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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2420-2426
NEOPLASIA
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
Kathlene Runyon,
Kwang Lee,
Krystyna Zuberek,
Mary Collins,
John P. Leonard, and
Kyriaki Dunussi-Joannopoulos
From the Genetics Institute, Wyeth-Ayerst Research,
Cambridge, MA.
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) 51Cr 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.
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