TCR gene therapy of leukemia

The power of adoptive immunotherapy with antigen-specific cytotoxic T lymphocytes (CTLs) was recently demonstrated in advanced-stage melanoma patients.¹  Antigen-specific immunotherapy of leukemia can be directed toward leukemia-specific antigens such as the products arising from translocations (eg, BCR/ABL) and mutations (eg, RAS), or against leukemia-associated self-antigens (eg, Wilms tumor antigen 1, proteinase 3, murine-double-minute 2 [MDM-2]) that are expressed at high levels in leukemic cells but also present in normal tissues. Following allogeneic stem cell transplantation, CTLs can also recognize leukemia-associated alloantigens, such as minor histocompatibility antigens (mHags) expressed in cells of the hematopoietic lineage (eg, HA-1, HA-2). While tolerance mechanisms are likely to blunt CTL responses against leukemia-associated self-antigens, they do not interfere with CTL responses against lineage-specific mHags. High-avidity donor CTLs can directly recognize and attack leukemia cells and patient hematopoietic cells, but spare patient non-hematopoietic tissues and donor hematopoietic cells. However, some mHags, such as the CTL-recognized HA-2 allele, are expressed in most humans, limiting immunotherapy options to rare HA-2-mismatched patient-donor combinations. In this issue, Heemskerk and colleagues (page 3530) demonstrate an elegant strategy that can, paradoxically, result in HA-2-specific CTL therapy in HA-2-matched patient-donor combinations.

This strategy takes advantage of TCR gene transfer and of the fact that T-cell receptor (TCR) recognition of HA-2 is HLA-A2 restricted. The genes encoding the TCR α and β chains were cloned from CTL clones isolated from a patient who received a rare HA-2-mismatched, HLA-identical transplant. Heemskerk et al demonstrated that retroviral vectors readily transferred the TCR genes and the HA-2 specificity to T cells of HLA-A2-positive individuals and, importantly, to T cells of HLA-A2-negative individuals. The TCR-transduced HLA-A2-negative CTLs specifically recognized the HA-2 peptide epitope presented by HLA-A2 class I molecules, indicating that the CTLs were HLA-A2 restricted. This provides a rationale for HA-2-directed immunotherapy of patients undergoing HA-2-matched, HLA-A2-mismatched stem cell transplantation. HA-2 specificity is created by TCR gene transfer into A2-negative donor T cells, and selective attack of patient hematopoietic cells, including leukemia cells, is achieved by the HLA-A2 restriction of the transferred TCR.

TCR gene transfer is a powerful new technology capable of producing antigen-specific CTLs without the need for prior antigen-specific immunization. In fact, as shown by Heemskerk et al, TCR gene transfer can be exploited to endow CTLs with novel specificities that are not present in the natural TCR repertoire. In the future, it will be possible to develop TCR gene therapy options that do not require allogeneic transplantation. For example, several technologies have been developed to bypass immunologic tolerance allowing isolation of high-affinity TCRs specific for leukemia-associated self-antigens.^2,3  The transfer of such TCRs into human CTLs has been reported,⁴  and experiments in mice have shown that TCR-transduced CTLs can eliminate tumor cells in vivo.⁵  It will be exciting to move, after appropriate risk assessment, to clinical studies with TCR-transduced CTLs in leukemia patients.