The Graft versus Leukemia effect is well known and put to good use in the treatment of leukemia. We report here on a graft versus myeloma effect obtained by autologous CTL and NK action against autologous Multiple myeloma cells. CTL are in a chronic state of activation in MM patients These cells are ineffective against myeloma cells. Eliminating the activated CTL by fas-mediated apoptosis enables naive T cells to be activated against myeloma cells. The cytokines responsible for suppression of the immune system in MM are controlled in vivo by TGF- 1 monoclonal antibody and IL-6 superantagonists. To optimize the immune response MM plasma cells are transfected with a adenovirus expressing the B7 HLA receptor and HLA expression is augmented with IFN- . This is the cure for multiple myeloma.

The reason the immune system does not recognize a neoplastic MM cell has eluded scientists for years. Looking at reports of graft-versus-leukemia, and graft-versus-myeloma effects (Verdonck et al 1996), we postulated that it is reasonable to assume that the immune system has the ability to eradicate MM completely. An in vitro observation confirmed by Bianchi (1995). The mechanisms employed by allo-immune cells are exactly the same as those employed by the MM patients immune system. Thus the immune cells are regulated in vivo by cell to cell messengers and a very intricate cytokine system. CD4+Th1 cells have been shown to be the important CD4+ anti-tumor effectors in vivo and specifically in B-cell malignancies, because the can specifically interact with HMC class II molecules highly expressed in B-cell malignancies. They can be suppressed by IL-6 produced by CD4+Th2 cells (Romagnani, 1994). Researchers from Stanford University working on HIV are expanding immune cells in vitro. The important step in the whole process is sequential activation of the T cell. (It won't help giving a soldier a gun before he knows how to shoot.) Thus we need naive T cells stimulated by a CD3/TCR followed by antigen stimulation, co-stimulated by CD28 and B7, then followed by cytokine addition. This we propose to be done by exposing MM PMC to anti-fas antibody inducing apoptosis in the activated lines. The naive CD45RA+ cells will then be able become activated in the normal in vivo manner and recognize the mortally wounded MM plasmacells.
The second step would be to remove as many of the wrongful cytokine signals as possible in the MM patient. IL-6 is the cytokine with the most effect on MM. Treating the patient for at least a 6 day period with a super antagonist (Moss et al, 1996) will reduce the immunosuppression effect on CD4+Th1 lymphocytes and the will in turn be able to activate the more important CD8+ lymphocytes involved in the sustained anti-tumor response. As shown in a murine model by Ellenhorn et al (1990). Using a TGF- 1 monoclonal antibody to restore a normal cytokine milieu would do some good.
Lastly we need to make the plasma cells as visible as possible to the naive immune cells. (The first time is never easy!). By adenoviral vector transfer B7 can be expressed in B7- cells. This can also be enhanced by adding IFN- . This can be done in vivo or in vitro. IFN- enhances the expression of HMC molecules and assists the immune system in this way.
These immune cells will now have the ability to eradicate the malignant clone and a normal immuno-surveillance should prevail.
Very soon we believe anti-viral drugs will work in much the same way in MM.



1. Verdonck Leo F, Lokhorst Henk M, Dekker Adriaan W, Nieuwenhuis Karel H, Peterson Eefke J. Graft-versus-myeloma effect in two cases. Lancet 1996; 347: 800-01
2. Sporeno E, Savino R, Ciapponi L, Paonessa G, Cabbibbo A, Lahm A, Pulkki K, Sun R, Toniatti C, Klein B, Ciliberto G. Human Interleukin-6 Super-Antagonists with high Potency and Wide Spectrum on MM cells. Blood 1996; 87: 4510-4519.
3. Romagnani, S. Lymphokine production by human T cells in disease states. Annual Reviews of Immunology 1994; 12: 227-257.
4. Bianchi A, Montacchini L, Barral P, Borrione P, Attisano C, Orsini E, Boccarodo M, Pileri A, Massaia M. CD3-induced T-cell activation in the bone marrow of myeloma patients: major role of CD4+ cells. British Journal of Haematology 1995; 90: 625-632.

This is just one of my theories.