The combination of chemotherapy and systemic immunotherapy with soluble B7-immunoglobulin G leads to cure of murine leukemia and lymphoma and demonstration of tumor-specific memory responses.
Major mechanisms underlying poor immune responses to autologous tumor-associated antigens are overwhelming tumor kinetics and the absence of effective T-cell costimulation by antigen-presenting cells. To address these issues, leukemia and lymphoma mice were treated with the combination of chemotherapy and systemic immunotherapy with recombinant soluble murine B7-immunoglobulin G (IgG) molecules. In this report, 3 murine models were used, a radiation-induced SJL acute myeloid leukemia, a transplantable spontaneous SJL lymphoma, and the C57BL/6 EL-4 thymic lymphoma. Various treatment modalities were evaluated: single treatments with either B7-IgG or chemotherapy as well as combination therapies. The results demonstrate the following: (1) in all tumor models, the combination of chemotherapy and soluble B7-IgGs is more potent than either therapy alone, leading to cure of tumor-bearing animals; (2) the therapeutic responses are T-cell-dependent, because combined therapy is not efficacious in severe combined immunodeficient mice; (3) the rejection of tumor cells leads to the development of tumor-specific immunity, because cured mice are immune to the rejected tumor but not to a different syngeneic tumor; and (4) (51)Cr release assays show that rejection of tumor cells leads to the development of very potent tumor-specific cytotoxic T-lymphocyte activity. On the basis of these results, it is proposed that chemotherapy-mediated tumor reduction, together with consequent augmented tumor-antigen presentation to activated T cells, are primary mechanisms leading to curative responses. The safety profile of the B7-IgG fusion proteins and their synergy with chemotherapy strongly suggest that the combination regimen is a promising strategy in cancer treatment.
Runyon
K
K
Genetics Institute, Wyeth-Ayerst Research, Cambridge, MA, USA.
Lee
K
K
Zuberek
K
K
Collins
M
M
Leonard
J P
JP
Dunussi-Joannopoulos
K
K
D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018122:B7-1 Antigen / Q000235:genetics / Q000627:therapeutic use*; D051940:B7-2 Antigen; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D007074:Immunoglobulin G / Q000235:genetics / Q000627:therapeutic use*; D007156:Immunologic Memory; D007167:Immunotherapy; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D007953:Leukemia, Radiation-Induced / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D013953:Thymus Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D003561:Cytarabine; D004317:Doxorubicin; D003520:Cyclophosphamide