intradermal (i.d) administration of tumor lysate-pulsed dendritic cells (DCs). EXPERIMENTAL DESIGN: Patients with stage IV solid malignancies were treated in cohorts that received 10(6), 10(7), and 10(8) DCs i.d. every 2 weeks for three vaccines. Each vaccine was composed of a mixture of half DCs pulsed with autologous tumor lysate and the other half with keyhole limpet hemocyanin (KLH). Peripheral blood mononuclear cells (PBMCs) harvested 1 month after the last immunization was compared with pretreatment PBMCs for immunological response. Delayed-type hypersensitivity reactivity to tumor antigen and KLH was also assessed. RESULTS: Fourteen patients received all three vaccines and were evaluable for toxicity and/or immunological monitoring. There were no grade 3 or 4 toxicities associated with the vaccines or major evidence of autoimmunity. Local accumulation of CD4(+) and CD8(+) T cells were found at the vaccination sites. There was a significant proliferative response of PBMCs to KLH induced by the vaccine. In 5 of 6 patients, the vaccine resulted in increased IFN-gamma production by PBMCs to KLH in an ELISPOT assay. Using the same assay, 3 of 7 patients' PBMCs displayed increased IFN-gamma production in response to autologous tumor lysate. One patient with melanoma also was observed to have an increased frequency of MART-1- and gp100-reactive CD8(+) T cells after vaccination. By delayed-type hypersensitivity testing, 8 of 9 and 4 of 10 patients demonstrated reactivity to KLH and autologous tumor, respectively. Two patients with melanoma experienced a partial and a minor response, respectively. CONCLUSION: The administration of tumor lysate-pulsed DCs is nontoxic and capable of inducing immunological response to tumor antigen. Additional studies are necessary to improve tumor rejection responses.

Adult↗

Immunobiology of primary CNS tumors in infancy and childhood. B- and T-cell dependent immunity and cytotoxicity and cell kinetic evaluation.

The authors report their experience on the immunological monitoring of children with posterior fossa medulloblastomas. The most important findings concerning humoral and cell-mediated immunity in this kind of patient are discussed. Among the main immunobiological pictures, the authors stress the remarkable failure of the T-cell dependent immune response, generally correlated to the degree of malignancy of the tumor, and the characteristic appearance of cells with natural cytotoxic activity, whose precise outlining is, at present, in progress. The B-cell dependent pool, mostly investigated through immunofluorescence studies, turned out to be very close to normal.

B-Lymphocytes↗

Older age and plasma viral load in HIV-1 infection.

BACKGROUND: The purpose of the study was to examine the relationship between age and plasma viral load in HIV-1-infected individuals. DESIGN: The experimental method was to recruit older (> 50 years of age) and younger (18-39 years of age) HIV-1-infected individuals. The plasma viral load was measured using the Roche Molecular Systems UltraSensitive Roche HIV-1 Monitor test reflexively with the standard Amplicor HIV Monitor test to quantify viral load in the range of 50-750,000 copies of HIV-1 RNA/ml plasma. SUBJECTS: A total of 135 HIV-1-seropositive individuals (at Centers for Disease Control and Prevention early symptomatic stage B or late symptomatic stage/AIDS C) were enrolled as part of a larger cohort also consisting of HIV-1-seronegative individuals. RESULTS: A generalized linear models statistical analysis was conducted in order to evaluate age category as a predictor of plasma viral load. The result was a significant effect of age category, with older age associated with a lower plasma viral load. The association held controlling for antiretroviral therapy usage, disease stage, antiretroviral medication adherence, HIV-1 serostatus duration, alcohol and substance use, recent sexually transmitted disease, and sociodemographics (except income). CONCLUSION: Older age was associated with lower levels of HIV-1 replication in this sample, independent of antiretroviral therapy usage, regimen adherence, and disease stage. It is suggested that the effect may be caused by changes in viral evolution or immunological monitoring specific to older individuals with HIV-1 infection.

Adult↗

Natural effector cells in patients with acute myeloid leukemia treated with the immunomodulator Linomide after autologous bone marrow transplantation.

