Research Topic

Genetic Variants as Targets for Immunotherapy of Hematological Tumors

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Over the past decades, patients with leukemia and other hematological malignancies have been successfully treated with allogeneic hematopoietic stem cell transplantation. The anti-tumor effect of this treatment is mediated by donor T cells targeting HLA-peptide complex disparities between patient and donor. ...

Over the past decades, patients with leukemia and other hematological malignancies have been successfully treated with allogeneic hematopoietic stem cell transplantation. The anti-tumor effect of this treatment is mediated by donor T cells targeting HLA-peptide complex disparities between patient and donor. These differences are encoded in the germline and thus ubiquitously present on patient cells. Therefore, donor T cells targeting polymorphic HLA-peptide complexes after allogeneic stem cell transplantation cause not only beneficial anti-tumor or Graft-versus-Leukemia (GvL) reactivity, but also respond against healthy tissues leading to undesired Graft-versus-Host-Disease (GvHD).

Germline polymorphisms that are targeted after allogeneic stem cell transplantation can reside in genes encoding the HLA surface molecule or in genes encoding its presented peptide. Donor T cell responses against patient-specific mismatched HLA alleles are often very strong, thereby causing severe GvHD and negatively affecting treatment outcome. Therefore, to limit GvHD, patients are preferably transplanted with HLA-matched donors. After HLA-matched allogeneic stem cell transplantation, allogeneic donor T cell responses still exist, targeting polymorphic peptides presented by HLA molecules that are shared between patient and donor. In 1995, the first polymorphic HLA-binding peptide or minor histocompatibility antigen was identified. Since then, the discovery and knowledge of minor histocompatibility antigens and their specific T cells rapidly accelerated. This knowledge has proven to be essential to understand and manipulate the delicate balance of GvL and GvHD after allogeneic stem cell transplantation.

The characterization of minor histocompatibility antigens also illustrated that cancer can be cured by T cells targeting HLA-binding peptides encoded by genetic variants that are absent in the thymus where the T cells have been educated. This has been confirmed by the finding that neoantigens, which are HLA-binding peptides created by somatic mutations, can be targeted in non-transplanted cancer patients. T cells recognizing neoantigens have a high affinity and strong capacity to selectively kill tumor cells over healthy cells. Moreover, immunotherapy induced or stimulated neoantigen-specific T cells, which are often found in patients with a high number of somatic mutations in their cancer cells, can induce long-term clinical remissions. Although hematological malignancies often have a low mutational load, neoantigens can be presented on these tumors and provide attractive targets for immunotherapy. Their relevance as immunotherapeutic targets have recently been demonstrated by the isolation of a T cell receptor for mutant NPM1. NPM1 is mutated in 30-35% of patients with acute myeloid leukemia and the T cell receptor can be used to specifically target leukemic cells and treat these patients with gene therapy.

We welcome Original Research, Review, Method, Systematic Review, Mini-Review, Hypothesis and Theory, Perspective, Clinical Trial, Case Reports, Classification, Opinion and Technology & Code articles that cover the following themes:

1. Prediction and discovery of minor histocompatibility antigens.
2. Detection and manipulation of T cells for minor histocompatibility antigens.
3. Prediction and discovery of neoantigens on hematological malignancies.
4. Detection and stimulation of T cells for neoantigens on hematological malignancies.
5. Association of minor histocompatibility antigens or neoantigens with disease or treatment response.


Keywords: minor histocompatibility antigens, neoantigens, hematological malignancies, allogeneic stem cell transplantation, immunotherapy


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