Tumor Vaccination after Allogeneic Bone Marrow Cell Reconstitution of the Nonmyeloablatively Conditioned Tumor-Bearing Murine Host

Abstract

Allogeneic bone marrow cell reconstitution of the nonmyeloablatively conditioned host is supposed to provide an optimized platform for tumor vaccination. We recently showed that an allogeneic T cell-depleted graft was well accepted if the tumor-bearing host was NK depleted. Based on this finding, a vaccination protocol in tumor-bearing, nonmyeloablatively conditioned, allogeneically reconstituted mice was elaborated. Allogeneically reconstituted mice, bearing a renal cell carcinoma, received tumor-primed donor lymph node cells (LNC), which had or had not matured in the allogeneic host. Primed LNC were supported by tumor lysate-pulsed dendritic cells, which were donor or host derived. Optimal responses against the tumor were observed with host-tolerant, tumor-primed LNC in combination with host-derived dendritic cells. High frequencies of tumor-specific proliferating and CTLs were recorded; the survival time of tumor-bearing mice was significantly prolonged, and in >50% of mice the tumor was completely rejected. Notably, severe graft-vs-host disease was observed in reconstituted mice that received tumor-primed LNC, which had not matured in the allogeneic host. However, graft-vs-host was not aggravated after vaccination with tumor-primed, host-tolerant LNC. Thus, the LNC were tolerant toward the host, but not toward the tumor. The finding convincingly demonstrates the feasibility and efficacy of tumor vaccination after allogeneic reconstitution of the nonmyeloablatively conditioned host.

Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD

“…Vaccination of the donor (before harvest of the hematopoietic cell graft) and then of the engrafted patient with multiple TAAs is 1 potential strategy which addresses both questions. [45][46][47][48] Several CEA-based vaccine formulations have proven to be safe in humans and not associated with autoimmune reactions, making vaccination of healthy individuals a potential approach for increasing the frequency of CEA-specific T cells in the donor hematopoietic cell graft. 31,[49][50][51][52] As for the vaccination of engrafted patients, timing of vaccine delivery could be critical for efficacy.…”

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

“…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).…”

Generation of RAGE‐1 and MAGE‐9 peptide‐specific cytotoxic T‐Lymphocyte lines for transfer in patients with renal cell carcinoma

“…[33][34][35] Cell-mediated immunotherapeutic protocols in RCC have been based on tumor lysate-loaded DCs. [36][37][38][39] Vaccination-induced remissions and an increase in the 5-year survival rate to 70% have been observed. [40][41][42] Application of tumor antigen cDNA 43 or of DC transduced with tumor antigen mRNA or cDNA 44,45 has been reported also to improve survival time, albeit to a minor degree.…”