Tumor Antigen-Specific Immunization of Bone Marrow Transplantation Donors as Adoptive Therapy Against Established Tumor

Abstract

Background: Persistence of the underlying malignancy remains the main obstacle to the successful treatment of human malignancies with high-dose chemoradiotherapy and bone marrow transplantation. Purpose: The aim of this study was to determine whether antigen-specific antitumor immune responses, elicited in normal donor mice by immunization with the soluble form of a surrogate tumor antigen (i.e., ovalbumin [OVA]), can be transferred via bone marrow transplantation into lethally irradiated, 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 donor mice were immunized twice with OVA emulsified in a muramyli-dipeptide-containing adjuvant. Syngeneic mice bearing a day-10 or day-11, approximately 1-cm subcutaneous E.G7-OVA tumor (E.G7-OVA tumor cells were derived 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 mice. In subsequent experiments, tumor-bearing mice, treated with TBI and OVA-immune bone marrow, were given additional therapy either with a single OVA immunization or by the adoptive transfer of 1 * 10 ⁷ in vitro activated spleen cells derived from OVA-immune donor mice and cultured 5 days with irradiated E.G7-OVA cells before transfer.Z 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 controls reconstituted with nonimmune bone marrow after TBI (logrank, P<.01). The antitumor effect of immune bone marrow was abrogated by T-cell depletion of the marrow graft (P<.O16). The antitumor effect of immune marrow was enhanced by the addition of OVA immunization of tumor-bearing recipients (P<.015). OVA-specific cytotoxic T-lymphocyte (CTL) activity 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 augmented by the addition of 1 x 10 ⁷ splenic E.G7-OVA-specific in vitro activated CTLs derived from OVA-immune mice (P<.03). Conclusion: These studies establish the principle that antigen-specific T-cell immunity against a defined tumor-specific antigen can be transferred with bone marrow 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. [J Natl Cancer Inst 1995; 87: 1289–96]