Endotoxin and the lipid-A portion of the molecule have a variety of biological effects, including the induction of necrosis and regression of malignancy. To date extensive clinical trials of endotoxin as a potential therapeutic agent have been shunned due to the toxicity of the material. Several lipid-A analogues have been described which have reduced toxicity and retain antitumor activity. We have investigated in a phase-I trial the clinical toxicity and immunological effects of monophosphoryl lipid A prepared from Salmonella typhimurium and Salmonella minnesota. Patients entered on the study received IV monophosphoryl lipid A twice weekly for a total of 4 weeks. At least three patients were entered sequentially at each of the dose levels of 10, 25, 50, 100, and 250 micrograms/m2 body surface area. One patient was treated at the dose level of 500 micrograms/m2. The major clinical toxicity was fever, chills, and rigor, which occurred in over 50% of the treatments at doses of 250 micrograms/m2. Two instances of bronchospasm occurred in one patient who received 250 micrograms/m2. One patient received 500 micrograms/m2 and became hypotensive. Sequential clinical data showed no evidence of renal or hepatic toxicity. A transient decrease in the WBC and platelets occurred during the first 24 h after therapy. Immune function testing measured T cells, monocyte cytostasis, monocyte suppressor cell activity, and NK activity. These data suggested a shift in monocyte populations with activated cells moving into the tissue. Direct objective antitumor activity or necrosis was not observed in this group of patients. We conclude that monophosphoryl lipid A can be given to patients in a dose of up to 100 micrograms/m2 with acceptable toxicity. Its clinical activity as a single agent in combination with other immunomodulators remains to be demonstrated.
Fifty-three patients with advanced lymphocytic lymphoma were randomly assigned to treatment with the combination cyclophosphamide, vincristine, and prednisone (CVP) or the same agents used successively in maximal doses (C-V-P). Complete remissions occurred in 68% with CVP and 48% with C-V-P. For patients with nodular lymphoma, the complete remission rate was 81% with CVP and 46% with C-V-P. In patients with diffuse lymphoma a complete remission rate of 50% was obtained with both regimens. The median duration of response was longer for patients who obtained complete remission with CVP (37+ months) than for those entering remission with C-V-P (25+ months). More patients treated with CVP still survive. Current results suggest that CVP is a better induction regime than C-V-P in patients with nodular lymphoma. However, in patients with diffuse lympoocytic lymphoma, neither regimen results in more than 50% complete remissions or significant numbers of prolonged responses. More effective therapy is needed.
The clinical efficacy of intralesional immunotherapy utilizing Mycobacterium smegmatis cell wall skeleton (CWS) and trehalose dimycolate attached to oil droplets was investigated in 15 patients with advanced malignant melanoma. Patients received 300 microgram to 1050 microgram of the CWS combined with one-half that amount of trehalose dimycolate every 1 to 2 weeks for a total of 8 treatments. Therapy was continued if regression of injected lesions only occurred. Therapy was discontinued if regression of noninjected disease also occurred. Six of the 15 patients had regression of at least one injected lesion. Four of these 6 patients also had regression of noninjected disease lasting 4+, 6, 16 and 18+ months. Response was highly related to immune status. Six (83%) of 7 patients who reacted to one of a battery of skin tests responded. All 8 patients who did not react to skin tests failed to respond to therapy. There was no correlation of response with sex, prior therapy, disease-free interval or presence of visceral disease. Mycobacterial CWS and trehalose dimycolate is an effective immunotherapeutic agent. Additional studies of purified immunoadjuvants are warranted.
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