lipid-a and Bone-Neoplasms

Our objective was to determine the clinical activity, toxicity, and immunological effects of active immunotherapy using UVB-irradiated (UVR) autologous tumor (AT) cells plus adjuvant DETOX in metastatic melanoma patients. Eligibility included nonanergic patients fully recovered after resection of 5 or more grams of metastatic melanoma. Treatment consisted of intradermal injections of 10(7) UVR-AT plus 0.25 ml of DETOX every 2 weeks x 6, then monthly. Peripheral blood mononuclear cells (PBMCs) were harvested for cytotoxicity assays, and skin testing was performed for delayed-type hypersensitivity (DTH) determinations before the first, fourth, seventh, and subsequent treatments. Forty-two patients were treated, 18 in the adjuvant setting and 24 with measurable disease. Among the latter group, there were two durable responses in soft-tissue sites and in a bone metastasis. Treatment was well tolerated. Thirty-five patients were assessable for immunological parameters; 10 of these patients, including the 2 responders, demonstrated early induction of PBMC cytotoxicity against AT cells that persisted up to 10 months on treatment before falling to background levels. In five of seven patients, the fall-off heralded progressive disease. Late induction of a weak DTH reaction to AT cells was observed in eight patients. Active immunotherapy with UVR-AT + DETOX had modest but definite clinical activity in advanced melanoma. The induction of both PBMC cytotoxicity and DTH reactivity to AT cells supported a specific systemic immune effect of treatment, although the former more closely followed disease course in this study.

Topics: Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Antigens, CD; Bone Neoplasms; Cancer Vaccines; Cytoskeletal Proteins; Cytotoxicity, Immunologic; Drug Combinations; Female; Humans; Hypersensitivity, Delayed; Immunity, Active; Immunoglobulin G; Immunotherapy; Lipid A; Male; Melanoma; Middle Aged; Neoplasm Staging; Skin Neoplasms; Soft Tissue Neoplasms; Survival Rate; Time Factors; Ultraviolet Rays

Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis of advanced cases is still poor. Recently, there have been several reports suggesting the relationship between innate immunity and OS, but the detailed mechanism is unknown. We demonstrate the relationship between OS and Toll-like receptor 4 (TLR4) which is one of the most important factors in innate immunity.. We established a syngenic mouse tumor model using C3H/HeN, C3H/HeJ mouse and a highly metastatic OS cell line, LM8. TLR4 activation with lipopolysaccharide (LPS) was performed on both mice and its influence on the progression of OS was evaluated. We also performed CD8 + cells depletion to examine the influence on TLR4 activation effects.. Tumor volume of C3H/HeN mice was significantly smaller and overall survival of C3H/HeN mice was significantly longer than C3H/HeJ mice. We found more CD8+ cells infiltrating in lung metastases of C3H/HeN mice and depletion of CD8+ cells canceled the antitumor effects of LPS.. TLR4 activation by LPS increased CD8+ cells infiltrating into lung metastases and suppressed OS progression in the mouse model. TLR4 activation may suppress the progression of OS via stimulating CD8+ cells and can be expected as a novel treatment for OS.

Topics: Adjuvants, Immunologic; Adolescent; Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cell Line, Tumor; Chemotherapy, Adjuvant; Child; Child, Preschool; Disease Models, Animal; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Lipid A; Lipopolysaccharides; Lung Neoplasms; Lymphocyte Depletion; Male; Mice; Middle Aged; Osteosarcoma; Prognosis; Progression-Free Survival; Signal Transduction; T-Lymphocytes, Cytotoxic; Toll-Like Receptor 4; Tumor Burden; Young Adult