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K.D. Cummins et al.
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Disease and key inclusion/ exclusion criteria
RR AML / ALL or MDS
- 18-80 yo
- High expression of Eps8 or WT1
- Ineligible for or declining salvage alloHSCT
RRAMLorALL
- Child, adult, older adult (ages not stated - if relapsed post prior alloHSCT must be
off immune suppression at least 2 wks
RRAML
- 3 - 80 yo
- CD123(+) in >90% of blasts
Location
Southern Medical University Zhujiang Hospital, Guangdong, China
SecondAffiliated Hospital of Xi’an Jiaotong University, Shaanxi, China
XianLu,Beijing,China
Trial number
NCT03291444
NCT03672851
NCT03585517
Intervention
CARTs*# (antigen target not stated) followed by intradermal injection of Eps8 or WT1 peptide specific dendritic cells
AntiCD123CARTs*#
AntiCD123 CARTs*# (IM23)
Strategy to mitigate potential adverse events including myeloablation
- Not stated
- Notstated
- Notstated
Information available from www.clinicaltrials.gov using search term“CART”and“AML”in January 2019.*Source of cells (autologous vs.allogeneic) not stated.#Method of chimeric antigen receptor (CAR) transduction not stated. ALL: acute lymphoblastic leukemia; alloHSCT: allogeneic hematopoietic stem cell transplantation; AML: acute myeloid leukemia; BPCDN: blastic plasmacytoid den- dritic cell neoplasm; CML: chronic myeloid leukemia; EGFRt: epidermal growth factor receptor; ELN: European LeukemiaNet; Gr: grade; GvHD: graft-versus-host disease; IHC: immunohistochem- istry; KO: knock-out; mAb: monoclonal antibody; MDS: myelodysplastic syndrome; mo: months; MPN: myeloproliferative neoplasms; PBMC: peripheral blood mononuclear cells; RR: relapsed refrac- tory; TCR: T-cell receptor; wks: weeks; yo: years old.
CART123 go hand-in-hand.11 In addition to likely hematopoietic toxicity, we and others have detected CD123 expression on the endothelium of small-calibre blood vessels.12 This raises the concern for additional tox- icity in the form of vascular leak, and indeed, the first patient who was treated with an anti-CD123 “universal” CART (UCART123) died from cytokine release syn- drome (CRS) and capillary leak syndrome (CLS) on day 9 post infusion.13 It is unclear if his death was due to CD123 vascular expression, or was multi-factorial due to CRS exacerbated by the patient’s age (78 years) and the extent of disease burden. It is important to note that severe CRS has clinical overlap with CLS. The FDA allowed the trial to re-open with a log-fold reduction in UCART123 dose, reduced lymphodepleting chemotherapy dose, and an upper limit for age of enrollment of 65 years old. In order to mitigate the risk of vascular toxicity, the first CART123 trial at the University of Pennsylvania was conducted using serial infusions of “bio-degradable” CART123 cells (clinicaltrials.gov identifier: 02623582). Rather than being transduced with lentivirus, which would endow the CART population the (usually desirable) capacity of exponential expansion in vivo, these CART123 cells were manufactured by electroporation of mRNA encoding the CAR. Thus, a CART123 cell stimulated by encountering its antigen would have a finite capacity to expand, since CAR mRNA is diluted between daughter T cells. Though there was no measurable anti-leukemic activity responses in this trial, evidence of CART bioactivity was manifest by fever, CRS and transient CART detection in vivo, with- out evidence of vascular toxicity or CLS.14 This favorable safety data paved the way for a phase I trial of lentiviral- ly-transduced second-generation CART123 (CD123CAR- 41BB-CD3ζ) which has begun enrollment at the University of Pennsylvania (clinicaltrials.gov identifier: 03766126). CART123 are infused with the intention of a subsequent rescue alloHSCT, due to the above-men- tioned anticipated marrow aplasia due to CD123 expres- sion on HSPC. The conditioning for the rescue alloHSCT could include a T-cell depleting agent (e.g. alemtuzumab)
to purge the CART123 population in vivo.
The City of Hope National Medical Centre in
California opened a CART-123 trial in 2015, using a lentivirally-transduced second-generation CAR (CD123CAR-CD28-CD3ζ-EGFRt), with a flat-dosing strategy and inter-patient dose escalation from 50x10e6 CAR+ cells (dose level 1, DL1) to 200x10e6 CAR+ cells (dose level 2, DL2). Interim data were reported at the end of 2018; seven patients with AML have now been treated.15 Of the two patients treated at DL1, one achieved a morphological leukemia-free state (MLFS) last- ing 70 days, and at recurrence of disease received a sec- ond CART123 infusion which reduced the blast count (from 77.9% to 0.9% by flow cytometry). Of the five patients treated at DL2, one patient achieved a complete remission with incomplete count recovery (CRi) at day 28, and one had a CR at day 84. Three patients had stable disease. No dose-limiting toxicities were reported, and all treatment-related cytopenias resolved by 12 weeks post treatment. No CD123-negative relapses have been observed to date, and longer-term data are awaited from this pioneering study.
New paradigms of chimeric antigen receptor T cells in acute myeloid leukemia
NKG2D ligand chimeric antigen receptor T cells
Given the paucity of suitable ‘traditional’ cell surface antigens in AML, alternative strategies to harness the potential of CART therapy for AML are needed. Natural killer group 2D (NKG2D) ligands are expressed on malig- nant cells and have a role in stimulating anti-tumor immunity, but have limited expression on healthy tissues, providing a potential target for CART therapy.16,17 However, many different types of cellular stress (includ- ing inflammation) can up-regulate NKG2D ligands on normal tissues,18-20 potentially reducing specificity of NKG2D-CARs for malignant tissues due to CART- induced CRS. Investigators at the Dana-Farber Cancer
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haematologica | 2019; 104(7)