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Multiple malignancies showed incredible success with immunotherapy treatment. Immunotherapy for AML is now heavily researched being a highly promising strategy, particularly in transplant-ineligible patients and minimal residual disease states despite many challenges in treatment related to heterogeneous antigen expression, cytokine release syndrome and off target toxicities.
Abbreviations: AML: Acute Myeloid Leukemia; DCs: Dendritic Cells; NK: Natural Killer; PRAME: Preferentially Expressed Antigen in Melanoma; IR: Immune Response; CAR T cells: Chimeric-Antigen-Receptor T cells; LSA: Leukemia-Specific Antigens; LAA: Leukemia-Associated Antigens; PD-L1: Ligands for PD-1+ cells; HMA: Hypomethylating Agents;TCRtg: T-cell Receptor Gene-Transduced
Myeloid cells (dendritic cells, macrophages, granulocytes, and platelets) play central role in immunity. They are critical in activating and sustaining adaptive and innate immunity. Immature myeloid cells, which resemble AML blasts in many respects, as well as mature myeloid cells can suppress immunity and are key mediators of mature lymphocyte tolerance. Myeloid cells, particularly dendritic cells, localize to sites of B and T cell development where they tolerize lymphocyte precursors that recognize myeloid cell-associated antigens. AML also evade the host immune system through downregulation of non-self-human leukocyte antigen, resistance to NK cells, decrease antigenicity, production of their own DCs leading to T-cell neutralization and release ligands to block T cell attacks.
Immunotherapy (defined as the generation of an efficacious anti-tumor IR) has garnered much interest over the past several decades because it can destroy leukemic cells without the morbidity of a stem cell transplant. Immunotherapeutic intervention aimed to increase response rates to chemotherapy, converting minimal residual disease, bridging to HSCT and treating refractory or relapsed patients .
Antigen-specific immunotherapies targeting various cell surface proteins on leukemic myeloblasts and leukemic stem cells include anti-CD47 (NCT02678338), anti-CD25 (NCT02588092), anti-CD56 (NCT02420873), ipilimumab (i.e., anti-CTLA4) (NCT01757639), and nivolumab (i.e., anti-PD1) (NCT02464657, NCT02397720), are in development in clinical trials and have not reported any in-depth results. Vadastuximab talirine (SGN-CD33A) is a novel antibody-drug conjugate. Vadastuximab is a CD33-directed antibody conjugated to pyrrolobenzodiazepine dimer. Vadastuximab has remarkable clinical activity with no off-target toxicity as a single agent and with HMAs in elderly patients. So far, no conventional antibody has achieved
approval for the treatment of AML.
CARs are genetically engineered cell membrane-bound
receptors that combine extracellular antibody binding and
intracellular effector cell signaling, thereby enabling both MHC
independent antigen binding and highly potent cytotoxic effector
cell function. Multiple targets include CD33, CD123, FRB,
CLL1 or CLEC12A, FLT3, B7H6, NKG2D and Lewis y (LeY) are in
development for directed CART therapy in AML. The biological
heterogeneity of AML due to the different myeloid progenitors
from which it arises is a challenge with the development of
effective broad-spectrum CART for AML. Several strategies
are being explored to circumvent unwanted on target offleukemia
toxicity resulting from persistence of current CART cell
constructs beyond 4 years in the human body.
DC-based immunotherapy involves utilizing antigen-loaded
DCs to induce a Th1 response which, in turn, generates cytotoxic
T cells that target and lyse antigen-expressing tumor cells. In
addition, peptide-based vaccine approaches have also been
utilized to generate an antigen-specific IRs. Vaccines are
constructed from intact radiation inactivated AML cells, LAA or
through LSA.LSA, are antigens specific to a tumor but may
be expressed in only a minority of AML types (e.g., PML-RARA)
while LAA, are antigens, associated with a tumor type but may
be present on normal cell lines.AML cells express a multitude
of LAA, including WT-1, PRTN3, PRAME and hTERT. LSA are
preferred targets to prevent inadvertent destruction of normal
myeloid cell lines. LAA are more common but less specific,
potentially inducing systemic toxicity to normal myeloid lines.
