https://www.amjmed.com/article/0002-9343(76)90431-9/pdf

The bimodal mortality pattern of systemic lupus erythematosus

Publisher Summary This chapter reviews the evidence for cell-mediated immune reactions against tumors in animals and man, particularly, the reactions that can lead to destruction of neoplastic cells cultivated in vitro. Various mechanisms by which tumor cells can escape from immunological destruction have been discussed, most notably one involving blocking factors, present in the serum. Findings analogous to those obtained when studying tumor immunity (coexistence of cell-mediated reactivity and blocking serum activity) have been summarized from three other areas (pregnancy, allografting, and chimeras). The studies reviewed in the chapter have given a relatively large amount of evidence for various cell-mediated and humoral immunological reactions against growing tumors, and at least some of the reactions observed in vitro appear to be able to influence tumor growth in vivo .

Lymphocyte-Mediated Cytotoxicity And Blocking Serum Activity To Tumor Antigens

Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. Established good prognostic factors are limited, but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98% of the tumor. Standard treatment includes resection, followed by concurrent chemotherapy and radiotherapy. GBM research is being conducted worldwide at a remarkable pace, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways, tumor stem cell identifica...

Glioblastoma multiforme: a review of where we have been and where we are going

Central nervous system involvement in systemic lupus erythematosus: A review of neuropathologic findings in 57 cases, 1955–1977

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

http://www.isarna-therapeutics.com/fileadmin/user_upload/documents/publications/Bogdahn_et_all_HGG_Neuro-Oncology_2010.pdf

Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study

Tumor immunity in patients with primary intracranial tumors was assessed in relation to the general status of host immunocompetence. Lymphocyte sensitization to tumor-specific membrane antigens was demonstrated by the proliferative response of lymphocytes in the presence of autochthonous tumor cells. Paradoxically, one-half of the patients could not be sensitized to a primary antigen, dinitrochlorobenzene; existing delayed hypersensitivity was also depressed, as measured by skin tests and lymphocyte transformation in response to common antigens. A heat-stable factor in patients' sera blocked cell-mediated tumor immunity. In addition, these "enhancing" sera consistently suppressed the blastogenic response of autologous and homologous lymphocytes to phytohemagglutinin and to membrane antigens on allogeneic cells in the one-way mixed lymphocyte culture. When patients' leukocytes were washed and autologous plasma replaced with normal plasma, reactivity in the mixed lymphocyte culture increased to normal values. In vitro immunosuppressive activity in patients' plasma or sera correlated with depressed delayed hypersensitivity. After removal of the tumor, suppressor activity disappeared. IgG fractions of patient sera contained strong immunosuppressive activity. These data suggest that the suppressor factor may be an isoantibody elicited by the tumor that also binds to receptors on the lymphocyte membrane. In addition to specifically blocking cell-mediated tumor immunity, enhancing sera may broadly depress host immunocompetence.

https://rupress.org/jem/article-pdf/136/6/1631/1085082/1631.pdf

Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor.

When identical twin sisters discordant for systemic lupus erythematosus (SLE) were immunized with keyhole limpet hemocyanin (KLH) the affected twin failed to develop delayed hypersensitivity and her lymphocytes failed to proliferate in response to KLH in vitro, unlike her normal sister. Subsequently, recently diagnosed SLE patients were skin tested with common antigens and 12 of 14 did not develop a positive skin reaction, in contrast to most patients with tuberculosis, who showed at least one positive response. There was no difference, however, in the leukocyte response to phytohemagglutinin between the two groups. These findings raised the question of a selective defect in cellular immunity in patients with SLE.

Impaired delayed hypersensitivity in systemic lupus erythematosus.

Cyclophosphamide was given to 11 patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in doses regulated by monitoring effects on small lymphocytes. Total leukocyte counts, the numbers of immunoglobulin-positive and Ig-negative small lymphocytes by immunofluorescence and the proliferative response of lymphocytes to phytohemagglutinin (PHA) were measured. The number of both Ig-positive and Ig-negative small lymphocytes decreased following cyclophosphamide. When dosage was reduced to maintenance levels, the Ig-positive cells remained less than 75% of baseline values, whereas the Ig-negative lymphocytes returned toward the baseline. During this time PHA values were normal or increased. On maintenance therapy, objective evidence of improvement was observed in 10 patients. These studies suggested a selective depletion of B-lymphocytes by cyclophosphamide and that a reduction of other leukocytes is not necessary for a favorable clinical response. Adverse side effects were rare. Direct quantitation of B-lymphocytes may be helpful in regulating clinically effective individual doses of cyclophosphamide in a manner that is relatively safe.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780170405

David A. Horwitz

Papers

Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor.

Impaired delayed hypersensitivity in systemic lupus erythematosus.

Selective depletion of Ig-bearing lymphocytes by cyclophosphamide in rheumatoid arthritis and systemic lupus erythematosu guidelines for dosage

Binding characteristics of Fc receptors for IgG on human peripheral blood Tγ lymphocytes and “L” lymphocytes: A technical report