Major mechanisms underlying poor immune responses to autologous tumorassociated 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 radiationinduced 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 tumorbearing 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
IntroductionMajor recent discoveries that have drastically modified the nature of T-cell-directed immunotherapy in cancer are the cloning of several tumor-associated antigens (TAAs) that elicit autologous cytotoxic T-cell responses 1,2 and the discovery of new molecules and pathways involved in T-cell activation and costimulation. 3,4 This knowledge has guided the design of numerous preclinical and clinical studies that, in turn, have generated remarkable insight into the mechanisms controlling host responses to cancer cells. Thus, it is now accepted that few spontaneous tumors are immunogenic, but most, if not all, are antigenic. 5,6 However, what ultimately determines the outcome of an endogenous antigen encounter is the context in which that particular antigen is presented to T cells. 7,8 In the absence of danger signals that accompany tissue destruction and inflammation (typically observed during viral infection), the outcome is immune ignorance. 9,10 At the level of antigenpresenting cell (APC)-T-cell interactions, the local danger signals translate primarily into the up-regulation of T-cell costimulatory signals provided by APCs at the time of antigen presentation.Costimulation is defined as a signal necessary for optimal T-cell activation and survival delivered to T cells along with the T-cell receptor (TCR) signal, provided by APCs, ie, activated B cells, macrophages, and dendritic cells. 11,12 Over the years, the CD28/B7 T-cell costimulatory pathway has emerged as the key regulator of T-cell responses. The signal involves the interaction of the T-cell surface antigen CD28 with the members of the B7 family molecules B7.1 (CD80) and B7.2 (CD86) expressed on APCs. 13,14 Following a TCR-mediated signal, ligation of CD28 results in up-regulation of the interleukin 2 (IL-2)-receptor, increased IL-2 messe...