Natural cytotoxic (NC) and natural killer (NK) cells have been defined by their ability to lyse certain solid or lymphoid tumor targets in vitro, without prior sensitization. Our present studies describe an attempt to characterize the structures involved in the effector-target recognition leading to tumor cell lysis. Addition of the monosaccharide D-mannose to the NC cell assay significantly blocked cytotoxicity of the fibrosarcoma Meth A target by the effector cells at 50 mM and lower concentrations. D-Galactose showed blocking activity in one of five experiments, only at 50 mM. L-Fucose, D-glucose, and N-acetyl-D-glucosamine did not affect NC cell cytotoxicity at similar concentrations. All of the sugars tested inhibited NK cell lysis of the lymphoma YAC-1 target. None of the sugars affected killing of the appropriate target by allosensitized cytotoxic T lymphocytes. The blocking of NC-mediated cytotoxicity was not due to a direct toxic action of the sugars on the effector cells. These findings suggest that, in the NC system, recognition involves lectin-like structures with a specificity for D-mannose (or D-galactose, or both), whereas, in the NK system, such lectin-like structures are less restricted. Such structures appear not to be involved in the specific cytotoxicity mediated by T cells.Although there has been extensive characterization of many features of natural cell-mediated cytotoxicity (CMC) in mice, especially of the "natural killer" (NK) type (1-3), little is known about the recognition structures or target sites involved in the effector-target cell interaction leading to lysis. In addition, when different tumor targets are studied, some heterogeneity of effector cells is found, and subtypes such as the "natural cytotoxic" (NC) cells, which react with adherent target cells derived from nonlymphoid tumors, have been described (4). In both the NK and NC systems, targets may be susceptible or resistant to lysis by such effector cells (1-4). Competitive ("cold-target") inhibition studies with NK cells (1-43) and assays that determine the binding of effector cells to sensitive targets (5) have suggested a certain degree of specificity of recognition. In addition, crude cell extracts, probably glycoprotein in nature, from NK-susceptible targets can inhibit or block the binding of effector NK cells to the appropriate susceptible target (6).In the present study we show that some simple sugars can Sugars. All the sugars tested (see Tables 1 and 2) were obtained from Sigma. Stock solutions were made in medium (see details below), and sterilized by filtration prior to use.NC Assay. The NC proline assay has been described in detail (4). Briefly, 103 [3H]proline-labeled Meth A target cells were allowed to adhere to the wells of a 96-well microplate (Falcon), for 24 hr, in 0.15 ml of RPMI 1640 medium supplemented with 10% heat-inactivated fetal calf serum, 1% L-glutamine, 1% penicillin/streptomycin, and 1% nonessential amino acids. The sugars, diluted in this medium, were added in 50-,gl amounts, fol...
This study was designed to evaluate the efficacy and safety of bortezomib as monotherapy in patients (pts) with indolent B-cell lymphoma who have relapsed following, or who are refractory to, rituximab therapy. A total of 60 patients enrolled and 59 were treated with 1.3 mg/m2 of bortezomib (IV bolus over 3–5 secs) Days 1, 4, 8, and 11 for up to eight 21-day cycles; pts with a CR could receive 4 additional cycles. Pts with <CR entered the maintenance phase with bortezomib administered on Days 1, 4, 8, and 11 of each 42- day cycle until progression; 55 patients completed 2 or more cycles and were therefore considered evaluable. Median age was 70 years, 53% female, 88% White, baseline ECOG 0/1/2 was 55%/43%/2%, Ann Arbor stage at baseline was III-IIIE (28%) and IV (65%); 34 pts (58%) had received 32 prior regimens. At baseline 58% of pts had normal Hgb and 73% had normal LDH. Pts received a median of 4 cycles of bortezomib (range, 1–18); 59% of pts had a dose delay, 25% had a dose reduction, 10% had a delay and reduction. 6 patients (10%) were <CR (including CRu) after 8 cycles went on to receive maintenance therapy. Main reasons for delay were thrombocytopenia or fatigue; doses were reduced mainly due to thrombocytopenia and discontinued mainly due to fatigue. Overall responses were: 1 CR (1.8%), 2 CRu (3.6%), 3 PR (5.5%), 34 SD (61.8%), and 11 PD (20.0%); 4 pts (7.3%) were NE. The clinical benefit rate (CBR: CR+Cru+PR+[SD36 mo]) was 30.9% (17 pts). For pts who relapsed within 6 months (mos) of prior rituximab, CBR was 16.4% (3.6% PR) vs 14.5% (1.8% CR, 3.6%CRu, 1.8% PR) in pts with relapses >6 mos following rituximab. By histology: follicular pts had CR or CRu (2/38, 5.3%) and PR (3/38, 7.9%); marginal zone pts had CRu (1/6, 16.7%) and no PR, and small lymphocytic pts (n=11) had no CRu or PR. We did not see any correlation between the FLIPI score and response in pts with follicular NHL. Median time to response was 2.2 mos (range 1.2–4.0) and duration of response was 7.5 mos (2.7–23.6). 1-yr survival was 71% and 2-yr survival was 46%. Median survival was 21.3 mos (range, 1.3–30.8), median PFS was 5.2 mos (range, 1.0– 27.7), and median TTP was 5.2 mos (range, 0.2–27.7). Median event-free survival was 2.0 mos (range, 0.1–27.7). For the 6 pts receiving maintenance cycles (median of 4; range, 2–10) the median PFS was 11.1 mos (range, 9.0–19.1). The most frequent treatment-related Grade 3–4 AEs included: thrombocytopenia (22%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8%, each). Reasons off treatment include: 24 (40%) disease progression; 19 (32%) AEs, primarily fatigue, neuropathy, nausea, diarrhea, or thrombocytopenia; 8 (13%) investigator request; 4 (7%) patient request; 2 (3%) other, 1 (2%) normal completion. 2 pts (3%) remain on treatment. Causes of death (n=23) were disease progression (n=19) and 1 each MDS, pneumonia, pneumonitis, and unknown (no autopsy performed). In conclusion, this study (the largest to date) reports the activity of single-agent bortezomib in low grade lymphoma. It demonstrates activity primarily in marginal zone (CBR = 50%) and in follicular lymphoma (CBR = 38%). We saw no activity in small lymphocytic disease; however, the sample size was small in this subset (n=11). As previously reported, the main toxicities were thrombocytopenia, fatigue, and neuropathy. Thus bortezomib should be considered a new, active agent for low-grade lymphoma. Maintenance resulted in increased PFS and should be explored further. Results of an ongoing phase 3 study in 670 pts comparing bortezomib combined with rituximab vs rituximab alone will be of interest in planning future studies for this disease. This research was supported, in part, from a research grant from Millennium Pharmaceuticals, Inc.
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