Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors.

Abstract

Regressions of metastatic solid tumors after allogeneic human leukocyte antigen (HLA)-matched stem cell transplantation (SCT) are often associated with detrimental graft-versus-host disease (GVHD). The graft-versus-host reaction of the HLA-matched donor is directed mainly against the multiple mismatched minor histocompatibility antigens (mHags) of the patient. mHags are strong HLA-restricted alloantigens with differential tissue distribution. Ubiquitously expressed mHags are the prime in situ targets of GVHD. The mHag HA-1 is hematopoiesis restricted, but displays additionally an aberrant expression on solid tumors. Thus, HA-1 might be an excellent target to boost the anti-solid tumor effect of allogeneic SCT without inducing severe GVHD. Here, we show that cytotoxic T lymphocytes (CTLs) solely targeting the human mHag HA-1 are capable of eradicating 3-dimensional human solid tumors in a highly mHag-specific manner in vitro, accompanied by interferon-gamma release. In vivo, HA-1-specific CTLs distribute systemically and prevent human breast cancer metastases in immunodeficient mice. Moreover, HA-1-specific CTLs infiltrate and inhibit the progression of fully established metastases. Our study provides the first proof for the efficacy of a clinically applicable concept to exploit single mismatched mHags with hematopoiesis- and solid tumor-restricted expression for boosting the anti-solid tumor effect of allogeneic SCT.

• Authors: Lothar Hambach, Marcel Vermeij, Andreas Buser, Zohara Aghai, Theodorus van der Kwast, Els Goulmy
• Journal: Blood (Blood) Vol. 112 Issue 5 Pg. 1844-52 (Sep 01 2008) ISSN: 1528-0020 [Electronic] United States
• PMID: 18544677 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HA-1 antigen
• Minor Histocompatibility Antigens
• Oligopeptides

Topics

• Animals
• Cell Line, Tumor
• Female
• Graft vs Tumor Effect
• Humans
• Immunotherapy, Adoptive
• Lung Neoplasms (immunology, pathology, prevention & control, secondary)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Minor Histocompatibility Antigens (metabolism)
• Neoplasms (immunology, pathology, therapy)
• Oligopeptides (metabolism)
• Stem Cell Transplantation
• T-Lymphocytes, Cytotoxic (immunology)
• Transplantation, Homologous