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Promising targets for MRD therapies in AML
continued from the previous page
MRD Drug name target
Dendritic WT1- mRNA cells dendritic cells
Trial
NCT00965224
Combination
None
None
None
None
GO in combination with standard induction and consolidation
Population Clinical phase
AML or II MDS RAEB1/2 inPRorCRor smoldering course with high risk
of relapse
AML in first or II second CR after induction or consolidation
Newly diagnosed II or first relapsed
AML in CR
ineligible for allo-SCT
AML in CR after II ≥ 1 course of chemotherapy
and age >60 years
or < 60 years
without allo-SCT donor
Untreated III de novo AML
Efficacy
Clinical response rate 13/30 (43%) 5-year OS 40%
vs. 24.7% historical control
Recurrence free at a median 52 months follow up 11/19 (74%)
4-year progression- free survival 71%
Clinical response rate 12/20 (43%) 5-years OS 40%
GO vs. control Median as:
27.5 vs. 21.8 months (P=0.16)
Median event-free survival: 17.3 vs. 9.5 months (P<0.01)
MRD negative Ref. rate
9/30 (30%) (91) by WT1
transcript
levels
Not reported (125)
Not reported (92)
9/13 by (126) normalization
of WT1 transcript
levels
Post- induction (106, 127) GO vs. control
39% vs. 7%, P<0.01 Post-treatment
GO vs. control 91% vs. 61%,P=0.03 by NPM1 mutation transcript levels
Dendritic hTERT- NCT00510133 cells dendritic cells
Dendritic AML/ dendritic cells cell fusion
NCT01096602
Dendritic DCPrime NCT00965224 cells (DCP-001)
CD33 Gemtuzumab NCT00927498 ozoganicin
MRD: minimal residual disease; Ref.: references; FLT3 TKD: fms-like tyrosine kinase 3 (FLT3) gene tyrosine kinase domain mutations; FLT3 ITD: FLT3 internal tandem duplications; AML: acute myeloid leukemia; CR: complete remission; CRi: complete remission with incomplete count recovery; CRp: complete remission with incomplete platelet recovery; CRc: complete remission - composite; MPFC: multiparameter flow cytometry; MLFS: morphological leukemia-free state; IDH1/ IDH2: isocitrate dehydrogenase-1 and -2; MC: mutation clearance; NGS: next- generation sequencing;BCL-2:B-cell lymphoma-2;FLAG-IDA:fludarabine,cytarabine,idarubicin,and granulocyte colony-stimulating factor;DNMT1:DNA methyltransferase 1;allo-SCT:allo- geneic stem cell transplant; NPM1: nucleophosmin 1; PD1: programmed death protein 1; MDS: myelodysplastic syndrome; WT1: Wilms tumor 1; RAEB 1/2: refractory anemia with excess blasts; PR: partial response; OS: overall survival; hTERT: human telomerase reverse transcriptase; GO: gemtuzumab ozogamicin
plantable in NOD/SCID mice suggesting a self-renewal ability.115 MCLA-117 is a potent bispecific T-cell engager that directs CD3+ T cells to leukemia cells expressing CLL1.116 A phase I clinical trial of MCLA-117 in patients with relapsed or refractory AML or in elderly patients not eligible for chemotherapy is currently recruiting patients (NCT03038230).
Chimeric antigen receptor therapy
Chimeric antigen receptors (CAR) are engineered extra- cellular receptors joined to intracellular signaling domains that reprogram immune cells for therapeutic purposes.117 The development of second-generation CAR with an additional CD28 or 41BB co-stimulatory domain has allowed for effective responses.117 CAR-T cells kill tumor cells and promote immune surveillance directly by persist- ing and indirectly by cross-priming tumor-infiltrating lym- phocytes through antigen release.10-12 CAR therapy target- ing CD19 is extremely effective in B-cell malignancies, resulting in the approval of tisagenlecleucel (Kymriah) for the treatment of pediatric B-cell acute lymphoblastic leukemia that is refractory or in second relapse and axicab- tagene ciloleucel (Yescarta) in large B-cell lymphomas after two or more lines of systemic therapy.
A phase I study of autologous CAR-T cells with speci-
ficity for a difucosylated carbohydrate antigen Lewis (Le)- Y coupled to the cytoplasmic domains of CD28 and TCR- ζ chain produced a transient cytogenetic remission in one out of three patients with MRD at the time of infusion. Another patient with MRD prior to the infusion of CAR- T cells had persistent cytogenetic MRD but sustained MRD negativity by multiparameter flow cytometry for 23 months. Although LeY CAR-T cells persisted up to 10 months after infusion, most patients relapsed within the first 5 months suggesting possible antigen escape. None of the patients developed grade 3 or 4 toxicity.118
In AML, the ideal CAR target that is highly expressed in myeloid blasts and spares normal myeloid progenitor cells and vital tissues has not yet been identified. In preclinical studies anti-CD33 CAR-T cells resulted in a reduction of normal myeloid progenitors.119,120 Similarly, anti-CD123 CAR-T cells have demonstrated myeloablation in a xenograft mouse model.121 CLL1 CAR-T cells are cytotoxic to normal mature myeloid cells but not to normal myeloid progenitor cells or hematopoietic stem cells.122 An exten- sive proteomic and transcriptomic analysis revealed four potential CAR targets, ADGRE2, CCR1, CD70, and LILRB2, with high expression in AML, AML leukemic stem cells, and low expression in normal tissues, normal hematopoietic stem and progenitor cells and resting/acti-
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