Memory T cells from minor histocompatibility antigen–vaccinated and virus-immune donors improve GVL and immune reconstitution

Abstract

IntroductionAllogeneic hematopoietic stem cell transplantation (alloSCT) can be a curative therapy for patients with hematologic malignancies. Mature donor T cells in the allograft are critical for reconstituting T-cell immunity in recipients and mediate an alloimmune antileukemia/lymphoma effect called GVL. In MHC-matched alloSCT, alloimmune T cells target minor histocompatibility antigens (miHAs), which are peptide products of polymorphic genes that distinguish hosts from donors. 1 Unfortunately, alloreactive T cells also attack normal host tissues, causing GVHD. A longstanding and elusive goal in the alloSCT field has been to develop approaches that preserve GVL and immune reconstitution while minimizing GVHD. A second challenge has been how to augment GVL to overcome GVL resistance, as cancer relapse is the single greatest cause of death after transplantation. 2 The risk of relapse is not spread evenly across cancer types. Some malignancies, such as chronic-phase chronic myelogenous leukemia (CP-CML), are extremely GVL sensitive, 3 whereas other types of leukemias, such as blast-crisis CML (BC-CML) and acute myelogenous leukemia, are relatively GVL-resistant. 3,4 One approach for improving GVL would be to broadly augment the alloimmune response by reducing the intensity of immunosuppression. However, this increases the risk for serious and lifethreatening GVHD. 5 Another strategy has been to develop T-cell therapies with a single target specificity, such as those that recognize a single miHA, with the idea that such T cells could augment GVL with a reduced risk for inducing GVHD. 1,6 These T cells can be clonal, polyclonal, or genetically modified to express defined antigen receptors. 7,8 Although there are some promising results, 9,10 such approaches have not yet been widely applied. Transferred cells have in general not survived well in vivo, perhaps because they were activated effectors. In addition, these methodologies are labor intensive and require technical expertise and facilities not available at most centers.We reasoned that an alternative to T-cell engineering would be to increase the frequency of allograft T cells that mediate GVL by vaccinating donors against a single miHA. There is evidence that functional T-cell memory against miHAs can be generated in vivo in humans. [11][12][13] GVHD is increased when donors are multiparous, 12 presumably because of priming against fetal miHAs. Blood transfusion of even aplastic anemia patients increases the risk of HLA-matched allograft rejection. 13 If donors could be vaccinated against single miHAs, then the selective transfer of donor memory T cells (T M ) could improve GVL. T M generated in the donor by prior pathogen infection would also be transferred, thereby augmenting immune reconstitution.In the present study, we show that miHA vaccination of donors greatly increases CD8 ϩ T M -mediated GVL against GVL-sensitive mouse CP-CML (mCP-CML) 14 and GVL-resistant mouse BC-CML (mBC-CML) 15 induced by bcr-abl or bcr-abl and NUP98/ HOXA9 fusion cDNAs, respec...

Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell grafts

“…Subjects received CD34-selected PBSCs and a defined dose of T M purged of CD45RA induced milder GVHD, and T EM did not cause significant GVHD (17)(18)(19)(20)(21)(22)(23). Importantly, T M transferred antipathogen immunity and had GVL activity in these models (17,22,24). Mechanistic studies demonstrated that TCR repertoire-independent and -dependent differences between T N and T M subsets contributed to differences in GVHD induction (20,(25)(26)(27).…”

MHC I–associated peptides preferentially derive from transcripts bearing miRNA response elements

“…Polymorphic MIPs, commonly referred to as minor histocompatibility antigens, are important in hematology because they elicit GVHD and the GVL effect after allogeneic hematopoietic cell transplantation. [33][34][35][36] The most common form of polymorphism is the single nucleotide polymorphism (SNP). We used software developed in-house (pyGeno) to estimate the frequency of SNPs (SNPs/bps) in the MIP-coding DNA sequences and compared it with the SNP frequency in the human exome (Table 1).…”

Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity

“…mCP-CML and mBC-CML are therefore excellent phenocopies and genocopies of their human counterparts, have defined stem cell populations (15,23), and, importantly, are GVL sensitive and GVL resistant, respectively (11). A powerful advantage of this approach is that, by transducing BM from gene-deficient mice, we can create gene-deficient leukemias as a means to explore mechanisms of GVL resistance (10,11,(24)(25)(26). Using these systems, we found that GVL against mCP-CML and GVL against mBC-CML share essential features: (a) both leukemias must express ICAM1; (b) T cell killing mechanisms are highly redundant; and (c) CD8…”