Efficacy and mechanisms of action of rmB7.2-Ig as an antitumor agent in combination with Adriamycin and Cytoxan chemotherapy.
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.
Zhou
H
H
Immunology and Hemostasis, Genetics Institute, Wyeth-Ayerst Research, Cambridge, Massachusetts 02140, USA.
Sequeira
M
M
Goad
M E
ME
Erickson
J
J
Wong
A
A
Clark
E
E
Dunussi-Joannopoulos
K
K
Li
R C
RC
Friedrich
S
S
Hayes
L L
LL
Wolf
S F
SF
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
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