An evaluation of the potential to use tumor-associated antigens as targets for antitumor T cell therapy using transgenic mice expressing a retroviral tumor antigen in normal lymphoid tissues.

Abstract

Stlmma.ryA major obstacle to the development of T cell therapy for the treatment of human tumors has been the difficulty generating T cells specifically reactive with the tumor. Most of the characterized human tumor antigens have been dassified as tumor associated, because of demonstrable expression at low levels in some normal cells, and thus have not been extensively studied as potential targets of a therapeutic immune response. However, the quantitative difference in expression of such antigens between the tumor and normal cells might permit the generation of antigen-specific T cells capable of selective antitfimor and not autoimmune activity. To address this issue, transgenic (TG) mice were generated that expressed low levels of Friend murine leukemia virus (FMuLV) envelope protein in lymphoid cells under the control of an immunoglobulin promoter. This protein is expressed at high levels by a Friend virus-induced erythroleukemia of C57BL/6 (B6) origin, FBL, and has been shown to serve as an efficient tumor-specific rejection antigen in B6 mice. The env-TG mice were tolerant to envelope, as reflected by the failure to detect an envelopespecific response after in vivo priming and in vitro stimulation with preparations of FMuLV envelope. However, adoptively transferred envelope-specific T cells from immunized non-TG B6 mice mediated complete eradication of FBL tumor cells in TG mice, and did not induce detectable autoimmune damage to TG lymphoid tissues. The transferred immune cells were not permanently inactivated in the TG mice, since donor T cells responded to envelope after removal from the TG mice. The lack of autoimmune injury did not reflect inadequate expression of envelope by TG lymphocytes for recognition by T cells, since TG lymphocytes functioned effectively in vitro as stimulators for envelope-specific T cells. The results suggest that this and analogous strains of TG mice may prove useful for elucidating principles for the generation and therapeutic use of tumor-reactive T cells specific for tumor-associated antigens.

Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model

“…Previous studies have shown that CD4 þ T cells can contribute to effective adoptive therapy in other models. 28,29 We have shown that in situ adenoviral vector delivery of AdIL-12 or AdIL-12/B7 into RM-9 tumors increased the number of tumor-infiltrating CD4 þ T cells two-to three-fold compared to Adbgal. 17 We also cannot rule out the possibility that NK cells contribute to the therapeutic effect.…”

Adenoviral Gene Transfer of Interleukin 12 into Tumors Synergizes with Adoptive T Cell Therapy Both at the Induction and Effector Level

“…These data imply that intratumoral treatment with AdCMVIL-12 simplifies the subsequent in vitro growth of effective CTLs. Although adoptively transferred CD4 1 cells have displayed antitumor activity in some systems (Hu et al, 1993), the presence of CD4 1 T cells in our adoptively transferred cultures is not a requirement and only the depletion of CD8 1 cells abrogated their in vitro and in vivo activity. Moreover, purified CD8 1 cells from those cultures were sufficient to execute, in a dose-dependent manner, the antitum or effect on adoptive transfer.…”

Leukemia-associated fusion proteins, dek-can and bcr-abl, represent immunogenic HLA-DR-restricted epitopes recognized by fusion peptide-specific CD4+ T lymphocytes

“…[1][2][3] In addition, the recent finding that CD8 + T lymphocyte-depleted donor lymphocyte infusion is effective for patients with relapsed chronic myelogenous leukemia (CML) 4 strongly suggests that CD4 + T lymphocytes also play an important role in the antileukemia immune response in humans. Although attention has been recently focused on tumor-specific CD4 + T lymphocytes, the number of tumorassociated antigens identified so far which are recognized by CD4 + T lymphocytes is still limited.…”