Roquinimex, Linomide, is a quinoline derivative with pleiotropic immunomodulatory activities which has been shown to enhance NK function. As part of a phase III placebo-controlled multicenter study patients were randomized to receive Roquinimex, 0.2 mg/kg body weight, or a placebo twice weekly for a duration of 2 yr following autologous bone marrow transplantation for acute myeloid leukemia in remission. At Arhus University Hospital 7 patients were randomized to receive the active drug and 6 to receive the placebo. Surviving patients were followed for 2 yr with immunological monitoring of their natural immune effector cells (NK- and LAK cell activity). Peripheral heparinized blood samples were obtained twice before the onset of conditioning therapy and at several time points after ABMT, and whole blood samples were analyzed by flow cytometry for the detection of leukocyte differentiation antigens as well as by 4 h 51Cr release assays for cytotoxicity. In contrast to previous experience with Linomide, in the present study we found that at 36 wk or later time points Linomide patients exhibited a significant suppression of circulating natural effector cell number and activity when compared with the control group. These observations underline the need for further exploration into novel and manageable immunostimulators.

Acute Disease↗

Diagnosis and treatment of acute cardiac allograft rejection.

Integration of data derived from immunologic monitoring techniques and endomyocardial biopsy currently permits more precise administration of immunosuppressive medications for the treatment of acute cardiac allograft rejection than was formerly possible, resulting in a substantially improved outlook for long-term survival. Indeed, the probability of survival for 5 years postoperatively of 50% exceeds that for several categories of cardiac patients currently undergoing other more common forms of heart surgery. The continuing demonstration of the potential for cardiac transplantation clearly warrants further application of this procedure for the treatment of appropriate patients with end-stage cardiac disease.

Adrenal Cortex Hormones↗

Recombinant interleukin-2 treatment before and after autologous stem cell transplantation in hematologic malignancies: clinical and immunologic effects.

Autologous bone marrow transplantation (ABMT) for hematologic malignancies is associated with a high relapse rate. Interleukin-2 (IL-2) administration is a therapy that may prevent relapse if used when the tumor burden is minimal. In this study we administered recombinant IL-2 (rIL-2) therapy to 12 patients affected by hematologic malignancies either before or after autologous stem cell transplantation (ASCT). rIL-2 was given by a 6 day continuous intravenous infusion with escalating doses, up to 18 x 10(6)/m2/day, depending on patient tolerance. The functional immune responses of the patients were assessed as natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities and in vitro interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis. During rIL-2 treatment, the expected side effects occurred; only 3 patients, who showed severe cardiovascular toxicity, required suspension of the treatment. All toxicities reversed after the end of the therapy. Immunologic monitoring was carried out the day before starting rIL-2 infusion and then repeated on days 3, 7, and 14 after rIL-2 was discontinued. Following every rIL-2 course, a pronounced increase in CD3+, CD8+, CD56+ cells was found, with a peak value on day 3. The NK and LAK activities showed a significant increase on day 3 (p < 0.001) over pretherapy values; the increase lasted until day 14, although the difference at later time points was not significant. Before transplant the synthesis of both IFN-gamma and TNF-alpha decreased following rIL-2 therapy, whereas higher levels of these lymphokines were found after posttransplant rIL-2 courses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Immunologic heterogeneity among potential transplant recipients. Prospects for predicting immune responses to allografts with in vitro tests.

The ability to accurately predict the response of a specific patient to a specific organ allograft has long been a goal of organ transplantation. The role of histocompatibility antigens in determining the acceptance or rejection of an allograft-recipient combination has been thoroughly investigated, but is being reevaluated as improved immunosuppressive agents become available. Early efforts at immunologic monitoring are reviewed in addition to more recent efforts that focus on the cellular and molecular mediators of immunity. The authors' own experience with lymphokine measurements in clinical transplantation is also reviewed, with emphasis on the role of interleukin-2 (IL-2) and its soluble receptor (IL-2R) in various transplant-associated conditions. The authors conclude that information useful in the management of transplant patients may be derived from serial measurements of IL-2 and IL-2R, but that infections, especially CMV, may not be ruled out with certainty by these measurements alone. The available data suggest that study of additional lymphokines such as interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) may be useful in discriminating rejection from infections in transplant patients.

Antigens, Surface↗