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Page 683 Gurska et al. Cancer Drug Resist 2023;6:674-87 https://dx.doi.org/10.20517/cdr.2023.39

immune checkpoint activation to suppress T cell responses, both on T cells and on AML cells themselves;
(3) induction of T cell exhaustion; and (4) the induction of an immunosuppressive environment by
increasing the numbers of regulatory T cells and other immunosuppressive populations in the bone marrow
to inhibit effector and cytotoxic T cell activity. All of these mechanisms ultimately promote AML cell
survival. This review complements several other recent review articles in this field, which illustrate the
importance of understanding the mechanisms of immune evasion in AML to overcome immunotherapy
resistance and improve AML outcomes [13,53,67-69] .

In our review of the current ICI landscape for hematologic malignancies, evident frustrations arise when
comparing the success of checkpoint inhibitors in solid tumors to the more limited progress made with
these agents in AML. The mechanisms highlighted above undoubtedly contribute to the slow adoption of
ICIs in AML. With many clinical trials underway in this space, continued research efforts identifying ways
to overcome immunotherapy resistance, such as combining ICIs with targeted therapies against
[70]
components of signaling pathways notoriously activated in AML, as seen in solid tumors , are warranted.
Furthermore, while not a major focus of this review, it remains a challenge to identify tumor-specific targets
for personalized immunotherapies for AML, such as CAR T cells and bispecific antibodies [71-73] .

While this review provides some insights into the roles of immune evasion mechanisms in relapse following
stem cell transplantation, as well as the clinical trials underway utilizing ICIs for this patient population, the
poor prognosis rates for AML patients who relapse after transplantation highlight the need for a review
focused on this specifically. Some groups have taken this initiative already, including a summary of the
current understanding of the downregulation of HLA molecules and inhibitory checkpoints between T cells
and AML cells . Additionally, recent insights into novel mechanisms by which an altered immune
[74]
landscape following transplantation – characterized by increased expression of TIGIT and CD161 within the
CD4+ T cell population post-transplantation – has begun to identify predictors of relapse . A more recent
[75]
review focuses on epigenetic mechanisms that underlie T cell evasion in the relapse post-transplant setting,
and is also a good source for this topic .
[76]

Lastly, this review does not cover the advances and limitations of emerging immunotherapy treatment
modalities in AML- notably chimeric antigen receptor (CAR) T- and NK-cell therapies, bispecific
antibodies, dual affinity re-targeting (DART) molecules, monoclonal antibodies, and antibody-drug
conjugates. While these agents are approved in other cancers [e.g., acute lymphocytic leukemia (ALL), non-
Hodgkin lymphoma (NHL) subtypes, and multiple myeloma (MM)], their adoption in AML has been slow,
due to the difficulty of finding AML-specific antigens that are not also expressed on HSCs or myeloid
progenitors. Furthermore, mechanisms of antigen escape, the AML immunosuppressive environment, and
the impaired quality of autologous cells are also potential problems with these approaches, as reviewed
elsewhere . Nonetheless, current clinical trials underway in relapsed/refractory AML include CD33, CD38,
[72]
CD123, and CD19 CAR-T cell therapies, allogenic CAR NK-cells, and CD33xCD3 and CD123xCD3
bispecific antibodies [11,41] .

Overall, as we continue to uncover the mechanisms underlying immune evasion in AML, exploiting these
mechanisms will be of high priority to unleash the potential of immunotherapy in this disease. This is
exemplified by the pivotal work done already, identifying a niche for immune checkpoint inhibitors after
[58]
observing increased checkpoint expression in AML cells following HMA treatment . Additionally, it will
be important to identify strategies to suppress regulatory T cell activity in AML to allow for the unleashing
of effector and cytotoxic and T cell activity. Thinking ahead, continued efforts to identify patient
populations at higher risk for immune evasion during available treatments or following stem cell