Targeting self-antigens through allogeneic TCR gene transfer

Abstract

Adoptive transfer of T-cell receptor (TCR) genes has been proposed as an attractive approach for immunotherapy in cases where the endogenous T-cell repertoire is insufficient. While there are promising data demonstrating the capacity of TCRmodified T cells to react to foreign antigen encounter, the feasibility of targeting tumor-associated self-antigens has not been addressed. Here we demonstrate that T-cell receptor gene transfer allows the induction of defined self-antigenspecific T-cell responses, even when the endogenous T-cell repertoire is nonreactive. Furthermore, we show that adoptive transfer of T-cell receptor genes can be used to induce strong antigen-specific T-cell responsiveness in partially MHCmismatched hosts without detectable graft versus host disease. These results demonstrate the feasibility of using a collection of "off the shelf" T-cell receptor genes to target defined tumor-associated self-antigens and thereby form a clear incentive to test this immunotherapeutic approach in a clinical setting. IntroductionMajor histocompatibility complex (MHC) molecules present peptides on the cell surface irrespective of whether they are derived from foreign proteins or from self-proteins. Different tissue types within the body each express a unique set of proteins, and peptide epitopes derived from such tissue-specific proteins can in principle be used as tumor-rejection antigens. 1 However, because most of these tumor-associated antigens (TAAs) are nonmutated selfantigens, the T-cell repertoire specific for such antigens is generally small in size and low in avidity. Indeed, both preclinical studies and clinical trials have provided evidence that a lack of T cells with the required reactivity is a major factor limiting T-cell-based immunotherapy. For instance, murine studies have demonstrated that tumor-specific T-cell responses against foreign tumor-associated antigens can readily be induced by vaccination. However, when the same tumor-associated antigen is considered "self" by the available T-cell repertoire, reactivity to these antigens is highly reduced. 2,3 In line with this, replacement of the endogenous T-cell compartment through a combination of allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion (DLI) forms an effective treatment strategy for patients with hematologic malignancies such as chronic myeloid leukemia (CML). 4 Importantly, the antileukemic effect of allo-SCT/DLI is dependent on the recognition of minor histocompatibility antigens (MiHAgs) of the recipient as "nonself" by the infused donor lymphocytes, and the development of T-cell responses against such antigens is predictive of remission. 5 The effects of DLI following allo-SCT provide an excellent example of how an endogenous antigen can become foreign by introduction of a novel T-cell compartment and how recognition of endogenous antigens by this exogenous T-cell compartment is associated with remission. The major drawback of this treatment protocol is that the introduced T-cell reactivity against self...

Generation of T Cell Help through a MHC Class I-Restricted TCR

“…Previously, we have shown that gene transfer of MHC class I-restricted TCRs into CD8 ϩ T cells yields CTLs that strongly expand upon in vivo Ag encounter and that such cells can mediate tumor rejection in immunocompromised mice and break tolerance to defined self Ags (18,36). Collectively, the recent work by Morris et al (7) and our current experiments demonstrate that gene transfer of class I-restricted TCRs into postthymic CD4 ϩ T cells can be used to produce a pool of helper cells that can provide efficient help to CTLs in terms of expansion, tumor protection, and memory T cell formation in mice.…”

Long-Term Functionality of TCR-Transduced T Cells In Vivo

“…The in vivo function of TCR modified T cells has been studied extensively in mouse models. Data obtained in these studies indicate that both cytotoxic (6) and helper T cell compartments (7,8) with a defined Ag reactivity can be generated and these cells can expand to high numbers upon in vivo Ag encounter (6,9). Furthermore, infusion of TCR-modified T cells can be used to circumvent self-tolerance to defined self-Ags (9), including Ags expressed in spontaneous tumor models (M. de Witte, G. Bendle, M. van den Boom, M. Coccoris, T. Schell, S. Tevethia, E. Mesman, J.…”

“…The functionality of TCR-modified T cells during primary T cell responses in RIP-OVA high mice can be assessed by analyzing the development of type I diabetes as a consequence of destruction of pancreatic ␤ cells (9). Primary T cell responses in recipients of both TCR transgenic and TCR modified T cells resulted in destruction of insulin producing cells in 100% of the mice (data not shown).…”

“…To establish whether TCR-modified T cells that are specific for a self-Ag can also form a long-lived Ag-responsive T cell population, we examined secondary Ag responsiveness of OT-I TCR-transduced T cells in RIP-OVA high mice. In these mice, OVA is expressed in pancreatic ␤ cells and, as a consequence, endogenous CD8 T cell responses against the OVA 257-264 epitope are below the level of detection (9). RIP-OVA high mice were infused with OT-I TCR-transduced T cells and infected with rVV-OVA (Fig.…”

Blockade of TGF-β Signaling Greatly Enhances the Efficacy of TCR Gene Therapy of Cancer

“…Toward this goal, genetic modification of T cells with defined tumor-reactive TCR genes-an approach called TCR gene therapyhas been developed, first in mouse models (3,4) and more recently also in clinical trials (5)(6)(7). These clinical trials, primarily in patients with metastatic melanoma and synovial sarcoma, have demonstrated the feasibility of this approach, and in particular the targeting of the NY-ESO-1 Ag has shown encouraging clinical responses (7).…”