DNA Immunization against Tissue-Restricted Antigens Enhances Tumor Immunity after Allogeneic Hemopoietic Stem Cell Transplantation

Abstract

Malignant relapse remains a major problem for recipients of allogeneic hemopoietic stem cell transplantation (HSCT). We hypothesized that immunization of allogeneic HSCT recipients against tissue-restricted Ags using DNA vaccines would decrease the risk of relapse without enhancing graft-vs-host disease (GVHD). Using the mouse B16 melanoma model, we found that post-HSCT DNA immunization against a single tumor Ag induces tumor rejection that is significantly greater than HSCT alone in a T cell-depleted MHC-matched minor Ag-mismatched allogeneic HSCT model (LP → B6). In treatment models, post-HSCT DNA immunization provides significantly greater overall survival than the vaccine alone. Donor leukocyte infusion further enhances tumor-free survival, including in treatment models. There was no GVHD in HSCT recipients treated with DNA vaccination and donor leukocyte infusion. Further analysis demonstrated that these effects are dependent on CD8+ T cells of donor origin that recognize multiple epitopes. These results demonstrate that DNA immunization against tissue-restricted Ags after allogeneic T cell-depleted HSCT can induce potent antitumor effects without causing GVHD.

Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

“…In this study, we asked whether KGF leads to improved antitumor immunity in response to vaccination. We and others have reported on the utility of tumor vaccines as a means of enhancing the graft-versus-tumor effect in allo-BMT recipients, [14][15][16][17][18][19][20][21][22] and this strategy also was reported in a clinical trial. 23 We previously showed in murine models that DNA tumor vaccination after allo-BMT is quite effective, capable of producing antitumor T-cell responses and rejection of subsequent tumor challenges and markedly improving the long-term survival of tumor-bearing mice in treatment models.…”

Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation

“…Frozen organs were homogenized and RNA was extracted with phenol/chloroform. Reverse-transcription was conducted with oligo-(dT) [12][13][14][15][16][17][18] …”

“…The combination of HSCT/DLI and tumordirected vaccination holds the potential to enhance the graft versus tumor (GVT) response, without favoring the graft versus host (GVH) effect (9). Indeed, posttransplant vaccines have previously been shown to augment the efficacy of HSCT/DLI against hematologic cancers (11)(12)(13)(14)(15) and in some instances also against transplantable solid tumors (16).…”

Concomitant Tumor and Minor Histocompatibility Antigen–Specific Immunity Initiate Rejection and Maintain Remission from Established Spontaneous Solid Tumors

“…8), the relative contribution of minor H-and TAA-specific T lymphocytes to tumor aggression is currently needed to define whether they should be further exploited in patients with solid cancer. Furthermore, the possibility to implement graft-versus-tumor without favoring GVHD, by posttransplant tumor-specific vaccination (9,10), remains largely to be explored.…”

“…TRAMP mice express the SV40 early genes (small and large T antigens; Tag) under the control of the androgen-driven rat probasin regulatory element (11). Consequently, at puberty, male mice invariably develop spontaneous prostate intraepithelial neoplasia (week [6][7][8][9][10][11][12], adenocarcinoma (week [12][13][14][15][16][17][18], with lymph node and visceral metastasis (week [18][19][20][21][22][23][24][25][26][27][28][29][30], closely mimicking the human pathology (12). Because of thymic Tag expression, high-affinity Tag-specific thymocytes in TRAMP mice are deleted (13).…”