Good prognosis cytogenetics in B-cell chronic lymphocytic leukemia is associated in vitro with low susceptibility to apoptosis and enhanced immunogenicity.

Chromosomal abnormalities in B-cell chronic lymphocytic leukemia (B-CLL) have been shown to correlate with prognosis. Little is known about the relationship between chromosomal abnormalities and biological behavior of B-CLL cells in vitro. The present study was designed to explore the impact of chromosomal abnormalities determined by interphase fluorescence in situ hybridization (FISH) on the in vitro survival and immunogenicity of B-CLL. Considerable heterogeneity was noted in the in vitro survival and expression of costimulatory, adhesion, and antigen-presenting molecules by B-CLL cells. Spontaneous apoptosis of B-CLL cells in vitro was significantly lower in samples with good prognosis cytogenetics when compared to samples with poor prognosis cytogenetics. In contrast, B-CLL cells from samples with good prognosis cytogenetics exhibited higher basal expression of molecules involved in costimulation, cellular adhesion, and antigen presentation, and induced significantly more T-cell proliferation in mixed lymphocyte cultures. We conclude that chromosomal aberrations of B-CLL cells correlate with the in vitro biological behavior of B-CLL. Our data indicate that good prognosis cytogenetics correlates with less spontaneous apoptosis but greater in vitro immunogenicity. These findings could have significant implications on the design of future therapeutic approaches in patients with CLL, and the likelihood of response based on cytogenetics.

Corticosteroids in advanced cancer.

Despite the fact that there are only a few controlled trials demonstrating the benefits associated with the use of corticosteroids in specific situations, these agents are administered frequently to patients with advanced cancer. Corticosteroids may be used alone or as adjuvants in combination with other palliative or antineoplastic treatments. For example, corticosteroids may help prevent nausea, vomiting, and hypersensitivity reactions to treatment with chemotherapy or radiation. They are also commonly used as appetite stimulants in patients with advanced cancer. In the adjuvant setting, corticosteroids help to alleviate pain in advanced cancer patients, including specific situations such as back pain related to epidural compression. This article reviews the evidence supporting the use of corticosteroids in a broad range of situations seen in patients with advanced cancer.

Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization.

Recent advances in our understanding of the immune response are allowing for the logical design of new approaches to cancer immunization. One area of interest is the development of new immune adjuvants. Immunostimulatory oligodeoxynucleotides containing the CpG motif (CpG ODN) can induce production of a wide variety of cytokines and activate B cells, monocytes, dendritic cells, and NK cells. Using the 38C13 B cell lymphoma model, we assessed whether CpG ODN can function as immune adjuvants in tumor antigen immunization. The idiotype served as the tumor antigen. Select CpG ODN were as effective as complete Freund's adjuvant at inducing an antigen-specific antibody response but were associated with less toxicity. These CpG ODN induced a higher titer of antigen-specific IgG2a than did complete Freund's adjuvant, suggesting an enhanced TH1 response. Mice immunized with CpG ODN as an adjuvant were protected from tumor challenge to a degree similar to that seen in mice immunized with complete Freund's adjuvant. We conclude that CpG ODN are effective as immune adjuvants and are attractive as part of a tumor immunization strategy.

Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma.

Bacterial DNA and synthetic oligodeoxynucleotides containing the CpG motif (CpG ODN) can activate various immune cell subsets, including natural killer cells and macrophages. We evaluated whether the combination of CpG ODN and antitumor monoclonal antibody is effective at preventing tumor growth in an immunocompetent murine lymphoma model. CpG ODN-activated murine splenocytes induced lysis of tumor targets more effectively than unactivated splenocytes. These effector cells were also superior to unactivated splenocytes or cells activated with a control methylated ODN at inducing antibody-mediated lysis of 38C13 murine lymphoma cells. In vivo, CpG ODN alone had no effect on survival of mice inoculated with 38C13 cells. However, a single injection of CpG ODN enhanced the antitumor response to antitumor monoclonal antibody therapy. Ninety percent of mice treated with monoclonal antibody alone developed tumor compared with 20% of mice treated with antibody and CpG ODN. These antitumor effects were less pronounced when treatment consisted of an identical ODN containing methylated CpG dinucleotides. A single dose of CpG ODN appeared to be as effective as multiple doses of interleukin-2 at inhibiting tumor growth when combined with antitumor monoclonal antibody. We conclude that immunostimulatory CpG ODN can enhance antibody dependent cellular cytotoxicity and warrant further evaluation as potential immunotherapeutic reagents in cancer.

T-cell activation induced by anti-CD3 x anti-B-cell lymphoma monoclonal antibody is enhanced by pretreatment of lymphoma cells with soluble CD40 ligand.

T cells play a key role in the control of abnormal B cell proliferation. Factors that play a role in inadequate T cell responses include absence of expression of costimulatory and adhesion molecules by the malignant B cells and lack of cytotoxic T cells specific for tumor-associated antigens. A number of approaches have been used to enhance T cell response against malignant B cells. Agents such as soluble CD40 ligand can enhance expression of costimulatory molecules by the malignant B cells and improve their ability to activate T cells. Anti-CD3-based bispecific antibodies can retarget T cells toward the tumor cells irrespective of T cell specificity. We used the V 38C13 murine lymphoma model to assess whether the combination of soluble CD40 ligand and anti-CD3-based bispecific antibody can enhance T cell activation induced by malignant B cells more effectively than either approach alone. Expression of CD80, CD86, and ICAM-1 on lymphoma cells was up-regulated by soluble CD40 ligand. Syngeneic T cells were activated more extensively by lymphoma cells when the lymphoma cells were pre-treated with soluble CD40 ligand. Bispecific-antibody induced T cell activation was more extensive when lymphoma cells pretreated with soluble CD40 ligand were present. The combination of soluble CD40 ligand plus bispecific antibody enhanced the median survival of mice compared to mice treated with bispecific antibody alone. We conclude that pretreatment of tumor cells with agents capable of inducing costimulatory molecule expression, such as soluble CD40 ligand can enhance the ability of malignant B cells to activate T cells. This effect is enhanced by the addition of bispecific antibody. The combination of enhanced expression of costimulatory molecules and retargeting of T cells by bispecific antibody may allow for a more effective T-cell-based immunotherapy.