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Background. The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. Methods. Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. Results. The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 [+ or -] 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 [+ or -] 3.7 weeks), with 1/18 alive at 1 year (>6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. Conclusions. Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted. Cancer 1995; 76:840-52. Key words: interleukin-2, lymphokine-activated killer cells, glioma, glioblastoma, astrocytoma, brain, immunotherapy, eosinophil, survival, biologic response modifiers.

Platelet autoantigen-autoantibody-monocyte interaction was studied by utilization of a specific monoclonal antibody (MoAb) 10E5 to trap and immobilize the GPIIb-GPIIIa complex on microtiter plates. Peripheral blood mononuclear cells (PBMC) or purified monocytes formed distinct morphologic clusters after incubation with immobilized antigen for 18 hours at 37°C. PBMC of 18 of 19 patients with autoimmune thrombocytopenic purpura (ATP) formed 48 ± 6.8 (SEM) clusters/well compared with 7.4 ± 1.0 for control subjects, P< .001. The number of clusters per well correlated inversely and exponentially with platelet count, r= .8. n = 21, indicating that the GPIIb-GPIIIa autoantigen is pathophysiologically relevant. Binding of ATP PBMC to immobilized GPIIb-GPIIIa could be inhibited by F(ab')2fragments of immunoglobulin (Ig) G of ATP patients, indicating that monocyte IgG bound to autoantigen by its F(ab')2domain. Optimal cluster formation could be obtained with normal monocytes if preincubated with ATP IgG but not with F(ab')2fragments of ATP IgG, indicating that ATP IgG binds to monocytes by its Fc domain. Armed monocytes (ie, normal monocytes preincubated with ATP IgG) bound to immobilized autoantigen 5.8-fold greater than normal monocytes incubated with immobilized autoantigen opsonized with ATP IgG. Armed monocyte adhesion could be inhibited 81 % from 18.9 ± 1.6 to 3.6 ± 0.5 clusters/well by prior fixation with 0.1% formalin, whereas fixation of IgG before arming of monocytes was not inhibitory. MoAb MM41, directed against the αm-chain of the Mac-1 adhesive protein receptor of monocytes, inhibited cluster formation by 79%. Thus, (1) armed monocyte interaction with autoantigen is considerably more effective than monocyte interaction with opsonized autoantigen; (2) armed monocyte interaction requires specific F(ab')2-antigen recognition; and (3) monocyte-autoantigen interaction requires a secondary nonimmunologic adhesive event.

It has been proposed that bacteria play a direct role in progression of cutaneous T cell lymphoma (CTCL), although definitive evidence is missing, and the underlying mechanism of how microbes contribute to disease progression remains unknown. The skin of CTCL patients is frequently colonized with Staphylococcus aureus (S. aureus)strains and infections with hospital and community associated strains of S. aureusare a frequent cause of morbidity and mortality among patients with advanced CTCL. Here we provide a comprehensive analysis of the association between CTCL and S. aureuscolonization, and use our unique pre-clinical animal model of CTCL to determine the cause-effect relationship between skin-associated S. aureusand CTCL progression.

Zanolimumab (previously referred to as HuMax-CD4) is a fully human monoclonal IgG1k antibody, targeting the CD4 molecule on T-cells. It exhibits cytotoxic and anti-proliferative effects and has previously shown efficacy in cutaneous T-cell lymphoma. We report the early safety and peripheral CD4+cell depletion results from the open-label, dose escalation part of a US phase III efficacy study. So far, 21 patients have been recruited and the results from the 4 mg/kg dose group (9 patients) and 8 mg/kg dose group (6 patients) are available. Zanolimumab was administered iv, once weekly for 12 weeks. In total, 2 Serious Adverse Events have been reported. Of these, 1 case of large cell transformation in a patient with large cells present prior to inclusion was judged possibly related to treatment by investigator. No increase in toxicity was seen upon dose escalation. Marked depletion of CD4+T-cells was observed after just 1 infusion of zanolimumab at both dose levels. One week following the last dose, the median (range) peripheral blood CD4+ T-cell count compared to baseline values was decreased from 831 per μL (167–1928) to 24 per μL (4–141) in 4 mg/kg dose-group and from 638 per μL (182–1024) to 9 per μL (4–19) in the 8 mg/kg dose-group. These initial data indicate that zanolimumab has an acceptable tolerability profile at the doses tested and results in a rapid and pronounced decrease in peripheral CD4+counts in MF CTCL patients.