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Current Advances in Immunotherapy for Acute Leukemia: An Overview of Antibody, Chimeric Antigen Receptor, Immune Checkpoint, and Natural Killer


Current Advances in Immunotherapy for Acute Leukemia: An Overview of Antibody, Chimeric Antigen Receptor, Immune Checkpoint, and Natural Killer

Yufeng Shang et al. Front Oncol.


Recently, due to the application of hematopoietic stem cell transplantation and small molecule inhibitor, the survival of acute leukemia is prolonged. However, the 5 year survival rate remains low due to a high incidence of relapse. Immunotherapy is expected to improve the prognosis of patients with relapsed or refractory hematological malignancies because it does not rely on the cytotoxic mechanisms of conventional therapy. In this paper, the advances of immunotherapy in acute leukemia are reviewed from the aspects of Antibody including Unconjugated antibodies, Antibody-drug conjugate and Bispecific antibody, Chimeric Antigen Receptor (CARs), Immune checkpoint, Natural killer cells. The immunological features, mechanisms and limitation in clinic will be described.

Keywords: acute lymphoblastic leukemia; acute myeloid leukemia; antibody-drug conjugate; bispecific antibody; chimeric antigen receptor; immune checkpoint; immunotherapy.


Figure 1
Figure 1
An overview of immunotherapy targets for acute myeloid leukemia and acute lymphoblastic leukemia. Myeloid tumor cell surface antigen targets include CLL-1, CD123, CD33, CD133, PR1/HLA-A2, VEGF-C, and FLT3. Anti-CLL-1 ADC, an antibody-drug conjugate (ADC) targeting CLL-1 that binds to pyrrole diazepine dimer. MCLA-117 is a full-length human IgG1 Bi-Specific T-cell Engagers (BiTE) targeting CLL-1 and CD3. CD3/CLL1 TDB, a CD3 T-cell-dependent bispecific (TDB) full-length humanized IgG1 antibody targeting CLL1. CSL360 and CSL362 are recombinant chimeric antibody targeting CD123 and fully humanized anti-CD123 antibody, respectively. SL-101, an CD123 ADC fused to Pseudomonas exotoxin A. MGD006 is a bispecific CD3xCD123 dual-affinity re-targeting (DART) molecule. XmAb14045, a structured anti-CD123 T cell recruitment antibody. GO, SGN-CD33A, and IMGN779 are CD33 ADC binding to N-acetylgamma-erythromycin, pyrrolidone dimer and DNA alkylation activity, respectively. AMG 330 is a CD33/CD3 BiTE and AMG 673 is the second CD33/CD3 BiTE. CD33/CD3 TandAbs is a directional tandem tetravalent bispecific antibody. CD16/CD33 BiKE is a Bi-Specific Killer Engagers (BiKE) targeting CD16 and CD33, and 161533 TriKE is a Tri-Specific Killer Engagers (TiKE) including a modified IL-15 crosslinking agent between CD 16 and CD 33 single-chain Fv fragments. PD-1EX with CD3xCD33 BiTE, fused the PD-1 extracellular domain (PD-1EX) with CD3xCD 33 BiTE. Hu8F4, a T-cell receptor-like monoclonal antibody targeting PR1/HLA-A2. PR1/HLA-A2 CART, PR1/HLA-A2-specific CART (h8F4-CAR-T cells), containing the scFv of h8F4 fused to CD3 zeta chain through the co-stimulatory domain of CD28. Anti-VEGF-C, an antibody targeting vascular endothelial growth factor C to reduce expansion and enhance differentiation. FLYSYN and 293 C3-SDIE are antibodies targeting FLT3 and CD133. Compound CART include 123b-33bc CART simultaneously targeting CD123 and CD33, and CD123/CLL1 CART simultaneously targeting CD123 and CLL1. Lymphoid tumor cell surface antigen targets include CD52, CD20, CD19, CD22, CD10. Rituximab and Ofatumumab are antibodies targeting CD20. CD20-TDB, is a CD3 TDB full-length humanized immunoglobulin G1 molecule targeting CD20. SAR 3419, SGN-CD19A, and SGN-CD19B are CD 19 ADC that binds to Maytansin, Monoinositol F and Pyrrolidine diazepine, respectively. Blinatumomab, a BiTE with dual specificity for CD19 and CD3. CARCIK-CD19, a cytokine-induced killer (CIK) cells transfected with the transposon CD19CAR. Epratuzumab and Inotuzumab ozogamicin are unconjugated human antibody targeting CD22 and humanized anti-CD 22 ADC, respectively. Alemtuzumab, an anti-CD52 antibody. Compound CART include CD19/CD20 CART simultaneously targeting CD19 and CD20, and CD19/CD22 CART simultaneously targeting CD19 and CD22. Immune targets include inhibitory receptors programmed cell death protein 1 (PD1), cytotoxic T-lymphocyte antigen 4 (CTLA4), T-cell immunoglobulin and mucin-domain containing-3 (TIM3), and stimulatory receptors OX40 on T-cell subsets and their ligands (PD-L1, PD-L2, B7, and OX40L) on AML blasts. IPH2101, anti antibody targeting KIR on NK cell surface.

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