The induction of graft versus host disease in mice treated with cyclophosphamide.

In these studies adult mice treated with cyclophosphamide and foreign immunologically competent cells developed a graft versus host disease which outwardly resembled that encountered in other experimental systems. Progressively larger doses of cyclophosphamide produced an increasingly severe disease whereas comparable doses of mechlorethamine were ineffective. Increasingly larger cell inocula from parental, allogeneic, and xenogeneic donors resulted in a correspondingly more severe disease. Nucleated cells obtained from the peripheral blood were found to be the most potent inducers of this syndrome, while cells from the spleen, bone marrow, and thymus displayed lesser degrees of reactivity in that order. No such graft versus host disease occurred in mice given saline, lysed, or heat-killed cells in place of viable foreign cells. Neither did the disorder develop when comparable inocula of isogeneic cells were used.

Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.

The clinical significance and management of fever in acute myelocytic leukemia.

In order to optimize the clinical management of fever in acute myelocytic leukemia (AML), our experience with febrile patients during two therapy periods was reviewed. A structured approach to the management of fever was then devised and evaluated during a third period. Among a total of 104 patients with AML, 77 were febrile at presentation. Only agranulocytic patients (15%) had severe infection, while 43% had localized sites which responded to specific antibiotic therapy. The remainder (42%) had fever functionally attributed to leukemia. In contrast, life-threatening infection occurred in most patients (90%) after antileukemic treatment was begun. During the trial therapy period, the empiric use of carbenicillin-gentamicin for fever greater than or equal to 101 degree F during aplasia reduced the incidence of sepsis from 90 to 30% and of bacteremia from 50 to 23%. The fall in the incidence of blood and localized site cultures positive for Pseudomonas aeruginosa from 65 to 15% corresponded to a reduction in the number of distinct organisms per site from 1.6 to 1.0. These data suggest that hematogenously born invasion of infected sites by endogenous organisms has been prevented. Aplastic patients with fever responded to therapy by defervescing (54%) or improving clinically (34%). Stopping antibiotics once started while evaluating persistent fever was detrimental. Although the early empiric use of amphotericin B reduced the incidence of fungemia, its proper use in fever management is yet to be determined.

Combination chemotherapy of the malignant lymphomas: a controlled clinical trial.

The Eastern Cooperative Oncology Group has studied 113 patients with generalized progressive malignant lymphomas in a randomized clinical trial. Pathologic diagnosis was subclassified by cell type and nodal pattern by The Pathology Panel for Lymphome Clinical Trials. Patients were randomly assigned treatment with either cyclophosphamide (C), vincristine (O), and prednisone (P) (COP) or CO without prednisone. Initial treatment was given for 8 weeks and further randomization of responders to observation or additional chemotherapy was carried out. A significant difference in complete remission rate between treatments was shown: with COP, 43%, and with CO, 17%, indicating an important role for prednisone in inducing CR. COP was also associated with longer remission durations and improved survival. Complete remission following initial chemotherapy is also associated with longer duration of disease-free time and survival. The initial pathologic cell types and nodal pattern also strongly influence survival. Extended "maintainence" CO treatment improved disease-free remission duration, but not survival.

Inhibition by streptovaricins of Rauscher leukemia virus splenomegaly.

Streptovaricins (Sv), ansa macrolide antibiotics, inhibited Rauscher leukemia virus (RLV) splenomegaly by 25-50%. All streptovaricins tested were effective when administered orally either by diet ad lib or by intubation from infection to time of killing. When delivered by intubation, Sv was measurable in plasma for up to 6 h. SvC, at 300 mg/kg/day, reduced mean spleen weight of infected mice from 478 plus or minus 51 (SE) mg to 300 plus or minus 55 (SE) mg. Rifampicin, at 250 mg/kg/day, had no similar activity. Decrease in caloric intake and in body-weight gain also resulted in an inhibition of RLV splenomegaly; although Sv-treated mice gained weight, the increase was usually slightly less than controls. However, mice treated with a Sv diet for a week prior to infection, after an initial period of weight loss, gained at a rate equivalent to control group, and when killed had a marked reduction in splenomegaly. The selectivity of streptovaricins and specificity for viral events was suggested by several observations: (1) Splenomegaly and mortality, induced by L1210 or a non-infective transplantable tumor of RLV origin, was not inhibited. (2) No inhibition of normal hematopoietic spleen colonies was observed. (3) Host immune responses, including cellular and humoral immunity and interferon production and action, were not inhibited. Thus, although the effect of slightly decreased weight and intake could not be unequivocally established, the findings were most compatible with a selective inhibition of RLV splenomegaly by Sv.