Cancer vaccine would be given in conjunction with standard
chemotherapeutic regimens in the hope that they could prevent
relapse through targeting chemo-refractory cells such as stem
Immune checkpoints are inherent methods to the immune
system to prevent occurrence of autoimmunity. In normal
circumstances, the checkpoint molecules prevent crossreactivity
with self via T-cell receptor ligand binding and
resultant inhibition of T-cell function. Tumors express PD-L1
thereby inducing T-cell dysfunction, or increase indoleamine
2,3-dioxygenase, an enzyme which catabolizes tryptophan
leading to regulatory T cell formation. Long-term checkpoint
molecules overexpression can reduce anti-tumor effect of
Monoclonal antibodies against checkpoint molecules block
inhibitory signals like PD1 on T cells or PD-L1 on malignant
cells, allowing for release of the “brakes” of anti-leukemic T cells.
PD-1 seems to be upregulated on T-cells in relapsed and to some extent in newly diagnosed AML compared to healthy donors. The
available data on PD-L1 expression in AML is equivocal. HMA
may induce the expression of PD-1 and PD-L1 in T-cells and AML
cells, respectively. This is supported by failure of checkpoint
inhibitors monotherapy to produce a meaningful benefit for AML
patients whereas promising clinical results were demonstrated
with combination therapy with HMA. PD-L1 upregulation
on AML cells upon T-cell activation has been suggested as a
potential resistance mechanism in an ex vivo system.
Several T cell-recruiting antibody constructs are under
preclinical and early clinical development. The optimal antigen
to target is still an open question. Novel class of molecules
composed of the single-chain variable fragment of two antibodies
of different specificity connected by a short peptide linker.
AMG 330 is a bispecific T cell engager (BiTE) construct which
engages CD33 and CD3. In contrast to the BiTE technology,
dual-affinity re-targeting (DART) molecules are composed
of heavy and light chain variable domains of two antigenbinding
specificities (A + B) on two independent polypeptide
chains (VLA-VHB-VLB-VHA), which are stabilized through
an additional C-terminal bridge. XmAb14045, developed by
Xencor, is a structurally distinct anti-CD123 T cell-recruiting
antibody construct in early clinical development. Addition of
a checkpoint inhibitor to T-cell recruiting antibodies might help
to circumvent resistance.
This is based on an ex vivo generation of TCR-gene
transduced T-cells using a retroviral vector. They target a
degraded, processed and presented antigen in the context of
HLA molecules on the surface of the malignant cell. WT1 is
the dominant antigen for TCRtg based immunotherapeutic
strategies. Very limited data has been published on adoptive
transfer of TCRtg cells in AML patients.
Based on drastic alteration in NK activity in leukemic
conditions, multiple immunotherapeutic strategies directed
at enhancing effective NK cell function are being prospectively
evaluated as AML therapy. Approaches to enhance the clinical
efficacy of allogeneic NK cells include: using NK cells in
conjunction with allogeneic stem cell transplant; improving
delivery of a diverse NK cell repertoire and/or functional
subsets; activation or priming of NK cells to induce greater anticancer
activity; and generation of autologous NK cells with CART
a. Identifying suitable intracellular and surface target
antigens.In AML, it is more difficult to choose an appropriate target antigen due to heterogeneous tumor
antigen expression in diverse AML subtypes and a more
ubiquitous expression pattern overlapping with healthy
b. Myeloid-associated lineage antigens like CD33
(expressed on >30% of healthy bone marrow cells), 
CD123, CLL-1 and FLT3 are also expressed within the
healthy myeloid compartment so Off-target toxicities to
normal myeloid progenitor and hematopoietic stem cells
may occur. It is expected that targeting AML-associated
antigens will result in prolonged drug-induced cytopenias
as well as life-threatening cytokine release syndrome and
neurological events. This will require the adjustment of
current protocols applied in ALL to the different setting in
AML. Various potential target antigens are studied for each
of the immunotherapeutic strategies.
c. Immune cell exhaustion.
d. Life-threatening complications of potent immune
e. Low endogenous immune responses in AML.
f. Intrinsic resistance mechanisms of the leukemic blasts
against immune response.
g. High tumor burden and clonal evolution of tumor cells
Immunotherapy in AML will induce the best treatment
responses for minimal residual disease eradication after
induction chemotherapy. The optimal time point for
immunotherapeutic intervention is poorly defined.