TUMOR ANTIGEN-SPECIFIC IMMUNIZATION OF BONE-MARROW TRANSPLANTATION DONORS AS ADOPTIVE THERAPY AGAINST ESTABLISHED TUMOR

Background: Persistence of the underlying malignancy remains the main obstacle to the successful treatment of human malignancies with high-d ose chemoradiotherapy and bone marrow transplantation. Purpose: The ai m of this study was to determine whether antigen-specific antitumor im mune responses, elicited in normal donor mice by immunization,vith the soluble form of a surrogate tumor antigen (i.e., ovalbumin [OVA]), ca n be transferred via bone marrow transplantation into lethally irradia ted, syngeneic recipient mice, An additional goal was to evaluate the ability of these adoptively transferred bone marrow cells to eradicate established recombinant OVA-expressing lymphomas that recurred after lethal-dose total-body irradiation (TBI), Methods: Female C57BL/6 dono r mice were immunized twice with OVA emulsified in a muramyl-dipeptide -containing adjuvant, Syngeneic mice bearing a day-10 or day-ii, appro ximately l-cm subcutaneous E,G7-OVA tumor (E.G7-OVA tumor cells were d erived from transfection of EL-4 thymoma tumor cells using the coding sequence of chicken OVA gene complementary DNA) were treated with TBI and reconstituted with bone marrow from nonimmune or OVA-immunized mic e, In subsequent experiments, tumor-bearing mice, treated with TBI and OVA-immune bone marrow, were given additional therapy either with a s ingle OVA immunization or by the adoptive transfer of 1 x 10(7) in vit ro activated spleen cells derived from OVA-immune donor mice and cultu red 5 days with irradiated E,G7-OVA cells before transfer, Results: E, G7-OVA tumor-bearing mice given TBI and OVA-immune bone marrow showed a significantly increased cure rate when compared with that among cont rols reconstituted with nonimmune bone marrow after TBI (logrank, P<.0 1), The antitumor effect of immune bone marrow was abrogated by T-cell depletion of the marrow graft (P<.016). The antitumor effect of immun e marrow was enhanced by the addition of OVA immunization of tumor-bea ring recipients (P<.015). OVA-specific cytotoxic T-lymphocyte (CTL) ac tivity was recovered from tumor-bearing recipients of immune marrow 14 days after bone marrow transplantation. The antitumor effect observed following the adoptive transfer of immune marrow was further augmente d by the addition of 1 x 10(7) splenic E.G7-OVA-specific in vitro acti vated CTLs derived from OVA-immune mice (P<.03), Conclusion: These stu dies establish the principle that antigen-specific T-cell immunity aga inst a defined tumor-specific antigen can be transferred with bone mar row from an immune donor, Implications: Active immunization of normal human bone marrow or T-cell donors with a refined, safe tumor antigen and transfer of immunity to the patient may represent a novel strategy for circumventing the obstacle of host immune suppression associated with the tumor-bearing state.