Normal antibody-dependent killer cell function in patients with chronic lymphocytic leukemia.

Unfractionated mononuclear peripheral blood leukocytes (PBL) and nylon wool-nonadherent (B-cell-depleted and T- and null-cell enriched) cells from normal control individuals and untreated patients with chronic lymphocytic leukemia (CLL) were tested for killer cell function in an antibody-dependent cell-mediated cytotoxicity assay. Killer cell activity was present in unfractionated cells from normal individuals and was enriched after removal of adherent cells. Target cell killing by unfractionated mononuclear cells from CLL patients was deficient in 5 of 6 patients tested, but after removal of adherent cells it was approximately equal to that of normal nonadherent cells. Our results indicate that the apparent deficit of killer cells in unfractionated PBL from some CLL patients is due to dilution of killer cells and not to an intrinsic defect in the function of these cells, the presence of suppressor cells in the adherent population, or suppression of killer cell function by serum factors.

Immunologic studies in chronic lymphocytic leukemia: defective stimulation of T-cell proliferation in autologous mixed lymphocyte culture.

Peripheral blood leukocytes from untreated patients with chronic lymphocytic leukemia (CLL) and normal age- and sex-matched control individuals were tested for the ability to respond with increased DNA synthesis after mixed lymphocyte culture (MLC) with allogeneic and autologous lymphocyte fractions. We performed these tests using, as responder cells, unfractionated mononuclear cells and T-cell-enriched populations obtained after nylon-wool column filtration. The results showed that nonadherent T-cell-enriched populations from both CLL patients and normal controls responded to allogeneic stimulation and that adherent cell fractions from normal individuals, and often from CLL patients, provided a stronger stimulus in MLC than did nonadherent cells. T-cell-enriched populations from normal individuals showed increased DNA synthesis after autologous mixed lymphocyte culture (AMLC) with adherent cells, but this phenomenon was uniformly lacking when the same experiment was performed with cell populations from CLL patients. This lack of response after AMLC was not due to serum factors or to short-range factors produced by inactivated CLL cells in culture. Possibly AMLC represents a recognition phenomenon between autologous T- and B-cells, and thus it may reflect the interaction of T-helper or suppressor cells and B-lymphocytes. The lack of autorecognition in CLL may reflect the monocional nature of the B-cells in this disease or a defect in helper or suppressor T-cells.

Some properties of a DNA-unwinding protein unique to lymphocytes from chronic lymphocytic leukemia.

Lymphocytes from a common human leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia, have a greatly enhanced capability of DNA repair and a concomitantly prolonged survival in vitro after damage to DNA. From these lymphocytes, we isolated and purified a DNA-binding protein with a molecular weight of 24,000. It binds tightly to both ultraviolet light (UV)-irradiated and single-stranded DNA. At 35 degrees it enhances the helix-coil transition of poly[d(A-T)] AND the UV-irradiated calf thymus DNA but is inefficient in ordinary native DNA. This protein also facilitates the rate of UV-endonuclease incision of UV DNA but does not induce any nicks by itself. This finding suggests that the protein may be involved in DNA repair by enhancing such activity, and also offers an explanation for our observation of increased DNA repair in chronic lymphocytic leukemia cells. When human metaphase chromosomes are exposed to the protein, it induces marked lengthening of chromatids suggesting that this protein may also act on complex chromosomes. By quantitative immunochemical determinations, such protein could not be found in lymphocyte extracts of three normal individuals.

Chemotherapy for inoperable, non-small cell bronchogenic carcinoma: EST 2575, generation II.

Between 1976 and 1978 the Eastern Cooperative Oncology Group tested ten regimens in 415 patients with histologically documented, inoperable non-small cell bronchogenic carcinoma. Most patients were ambulatory (69%) and had extensive disease (69%). Patients were stratified by cell type: squamous cell carcinoma (SQ), large cell anaplastic carcinoma (LC), or adenocarcinoma (AD). Ineffective single agents (including cell types tested and percent complete and partial responses) were dactinomycin (SQ, 6%), dianhydrogalactitol (SQ, 0), ftorafur (AD and LC, 3%), and piperazinedione (AD and LC, 7%), Ineffective combination regimens included the contemporary standard regimen cyclophosphamide (CYT) plus CCNU (SQ, AD, and LC, 9%), methotrexate plus doxorubicin (ADR) plus CYT plus CCNU (MAC) (SQ and AD, 12%), and mitolactol plus ADR (AD and LC, 8%). When compared to CYT plus CCNU the following regimens demonstrated significant activity: CYT plus bleomycin plus cisplatin (SQ, 23%; P = 0.02) and ADR plus 5-FU plus cisplatin (AD and LC, 24%; P = 0.006). Mitomycin demonstrated marginal activity in squamous cell cancer (19%, P = 0.06). Neither "active" regimen improved survival although responders to any regimen had a significant prolongation of median survival (31.6 vs 15.7 weeks, P = 0.002). The MACC regimen, piperazinedione, and mitomycin were substantially more toxic than the two effective regimens, which were adequately tolerated. Ambulatory performance status, limited disease, and prior surgery were significant positive prognostic variables whereas prior radiation and pretreatment weight loss adversely affected response or survival.

The phase II evaluation of Bacillus Calmette-Guerin plus megestrol acetate in patients with metastatic renal adenocarcinoma.

The case is reported of a patient with pulmonary metastases from a renal adenocarcinoma who experienced subjective improvement and objective tumor regression on Bacillus Calmette-Guerin (BCG) and megestrol acetate therapy. In a subsequent Phase II trial, no objective responses were noted among 15 patients treated with megestrol acetate (160 mg/day X 56 days) and BCG (five immunizing doses intradermally, every 2 weeks X 5). It is concluded that this treatment regimen is not clinically useful in patients with metastatic renal adenocarcinoma.