A simple and effective method for cancer immunotherapy by inactivated allogeneic leukocytes infusion

Abstract

Allogeneic mixed leukocytes reaction has been reported to activate vast numbers of T lymphocytes and produce large amounts of type 1 cytokines that are linked to an initiation of antitumor immunity. Using poor immunogeneic B16-F10 and Lewis lung carcinoma (LLC) tumor model, we evaluated the effects of inactivated allogeneic leukocytes infusion (ALI) on the generation of antitumor immune response, as well as its effect on the primary and metastatic tumor. Allogeneic response promoted the generation of both specific and nonspecific antitumor immunity in an in vitro mixed lymphocytes-tumor cell culture system. Introveinous infusion of mitotically inactivated allogeneic leukocytes resulted in increased type-1 cytokines (including IL-2 and IFN-c) release, proliferation of various lymphocyte subsets, and generation of both specific and nonspecific antitumor immune response. As a result of such immune response, ALI caused a delayed tumor growth and a prolonged survival in established B16-F10 melanoma model. In LLC pulmonary spontaneous metastases model, ALI treatment significantly reduced postoperative tumor metastasis as the lung weights were far smaller than control group (0.16 vs. 0.34 g). Furthermore, after primary tumor resection and ALI treatment, 62.5% mice obtained long-term survival (>120 days) and there were no tumor growths in these mice when they were rechallenged with the same tumor. These experiments demonstrate that inactivated ALI could activate innate and adoptive antitumor immune response. It would be a simple, effective and secured method for cancer immunotherapy. ' 2008 Wiley-Liss, Inc.Key words: cancer; immunotherapy; alloantigen; metastasis Allogeneic transplantation (including heametopoietic stem cell transplantation) has been used as a successful therapeutic modality for various diseases, including malignancies. 1 Nevertheless, there is always a major limitation in the allogeneic transplantation: either host vs. graft (HVG) or graft vs. host (GVH). With a clear manifestation of the mechanisms of transplantation immunology, it is well recognized that alloantigen, a potent immunostimulator, elicits strong and rapid cellular and humoral immune responses, plays a key role in HVG or GVH. However, both HVG and GVH biology share several mechanisms that contribute to antitumor effects that occur outside of allogeneic transplantation, including IFN-g secreting type 1 T cells, 2 antigen presenting cells (APCs) activation, 3 and fas-and perforin-based cytolysis. 4 Therefore, it is possible to harness these characteristics as a therapeutic modality for malignancy.Actually, hematopoietic stem-cell transplantation (HSCT) is under study as a immunotherapeutic modality and achieve considerable effect in a wide range of hematologic and nonhematologic malignancies. 1,5 The basis of this treatment rests on an immune mechanism called the graft-versus-leukemia or graft-versus-tumor effect. Presumably, alloreactive T cells (CD4 and CD8 T cells) in the allograft participate in these phenomena, but the relevant antige...

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