In a couple of previous posts I wrote about investigators who harnessed concepts derived from the study of evolution to generate therapeutic agents, in one case for a viral infection (2009a) and in another case for cancer (2009b). Below, I discuss a study from 2009 that illustrates how evolution of cellular populations can undermine treatment for acute myeloid leukemia or myelodysplastic syndrome, serious conditions affecting the hematopoietic system.
Vago et al. studied patients with the conditions cited above who had undergone haploidentical hematopoietic stem cell transplantation from related donors and, in addition, infusion of donor T cells. In this context, “haploidentical” refers to the sharing of HLA class I and class II alleles at all of the loci located in the relevant region on either a maternal or paternal chromosome 6 (i.e., a shared haplotype). Typically, there are one or more HLA allele mismatches at the non-shared parental chromosome 6 (i.e., a non-identical haplotype). In other words, for this kind of transplant, the recipient typically shares one of two HLA haplotypes with the donor and has different alleles at one or more loci on the unshared haplotype.
Such transplants plus lymphocyte infusions offer the prospect of restoring the bone marrow function that is damaged in the pre-transplant therapeutic attack on the malignant cells of the recipient as well as providing a beneficial immune response against any residual tumor cells (graft-versus-leukemia effect). Another way to describe this latter aspect of the therapy is to say the donor T cells select against the remaining malignant cells that express unique recipient HLA molecules (encoded by the pertinent loci associated with the recipient HLA haplotype that is not shared with the donor).
Of course, when selection is strong, one should not be surprised if unusual genetic events come to attention by virtue of their ability to reduce or eliminate that selection. Vago et al. studied five patients treated by haploidentical hematopoietic stem cell transplantation from related donors such that donor T cells were part of the initial transplant inoculums or were separately infused later. In each of these patients there was a relapse, and blast cells reappeared in the peripheral blood. What was particularly interesting about these resurgent leukemia cells is that they now failed to express the HLA class I and class II molecules uniquely associated with the recipient.
Analysis of relevant genetic markers by multiple methods revealed that in the blast cells from each of these victims of relapse, the region on the short arm of chromosome six that contained the recipient-specific alleles at the HLA class I and class II loci had been replaced by genes encoding the alleles shared between the recipient and the donor (uniparental disomy of part of chromosome 6). It was clearly established that the blast cells were of recipient origin. Immunological testing revealed that the donor T cells that had been able to respond to and kill the leukemic blasts present at diagnosis were no longer able to recognize or kill the blast cells obtained during relapse.
Thus, the authors of this study present a good case for the selection of rare genetic variants of hematologic cancer cells by T-cell-mediated immunity. Previous studies have shown in both experimental animals (Zheng et al., 1999; Garcia-Lora et al., 2001; Garcia-Lora et al., 2003) and patients (Restifo et al., 1996; reviewed in Khong and Restifo, 2002) that T cells can select for escape variants among solid tumor cells.
The 5 patients exhibiting loss of HLA heterozygosity represented 29% of the 17 patients who suffered relapse in their overall study group. Apparently, other mechanisms contribute to relapse in this clinical context. The contribution of genomic instability to the process by which the variants were generated was not experimentally addressed, but remains an area for further investigation. It has previously been documented that somatic genetic events can result in partial uniparental disomy in myeloid malignancies (Rhagavan et al., 2005; Gorletta et al., 2005; Dunbar et al., 2008; Rhagavan et al., 2008).
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