Clinical phase 1/2 studies exploring the efficacy and toxicity of adoptive transfer of mHAg-specific T cells are essential to evaluate the applicability, potential risks, and benefits of specific cellular immunotherapy in the context of allogeneic stem cell transplantation for the treatment of hematologic cancers.

Cellular immunotherapy with donor-derived T cells recognizing specific antigens on the malignant cells from the patient is one of the major advantages of allogeneic hematopoietic stem cell transplantation over autologous stem cell transplantation in the treatment of hematologic cancers. Treatment of patients who relapse with leukemia, lymphoma, or multiple myeloma after allogeneic transplantation with donor T cells has illustrated that cellular immunotherapy can lead to complete eradication of cancer cells, resulting in cure of the disease.1 

In the nontransplantation situation, an immune response from donor T cells recognizing alloantigens on hematopoietic cells from the patient will lead to destruction of the patient's hematopoietic system. If the malignant counterpart of these cells also expresses these alloantigens on their cell membrane, this immune response will also eradicate hematopoietic cancer cells. In contrast, donor-derived hematopoiesis after transplantation will be left unharmed, because donor-derived T cells have been educated in the donor to recognize donor hematopoiesis as “self” tissue. This graft-versus-leukemia/lymphoma (GVL) or graft-versus-tumor (GVT) reactivity is the major beneficial effect of allogeneic stem cell transplantation. Characterization of hematopoiesis-restricted alloantigens that can be targeted in GVL reactivity may allow more specific and effective cellular immunotherapy.

After HLA-matched stem cell transplantation, donor-derived T cells can recognize polymorphic peptides presented in the context of (self-)HLA molecules as foreign antigens. Because the human genome contains a broad variety of single nucleotide polymorphisms (SNP) resulting in small differences in amino acid sequences of many proteins, processing of these polymorphic stretches of amino acids that differ between the donor and recipient can lead to strong immune responses. Polymorphic peptides that can be recognized in the context of (self-)HLA molecules are defined as minor histocompatibility antigens (mHAgs).2  From an evolutionary standpoint, this mHAg-specific immune response mimics the recognition of virus-derived foreign peptides presented in the context of self-HLA molecules and this provides a clear rationale for the strong avidity of T cells for these antigens. Donor-derived T cells recognizing mHAgs on recipient malignant cells are capable of mediating a strong GVL response.3  Unfortunately, donor T cells recognizing polymorphic peptides presented on normal nonhematopoietic tissues from the recipient can also mediate graft-versus-host disease (GVHD), which is the main cause of morbidity and mortality after transplantation.2,4  Treatment of patients with unmodified donor lymphocyte infusion (DLI) after transplantation may lead to cure of the disease but at the risk of severe GVHD. Separation of GVL reactivity from GVHD would improve cancer therapy in the context of hematopoietic stem cell transplantation with no or limited toxicity. Previously, the potential effectiveness of in vitro–selected and –expanded virus-specific T cells has been illustrated.5  Infusion of ex vivo–selected and –expanded T cells recognizing (leukemic) hematopoietic cells from the patient, but not nonhematopoietic cells, is being explored to more effectively provide GVL reactivity.6,7 

As reported in this issue of Blood, Warren and colleagues have explored the adoptive transfer of T cells selected ex vivo to recognize minor histocompatibility antigens for the treatment of patients with relapsed leukemia after allogeneic hematopoietic stem cell transplantation.8  By selecting T cells that recognize mHAgs preferentially expressed on recipient hematopoietic cells, they attempted to separate GVL reactivity from GVHD. Recognition of hematopoietic cells from recipient origin and absence of recognition of skin fibroblasts were evaluated as the criteria for selecting T-cell responses that do not elicit GVHD. They evaluated whether in vitro expansion of such mHAg-specific T cells to large numbers was feasible and could lead to in vivo persistence and migration of the cells to the bone marrow, resulting in a specific therapeutic effect.

The authors demonstrate that despite the logistic complexity of in vitro isolation, characterization, and expansion of clonal mHAg-specific T cells, they were capable of generating therapeutic doses of T cells, resulting in a strong biologic effect in patients. Unfortunately, the selection criteria did not result in the prevention of GVHD. Pulmonary toxicity was the most frequent sign of undesired GVHD, illustrating that more stringent selection of the right specificity is necessary, which was further substantiated by successful molecular characterization of some of the mHAgs. Although the side effects were obviously disappointing, the authors demonstrate in their paper proof of principle that antigen-specific T cells can be isolated, expanded, and infused and can elicit a clinical effect. The antileukemic effects unfortunately did not persist, possibly due to exhaustion of the T cells resulting in relatively short in vivo survival.

The clinical study of Warren and colleagues is an important study that demonstrates the feasibility of adoptively transferring in vitro–selected and –expanded mHAg-specific T cells in the context of allogeneic stem cell transplantation. Combining various strategies—for example, first depleting alloreactive T cells from the graft (T-cell depletion), followed by administration of more stringently selected T cells recognizing mHAgs specifically expressed on hematopoietic cells—and better selection of T-cell subsets as previously suggested by the authors9  may lead in the future to separation of GVL from GVHD and better outcome of allogeneic hematopoietic stem cell transplantation.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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