. Author manuscript; available in PMC: 2015 Dec 15.

Published in final edited form as: Clin Cancer Res. 2014 Oct 16;20(24):6233–6241. doi: 10.1158/1078-0432.CCR-14-0900

Table 2.

Select Immunotherapeutic Strategies

Target	Agent	Mechanisms/Studies in AML
*Inhibitory pathways*
*CD28/B7 family receptors*
CTLA-4 (Cytotoxic T lymphocyte antigen-4)	Ipilimumab^*	CTLA-4 blockade enhances AML-specific T cell responses; CTLA-4 polymorphism associated with relapse (65, 66). ^*Clinical study in relapsed AML and after alloHSCT.
PD-1 / PD-L1 (Programmed death-1)	Nivolumab, MK-3475^, CT-011^, MEDI0680 BMS-936559, MEDI4736, MPDL3280A	PD-L1 is expressed on AML blasts ; PD-1 expression increased on circulating T cells in leukemia patients; leukemia -specific T cell immunity and survival upon AML challenge increased in PD-1 knockout mice or upon PD-L1 blockade (61, 69, 70). ^*Clinical study of CT-011 and vaccine; and MK-3475 in MDS.
*non-CD28/B7 family receptors*
LAG-3 (Lymphocyte activation gene-3)	BMS-986016, IMP321	No studies in AML.
TIM-3/ galectin-9 (T cell immunoglobulin domain and mucin domain 3)	mAb, TIM-3 fusion protein	Galectin-9 is expressed on AML cells; co- expression of TIM-3 and PD-1 identifies exhausted T cells in mice with advanced AML and increases during AML progression; combined blockade of TIM- 3/ PD-L1 had an additive effect in improving survival of AML-bearing mice(77).
Inhibitory enzymes
IDO (Indoleamine 2,3-dioxygenase)	INCB024360^*, indoximod, NLG919	IDO overexpressed in AML cells, predicts poor prognosis, depletes tryptophan, thus, limiting T cell proliferation and stimulating Tregs accumulation. (78–80) ^*Clinical study in MDS.
Targeting T regs	CD25 (Basiliximab^, Daclizumab, denileukindiftitoximmunotoxin); Metronomic* cyclophosphamide; Immunomodulatory drugs (Pomalidomide^* Lenalidomide^, Thalidomide); Fludarabine*	^*Several clinical studies of anti-CD25 plus vaccine and chemotherapy plus immunomodulatory drugs ongoing in AML.
Targeting NK cells
KIR(Killer-cell immunoglobulin-like receptors) CD200 / CD200R	^*Anti-KIR Ab (IPH2101, lirilumab) mAb (anti-CD200)	^*Phase I, II clinical studies-maintenance in older AML patients (81). CD200 is overexpressed in AML cells, correlates with poor prognosis, increases BM Tregs and directly inhibits the cytotoxic activity of NK cells (82, 83).
CD123/CD33/CD16	Triplebody (SPM2)	Increased patient's NK cell cytolytic activity against AML cells ex vivo (84).
CD16 X CD33	CD16xCD33 bispecific killer cell engager (BiKE)	Reversed MDSC (myeloid-derived suppressor cell) immunosuppression of NK cells and induced CD33+ MDS and MDSC target cell lysis ex vivo (85).

Denotes therapeutics in clinical studies in AML and MDS.