The Biological Response Modifiers Programme (BRMP) is a comprehensive programme of the National Cancer Institute to evaluate the therapeutic effect of biological substances that might be useful in the treatment of cancer. Immunomodulation agents, interferons, cytokines, growth and maturation factors, antitumour effector cells and antibodies, and chalones are all potential biological response modifiers (BRM). The BRMP has a biologic preclinical evaluation capability whereby new agents can be evaluated as potential BRM in preclinical models. Effective biological response modifying activity in preclinical models with a therapeutic efficacy in cancer is a requirement for an agent to continue on into clinical testing. Initial results with interferon, thymic factors and other immune modulators are interesting but very preliminary. These agents are being tested for the ability to alter biological responses as well as for toxic and therapeutic effects. Optimization of the biological response modification capability may be predictive for therapeutic efficacy. Purified cytokines, specific tumour-associated antigens, and monoclonal antibody directed toward antigenic specificiteis on the cancer cell all provide exciting avenues for future investigation. Components of the BRMP will be described and preliminary results with selected BRM will be presented. The interaction between BRM and cancer chemotherapy should be investigated further. Certain cytokines are known to enhance bone-marrow-stem cell function and many of these may be useful in conjunction with cancer chemotherapy to lessen the toxic on normal cell populations often encountered with chemotherapy.

Misonidazole is a 2-nitroimidazole compound currently being assessed as a radiosensitizing agent. The effects of misonidazole on human bone marrow hematopoiesis were assayed by culture of committed granulocyte-macrophage progenitor cells (CFU-C). Three groups of patients with nonhematologic malignancies were selected for study. The first group of patients received a single, large dose of misonidazole; the second group received smaller, multiple doses of misonidazole; and the third group who did not receive any misonidazole served as irradiation controls. In 14 of 16 patients who received single or multiple doses of misonidazole, there was a significant decrease in the number of CFU-C present in the bone marrow after misonidazole therapy. In five patients who received irradiation only, there was no difference in the number of pre- and post-treatment bone marrow CFU-C. In misonidazole treated patients, extensive washing of post-treatment bone marrow samples failed to return CFU-C growth to control values. Suppression of CFU-C growth persisted for 3 weeks and returned to control values by 8 weeks. This reduction in the proliferative capacity of human bone marrow progenitor cells suggests that misonidazole may add to the myelotoxicity already associated with radiotherapy, systemic chemotherapy, or as combination of the two.

The results of a prospective study of 58 patients with refractory anemia and partial blastic infiltration of the bone marrow lead to the following conclusions. The median survival (12 months from diagnosis) is shorter and the rate of acute leukemia as cause of death (60%) higher than in other retrospective series. This group of patients, however, appears to be a "continuum" of preleukemic states with more or less rapid evolution, so that the exclusion of the most severe cases appears unjustified. Based on the degree of bone marrow blastosis, and also on the degree of blood cytopenias, the anomalies of 59 Fe incorporation kinetics and the bone marrow stem-cell cultures, it is possible to derive a plausible prognosis for individual patients, which could aid the choice of therapy. Androgen therapy does not accelerate leukemic evolution, but does not improve the bone marrow insufficiency. Cytosine-arabinoside at low dosage exhibited no toxicity, but did not delay the appearance of overt leukemia.

The effect of Levamisole on the human granulopoiesis was studied in patients randomized to receive, in addition to adjuvant chemotherapy for primary breast cancer, either no other treatment or additional unspecific immune therapy with Levamisole. The reaction of granulopoiesis to the cytostatic drugs, as characterized by changes of peripheral blood polymorphonuclear neutrophils (PMN), functional bone marrow granulocyte reserve, serial bone marrow cytology, and granulopoietic stem cells (CFU-C) in marrow and blood, was not affected by administration of Levamisole. The data support the concept that Levamisole has no direct effect on human bone marrow granulopoiesis, but that an allergic mechanism is involved in the pathogenesis of Levamisole-induced agranulocytosis. The expectation that Levamisole exerts a beneficial effect by stimulation of the granulopoiesis, as previously suggested for BCG and Corynebacterium parvum, could not be substantiated in our studies.

In a prospective, controlled trial 26 anaemic, neutropenic children with newly diagnosed acute lymphocytic leukaemia were randomised in pairs to receive either transfusion to a haemoglobin of 10--12 g/dl where clinically indicated (group A) or hypertransfusion to a haemoglobin of 16--18 g/dl (group B). Compared with group A (11 of 13 transfused), group B (all transfused) had a significantly more rapid rise in neutrophils at 7 and 10 days post-transfusion, a lower incidence of infection, and less interruption to chemotherapy. Hypertransfusion restored the myeloid/erythroid ratio to normal in bone-marrow of 5 of 6 children and the proportion of early myeloid precursors was greater than in controls.

The etiology of aplastic anemia is unknown. A stem cell lesion caused by a toxin, virus or microenvironment defect is the main hypothesis. An autoimmune origin has been recently suspected. In an attempt to demonstrate the autoimmune origin of the disease, 17 patients with severe aplastic anemia were treated with antilymphocyte globulin (ALG). Nine patients showed no improvement, developed infectious or hemorrhagic complications and died within 1 to 7 months. In contrast, eight patients had a prompt rise of granulocyte and reticulocyte counts. Although the hematological reconstitution is not complete, these eight patients are still alive between 11 months and 24 months after treatment. This study shows that ALG may have a beneficial effect in the treatment of patients with severe aplastic anemia.

Thirty two patients with malignant lymphoma - mainly Hodgkin's disease - were randomized for simultaneous treatment by high doses of metenolone during MOPP chemotherapy, to reduce its hematological toxicity. The results have shown surprisingly an increased hemato-toxicity in patients receiving androgens, with significantly more marked anemia and thrombocytopenia, reducing the total doses of anti-cancer drugs. This side effect could be explained by a cycling of the hematopoietic stem-cells and call to some caution when androgens are used during cancer chemotherapy.

In a prospective, randomized controlled study, 30 children who were receiving chemotherapy for malignant disease and who were anaemic and neutropenic, were randomized: 18 to receive transfusion to a Hb of 10-12 g/dl (group A) and 12 to receive moderate hypertransfusion to a Hb of 14-16 g/dl (group B). Children in group B had a significantly more rapid rise in polymorph count, lower incidence of infection, and lower incidence of interruption to chemotherapy. The findings of this study provide evidence for the existence of a common stem cell in human marrow, at least for erythroid and myeloid cell lines, and demonstrate that the concept of "stem-cell competition" derived from animal experiments has a human counterpart which is clinically significant.