Har-Noy M, Slavin S
Hadassah-Hebrew University Medical Center, Department of Bone Marrow Transplantation and Cancer Immunotherapy, PO Box 12000, Jerusalem 91120, Israel.
Med Hypotheses. 2008;70(6):1186-92. doi: 10.1016/j.mehy.2007.10.008. Epub 2007 Dec 3.
The anti-tumor immune response that occurs in allogeneic bone marrow/stem cell transplant (BMT) settings is capable of eradicating tumors that are resistant to chemotherapy/radiation treatment. This anti-tumor immune response, known as the graft vs. tumor (GVT) effect, is the most effective immunotherapy treatment ever discovered. Unfortunately, the clinical application of GVT is severely limited due to the intimate association of GVT with the extremely toxic and often lethal side-effect known as graft vs. host disease (GVHD). It is a major research focus in the field of BMT to develop methods to separate the beneficial GVT effect from the detrimental GVHD toxicity. However, due to the intimate association of these effects, attempts to limit GVHD also have a tendency to limit the GVT effect. We propose a new concept for harnessing the power of the GVT effect without the toxicity of GVHD. Rather than trying to separate GVT from GVHD, we propose that these naturally coupled effects can 'mirrored' onto the host immune system and maintain their intimate association. The 'mirror' of GVHD is a host rejection of a graft (HVG). As rejection of an allograft would not be toxic, an HVG effect coupled to a host vs. tumor (HVT) effect, the 'mirror' of the GVT effect, would provide the anti-tumor effect of BMT without GVHD toxicity. In the 'mirror' setting, the HVT effect must occur against syngeneic tumors, while in the BMT setting the GVT effect occurs in the allogeneic setting. Previous attempts to elicit syngeneic anti-tumor immunity using therapeutic tumor vaccines have had disappointing results in the clinic due to the influence of tumor immunoavoidance mechanisms. We propose that the 'danger' signals that are released as a result of GVHD in the allogeneic BMT setting serve as an adjuvant to the GVT effect disabling tumor immunoavoidance. The chemotherapy/radiation conditioning prior to transplant is a required initiating event to the coupled GVT/GVHD effects. The conditioning releases 'danger' signals that mediate this adjuvant effect. To imitate this immunological event in immunocompetent, non-conditioned patients we propose that infusion of freshly activated, polyclonal CD4+ memory Th1 cells which express CD40L on the cell surface will stimulate a HVT/HVG 'mirror' effect, providing a non-toxic means to elicit the effective immune-mediated anti-tumor effect of BMT without the GVHD toxicity and without the requirement for a matched donor.
在异基因骨髓/干细胞移植（BMT）环境中发生的抗肿瘤免疫反应能够根除对化疗/放疗有抗性的肿瘤。这种抗肿瘤免疫反应，即移植物抗肿瘤（GVT）效应，是迄今发现的最有效的免疫治疗方法。不幸的是，由于GVT与被称为移植物抗宿主病（GVHD）的极具毒性且往往致命的副作用密切相关，GVT的临床应用受到严重限制。开发将有益的GVT效应与有害的GVHD毒性分离的方法是BMT领域的一个主要研究重点。然而，由于这些效应密切相关，限制GVHD的尝试也往往会限制GVT效应。我们提出了一个利用GVT效应的力量而不产生GVHD毒性的新概念。我们不是试图将GVT与GVHD分离，而是提出这些自然耦合的效应可以“映射”到宿主免疫系统上并保持它们的密切关联。GVHD的“映射”是宿主对移植物的排斥（HVG）。由于同种异体移植物的排斥不会有毒性，与GVT效应的“映射”即宿主抗肿瘤（HVT）效应相结合的HVG效应，将提供BMT的抗肿瘤效应而无GVHD毒性。在“映射”环境中，HVT效应必须针对同基因肿瘤发生，而在BMT环境中GVT效应发生在异基因环境中。先前使用治疗性肿瘤疫苗引发同基因抗肿瘤免疫的尝试在临床上由于肿瘤免疫逃避机制的影响而取得了令人失望的结果。我们提出，在异基因BMT环境中由于GVHD而释放的“危险”信号作为GVT效应的佐剂，使肿瘤免疫逃避失效。移植前的化疗/放疗预处理是耦合的GVT/GVHD效应所需的起始事件。预处理释放介导这种佐剂效应的“危险”信号。为了在有免疫能力、未经预处理的患者中模拟这一免疫事件，我们提出输注新鲜激活的、多克隆的、细胞表面表达CD40L的CD4 + 记忆性Th1细胞将刺激HVT/HVG“映射”效应，提供一种无毒的方法来引发BMT有效的免疫介导抗肿瘤效应，而无GVHD毒性且无需匹配的供体。
