title: Control of relapse due to minimal residual disease (MRD) by cell-mediated cytokine-activated immunotherapy in conjunction with bone marrow transplantation.
abstract: In conclusion, lessons from the animal model of lymphoid leukaemia suggest that in the setting of allogeneic BMT, under certain conditions GVL effects may be separable from GVHD; more specifically, GVL effects may be induced despite development of tolerance of donor cells against allogeneic host alloantigens. The latter phenomenon suggests that either curative GVL effects may be inducible despite subclinical GVHD or alternatively that effector cells of GVL may recognize different tumour-associated targets different from cell surface determinants of 'normal' alloantigens. Alternatively, effector cells of GVL may be distinguished from effector cells of GVHD. It is tempting to suggest that NK and IL2-aspirated NK cells may play a major role as effector cells of GVL in an MHC non-restricted fashion, different from classical CD8+ cytotoxic cells that certainly play a major role in GVHD and GVL. Once proven, the latter hypothesis may help develop new and safer therapeutic approaches since NK cells and products of the NK cell family are unlikely to play a major role, if any, in GVHD. The feasibility of induction of GVL-like effects by MHC non-restricted effector cells, such as that observed by CMI, most likely through cytokine-activated NK cells, seems promising because such effector mechanisms may be utilized clinically through either adoptive transfer of in vitro-activated lymphocytes or activation of lymphocytes in vivo by administration of cytokines such as IL2 and alpha IFN. Similarly, induction of CCI following ABMT may permit establishment of GVL-like effects with no major risk of GVHD. Our animal models suggest that both approaches may be beneficial and perhaps even combined. From a practical standpoint, activation of antitumour effector cells in vivo is much more feasible, in comparison with the cumbersome and expensive technologies for large-scale in vitro manipulation of IL2-activated 'LAK' cells or tumour-infiltrating lymphocytes ('TIL') at dose ranges required for obtaining clinically meaningful responses. No less important is the fact that more potent immunotherapy may be inducible by cytokine combinations (such as IL2 and alpha IFN). We are currently investigating additional cytokine combinations in order to attempt to optimize antitumour effects inducible by allogeneic and syngeneic lymphocytes since it appears logical that amplifying in vivo antitumour responses by multiple cytokine combinations may yield better antitumour effects.
authors.forename: S
authors.initials: S
authors.lastname: Slavin
authors.forename: A
authors.initials: A
authors.lastname: Ackerstein
authors.forename: U
authors.initials: U
authors.lastname: Vourka-Karussis
authors.forename: A
authors.initials: A
authors.lastname: Nagler
authors.forename: R
authors.initials: R
authors.lastname: Or
authors.forename: E
authors.initials: E
authors.lastname: Naparstek
authors.forename: L
authors.initials: L
authors.lastname: Weiss
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D016219:Immunotherapy, Adoptive; D007942:Leukemia, Experimental / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D012074:Remission Induction