Table 1.

Examples of novel targeted therapeutics with potential application in IEI/DNARD associated malignancy.

Class of agent	Clinical example	Target	Mechanism of action	Relevance in IEI/DNARD
Monoclonal antibody	Rituximab Alemtuzumab Daratumumab Trastuzumab Cetuximab	CD20 CD52 CD38 Her2 EGFR	Direct and indirect cellular toxicity through activation of immune targeting Competitive binding of cell surface molecule and ADCC
Antibody-drug conjugate	Brentuximab vendotin Inotuzumab ozogamicin	CD30 CD22	Targeted delivery of cytotoxic drug	No residual immune function required
Bi-specific T-cell engaging antibody	Blinatumomab	CD19-CD3	Antigen directed T cell targeting	Require functioning cytotoxic T cells
Immune checkpoint inhibitor	Nivolumab Atezolizumab	PD-1 PD-L1	Inhibit negative regulation of T cell activation	Activity may correlate with hypermutant tumors, common in CMMRD. Require functioning cytotoxic T cell
CAR-T cells	Tisagenlecleucel	CD19	Autologous T-cells expressing chimeric T-cell receptor	Requires autologous T-cell harvest – optimal efficiency likely only in functionally normal T-cells. Allogeneic options in development
Small molecule inhibitor	Ibrutinib/Acalabrutinib Idelalisib Everolimus Trametinib Crizotinib	BTK PI3Kδ mTOR MEK ALK	Inhibits BCR signaling Inhibits PI3K/AKT signaling Inhibits mTOR pathway signaling Inhibits MAPK/ERK signaling Inhibits ALK signaling	Under investigation in sporadic B/T cell malignancies commonly seen in IEI/DNARD.

CMMRD, constitutional mismatch repair deficiency syndrome; TCR, T cell antigen receptor; BCR, B cell antigen receptor.