Strategies for the identification of T cell-recognized tumor antigens in hematological malignancies for improved graft-versus-tumor responses after allogeneic blood and marrow transplantation

Abstract

Allogeneic blood and marrow transplantation (allo-BMT) is an effective immunotherapeutic treatment that can provide partial or complete remission for patients with hematological malignancies. Mature donor T cells in the donor inoculum play a central role in mediating graft-versus-tumor (GVT) responses by destroying residual tumor cells that persist after conditioning regimens. Alloreactivity towards minor histocompatibility antigens (miHA), which are varied tissue-related self-peptides presented in the context of major histocompatibility complex (MHC) molecules on recipient cells, some of which may be shared on tumor cells, is a dominant factor for the development of GVT. Potentially, GVT can also be directed to tumor-associated antigens or tumor-specific antigens that are more specific to the tumor cells themselves. The full exploitation of allo-BMT, however, is greatly limited by the development of graft-versus-host disease (GVHD), which is mediated by the donor T cell response against the miHA expressed in the recipient's cells of the intestine, skin, and liver. Because of the significance of GVT and GVHD responses in determining the clinical outcome of patients, miHA and tumor antigens have been intensively studied, and one active immunotherapeutic approach to separate these two responses has been cancer vaccination after allo-BMT. The combination of these two strategies has an advantage over vaccination of the patient without allo-BMT because his or her immune system has already been exposed and rendered unresponsive to the tumor antigens. The conditioning for allo-BMT eliminates the patient's existing immune system, including regulatory elements, and provides a more permissive environment for the newly developing donor immune compartment to selectively target the malignant cells. Utilizing recent technological advances, the identities of many human miHA and tumor antigenic peptides have been defined and are currently being evaluated in clinical and basic immunological studies for their ability to produce effective T cell responses. The first step towards this goal is the identification of targetable tumor antigens. In this review, we will highlight some of the technologies currently used to identify tumor antigens and anti-tumor T cell clones in hematological malignancies.

Keywords: Blood and marrow transplantation; Hematological malignancy; Minor histocompatibility antigens; Tumor vaccination; Tumor-associated antigens; Tumor-specific antigens.

Figure 1

Schematic representation of a forward immunology method for the identification of miHA as tumor targets. Panel (A-1): Identification and expansion of T cell clone with strong GVT/GVHD reactivity. Panel (A-2): The reactive T cell clone is then scanned against a cDNA library with EBV-LCL from CEPH families to identify the cDNA clone eliciting cytotoxic activity. Genetic linkage analysis is performed on this cDNA clone to identify genes encoding the potential tumor miHA. Panel (B): Preparation of cDNA library from patient-derived tumor cells or from EBV-LCL from CEPH families. Current methods for the production and expansion of T cell clones are discussed in more detail in the “Production of bulk T cells as a tool for discovery of TAA” section of this review.

Figure 2

Schematic representation of reversed immunological methods to determine miHA peptides. Steps for determining and validating miHA epitopes eliciting relevant antitumor T cell activity are depicted in this figure. A first phase of computational prediction determines a number of putative epitopes, which are then confirmed experimentally for their capacity to induce an in vivo T cell response.