Targeting Multiple-Myeloma-Induced Immune Dysfunction to Improve Immunotherapy Outcomes

Table 1

Immune suppressive circuits and molecular targets for immunotherapeutic approaches in MM. The mechanisms of immune evasion mediated by MM cells and the currently available strategies to target them are summarized.

Determinant(s) of immune dysfunction	Effect(s) on antimyeloma immune responses	Target(s) for intervention	Immunotherapeutic strategy	Phase of development (either pre-clinical or clinical)	Reference(s)
Secretion of proangiogenic cytokines within the MM microenvironment	-Induction of tolerogenic DC; -Induction of IDO1		Anti-HGF antibodies	Not yet into the clinic for MM	[27, 28]
			MET inhibitors	Not yet into the clinic for MM	[29]
		HGF	Anti-MET antibodies	Not yet into the clinic for MM	[30]
			NK4 (HGF antagonist)	Not yet into the clinic	[31, 32]
		VEGF	Bevacizumab	Phase II, randomized	[33]
Expansion of CD25^+Foxp3^+ Treg cells	Inhibition of antimyeloma immunity	CD25	-Denileukin Diftitox (ONTAK); -CTLA4-Ig	Not yet into the clinic for MM	[34]
Enhanced tryptophan catabolism	Inhibition of antimyeloma immunity	IDO1	IDO1 chemical inhibitors	Not yet into the clinic for MM	[35, 36]
Expression of co-inhibitory receptors and other immune suppressive molecules	Expansion of Treg cells and inhibition of antimyeloma immunity	PD-L1	Anti-PD-1 antibodies (CT-011)	Pre-clinical	[15, 16]
		TGF-β	Anti-TGF-β antibodies	Not yet into the clinic	[37]
		IL-10	Anti-IL-10 antibodies	Not yet into the clinic	[38]
DC dysfunction	Inhibition of antimyeloma immunity	-MUC1; -Other MM antigens	DC/myeloma fusion cells	Phase I	[39]
Weak immunogenicity of MM-associated Id proteins	Weak antimyeloma immunity	Patients’ idiotype	Id-based and DC-based vaccines	Phase I/II	[40–42]
Maintenance of clonogenic MM precursors	Unrestrained growth of MM cells	SOX2	Generation of SOX2-specific T cells with peptides spanning the SOX-2 protein	Not yet into the clinic	[21]