Dissecting graft-versus-leukemia from graft-versus-host-disease using novel strategies

Abstract

The intrinsic anti-leukemic effect of allogeneic hematopoietic cell transplantation (HCT) is dependent on genetic disparity between donor and recipient, intimately associated with graft-versus-host disease (GVHD), and mediated by lymphocytes contained in or derived from the donor hematopoietic cell graft. Three decades of intense effort have not identified clinical strategies that can reliably separate the graft-versus-leukemia (GVL) effect from the alloimmune reaction that drives clinical GVHD. For patients who require HCT and for whom two or more human leukocyte antigen (HLA)-A, -B, -C, and -DRB1-matched donor candidates can be identified, consideration of donor and recipient genotype at additional genetic loci both within and outside the major histocompatibility complex may offer the possibility of selecting the donor [candidate(s)] that poses the lowest probability of GVHD and the highest probability of a potent GVL effect. Strategies for engineering conventional donor lymphocyte infusion also hold promise for prevention or improved treatment of post-transplant relapse. The brightest prospects for selectively enhancing the anti-leukemic efficacy of allogeneic HCT, however, are likely to be interventions that are designed to enhance specific antitumor immunity via vaccination or adoptive cell transfer, rather than those that attempt to exploit donor alloreactivity against the host. Adoptive transfer of donor-derived T cells genetically modified for tumor-specific reactivity, in particular, has the potential to transform the practice of allogeneic HCT by selectively enhancing antitumor immunity without causing GVHD.

Figure 1

Actuarial probability of relapse among 2,254 recipients of allogeneic BMT from HLA-identical sibling donors transplanted for CML in first chronic phase, ALL in first remission, or AML in first remission, according to the type of graft and the development of acute or chronic GVHD. Reproduced with permission from Horowitz et al. (3).

Figure 2

(A) Map of genetic loci that can influence histocompatibility in the allogeneic HCT setting. The chromosomal location of the MHC, and of two other multigene clusters, the NKC and the KIR locus, are indicated by red labels and arrowheads to the left of the corresponding chromosomes. The chromosomal locations of genes that have been shown to encode T lymphocyte-defined minor histocompatibility antigens are indicated by labels and arrowheads to the right of the corresponding chromosomes; genes that encode class I MHC-restricted minor H antigens recognized by CD8⁺ T cells are indicated by black labels, those that encode class II MHC-restricted minor H antigens recognized by CD4⁺ T cells are indicated by green labels, and those that encode both class I- and class II MHC-restricted minor H antigens are indicated by blue labels.

Figure 3

Basic organization and gene content of the human KIR locus on chromosome 19q. Two hypothetical haplotypes are illustrated: an A (top) and a B (bottom) haplotype. Framework genes (which can be coding genes or pseudogenes) are illustrated in blue; non-framework activating genes are in green, inhibitory genes in red, and pseudogenes in purple. Adapted from http://www.ebi.ac.uk/ipd/kir/sequenced_haplotypes.html.

Figure 4

Reciprocal relationship between the intensity of conditioning regimens that have been used for allogeneic HCT and the required antileukemic contribution from the GVL effect to achieve a comparable rate of posttransplant relapse. The relative degree of tissue injury typically observed with each regimen is also indicated. TBI and tbi: total body irradiation; BU: busulfan; CY: cyclophosphamide; FLU: fludarabine; AraC: cytarabine; ATG: anti-thymocyte globulin.