The anti-tumor effect of allogeneic bone marrow/stem cell transplant without graft vs. host disease toxicity and without a matched donor requirement?

Abstract

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.