title: Efficacy and mechanisms of action of rmB7.2-Ig as an antitumor agent in combination with Adriamycin and Cytoxan chemotherapy.
abstract: The efficacy of chemotherapy for cancer is often limited by toxicity. Immune approaches to cancer immunotherapy, while promising for specificity and long-term protection, have not typically proven potent enough to generate significant therapeutic responses. We have shown therapeutic benefit using recombinant murine B7.2-Ig (rmB7.2-Ig) in murine tumor models. Efficacy was dependent on immune activity and was not associated with toxicity. Recently, the efficacy of rmB7.2-Ig was demonstrated in leukemia tumor models in combination with chemotherapeutic agents. To further explore the potential of this approach, we evaluated the efficacy in solid tumor models of rmB7.2-Ig given in combination with chemotherapeutics commonly used in clinical practice, testing the effects of dose and schedule. RmB7.2-Ig in combination with some chemotherapeutics enhances the activity and efficacy of reduced chemotherapeutic doses. However, the relative timing of chemotherapy and rmB7.2-Ig dosing can be important. Investigation of mechanisms of action based on histological studies suggests that inflammatory as well as T cell mechanisms comprise the response. Additional studies of mice deleted of B7.1, B7.2, and CTLA-4 suggest that the enhanced response induced by rmB7.2-Ig may not be mediated through CD28 ligation alone. The efficacy suggests potential for recombinant human B7.2-Ig as an adjuvant to chemotherapy in promoting immune-mediated mechanisms to augment the activity of chemotherapy.
authors.affiliation: Immunology and Hemostasis, Genetics Institute, Wyeth-Ayerst Research, Cambridge, Massachusetts 02140, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Sequeira
authors.forename: M E
authors.initials: ME
authors.lastname: Goad
authors.forename: J
authors.initials: J
authors.lastname: Erickson
authors.forename: A
authors.initials: A
authors.lastname: Wong
authors.forename: E
authors.initials: E
authors.lastname: Clark
authors.forename: K
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
authors.forename: R C
authors.initials: RC
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Friedrich
authors.forename: L L
authors.initials: LL
authors.lastname: Hayes
authors.forename: S F
authors.initials: SF
authors.lastname: Wolf
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051940:B7-2 Antigen; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology / Q000627:therapeutic use*; D007167:Immunotherapy; D008562:Membrane Glycoproteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin; D003520:Cyclophosphamide