PMID- 18054441
OWN - NLM
STAT- MEDLINE
DCOM- 20080813
LR  - 20080506
IS  - 0306-9877 (Print)
IS  - 0306-9877 (Linking)
VI  - 70
IP  - 6
DP  - 2008
TI  - The anti-tumor effect of allogeneic bone marrow/stem cell transplant without 
      graft vs. host disease toxicity and without a matched donor requirement?
PG  - 1186-92
AB  - 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.
FAU - Har-Noy, M
AU  - Har-Noy M
AD  - Hadassah-Hebrew University Medical Center, Department of Bone Marrow 
      Transplantation and Cancer Immunotherapy, PO Box 12000, Jerusalem 91120, Israel. 
      harnoy@immunovative.co.il
FAU - Slavin, S
AU  - Slavin S
LA  - eng
PT  - Journal Article
DEP - 20071203
PL  - United States
TA  - Med Hypotheses
JT  - Medical hypotheses
JID - 7505668
RN  - 147205-72-9 (CD40 Ligand)
SB  - IM
MH  - Bone Marrow Transplantation/*immunology
MH  - CD40 Ligand/immunology
MH  - Graft vs Host Disease/immunology
MH  - Humans
MH  - *Models, Immunological
MH  - Neoplasms/*immunology/*therapy
MH  - *Stem Cell Transplantation
MH  - Th1 Cells/immunology
MH  - Transplantation Immunology/*immunology
MH  - Transplantation, Homologous
EDAT- 2007/12/07 09:00
MHDA- 2008/08/14 09:00
CRDT- 2007/12/07 09:00
PHST- 2007/09/11 00:00 [received]
PHST- 2007/10/15 00:00 [accepted]
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/08/14 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
AID - S0306-9877(07)00614-7 [pii]
AID - 10.1016/j.mehy.2007.10.008 [doi]
PST - ppublish
SO  - Med Hypotheses. 2008;70(6):1186-92. doi: 10.1016/j.mehy.2007.10.008. Epub 2007 
      Dec 3.