Antitumor efficacy of a human major histocompatibility complex nonrestricted cytotoxic T-cell line (TALL-104) in immunocompetent mice bearing syngeneic leukemia.
The human MHC nonrestricted cytotoxic T-cell line TALL-104 displays potent tumoricidal activity both in vitro and in animals bearing either spontaneous or induced tumors. In the present study, we used B6D2F1 mice engrafted with the syngeneic pre-B leukemia cell line 7OZ as a model system to investigate the mechanisms by which TALL-104 cells display antitumor activity in an immunocompetent host. In vitro studies indicated that 7OZ cells are resistant to TALL-104 cell-induced necrotic death, as measured in 51Cr release assays, but can be killed by the xenogeneic effectors via apoptotic mechanisms. Adoptive transfer experiments showed that 70% of cyclosporin A-treated mice that received multiple i.p. injections of gamma-irradiated (nonproliferating) TALL-104 cells at an early or intermediate stage of disease did not develop any clinical or molecular signs of leukemia. If the same treatment was initiated at an advanced disease stage, it doubled the survival of the animals. Importantly, 100% of the treated mice that remained disease-free in a 4-month follow-up period rejected a further challenge of high-dose 7OZ cells; these mice had developed tumor-specific Immoral and cellular responses. In another set of experiments, marrows from leukemic mice containing </= 10% 7OZ cells were purged ex vivo with irradiated TALL-104 cells and engrafted into sublethally irradiated B6D2F, mice; up to 80% of the recipients failed to develop leukemia, and 40% of them were protected against a 7OZ rechallenge 4 months later. TALL-104 purging efficacy was lower if the marrows were infiltrated by >/= 30%. Ex vivo purging with a human lymphokine-activated killer cell preparation in the same conditions proved to be less effective. The overall data indicate the potent antileukemic effects of TALL-104 cells in vivo and provide evidence that xenogeneic effectors can induce tumor regression via a dual mechanism of direct tumoricidal activity and recruitment of endogenous antitumor immunity.
Cesano
A
A
The Wistar Institute, Philadelphia, Pennsylvania 19104.
Visonneau
S
S
Pasquini
S
S
Rovera
G
G
Santoli
D
D
D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D017209:Apoptosis; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation; D003602:Cytotoxicity, Immunologic; D004261:DNA Replication; D006801:Humans; D007121:Immunocompetence; D016219:Immunotherapy, Adoptive; D051379:Mice; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D011828:Radiation Chimera; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000528:radiation effects / Q000637:transplantation; D014183:Transplantation, Heterologous
D000912:Antibodies, Neoplasm