Autologous T cells on the attack against AML

In this issue of Blood, Greiner and colleagues describe how peptides derived from the mutated nucleophosmin 1 gene (NPM1^mut) can elicit in vitro CD4⁺ and CD8⁺ T-cell responses in patients with acute myeloid leukemia, which can lead to antigen-specific lysis of leukemic blasts.¹ 

Acute myeloid leukemia (AML) with normal karyotype is a heterogeneous entity with regard to prognosis. The cases with NPM1^mut but without the FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD^neg) have a better prognosis. This may be related to the specific immune response that the mutated NPM1 can elicit in AML patients. At first sight, it is difficult to believe that the immune system can offer protection against such an overwhelming disease as AML. Yet, clinical evidence for a T-cell response against AML has come from allogeneic hematopoietic stem cell transplantation, where it is clear that allogeneic T cells in the transplant and in donor lymphocyte infusions can bring about a graft-versus-leukemia effect. Evidence for the importance of an autologous T-cell response against AML has come from the tumor vaccination field. Vaccination against the leukemia-associated antigens²  Wilms tumor protein 1 (WT1),^3-6  PR1 (derived from proteinase 3),⁴  and receptor for hyaluronic acid–mediated motility (RHAMM)⁷  can bring about clinical antileukemic effects in AML. The clinical response was generally correlated with the T-cell responses elicited.^3,4,6  Loss of clinical response has been reported to be associated with decrease or loss of specific T-cell immunity.

But can an antileukemic immune response be elicited in patients not receiving immunotherapy? The answer comes from a vast body of work, demonstrating that, contrary to general belief, certain chemotherapeutic agents can augment immune responses against tumors.⁸  Chemotherapy thus not only has direct cytotoxic effects on cancerous cells, but can also boost the immunity against them by different mechanisms, including stimulating tumor antigen presentation by dendritic cells to cytotoxic T lymphocytes. This is particularly true of anthracyclines, still the mainstay of treatment of AML, which have been demonstrated to be a prototype of immunogenic chemotherapy.⁹  It was already known for a while that the antitumoral effect of doxorubicin in certain animal models was strongly reduced if the immune system was not functioning properly.

In the case of NPM1^mut AML, especially if it is also FLT3-ITD^neg, the autologous T-cell response induced by the mutated NPM1 could bring about a significant antileukemic effect directly after chemotherapy (figure panels A and C). At this stage, the number of leukemic cells would significantly be reduced, the immune response could be strengthened, and the stimulated anti-NPM1^mut cytotoxic T lymphocytes could mount a final attack against the remaining leukemic cells. This could account for the cures seen with chemotherapy alone in NPM1^mut AML. But not all patients with NPM1^mutFLT3-ITD^neg AML are cured by chemotherapy alone. The findings by Greiner et al theoretically suggest the possibility that postremission immunotherapy directed against NPM1^mut could induce cures and/or longer-lasting remissions in this type of AML and maybe even in NPM1^mutFLT3-ITD^pos AML, especially if there is molecular evidence of residual disease.

An additional potential advantage of the T-cell immune response directed against certain leukemia antigens is that it may also be directed against the leukemic stem cells.²  Leukemic stem cells are relatively resistant to chemotherapy,¹⁰  accounting at least in part for the (minimal) residual disease persisting after cytotoxic treatment in a majority of AML cases (figure panel B). The chemotherapy resistance of minimal residual disease has led to the development of another type of postremission treatment, that is, immunotherapy, to try to definitively cure AML patients (figure panel D). NPM1^mut, a leukemia-specific antigen,²  is expressed in leukemic stem cells,¹¹  making those cells vulnerable to immune eradication, as discussed above.