Adoptive immunotherapy for acute leukemia: New insights in chimeric antigen receptors

Table 1 Ongoing clinical trials recruiting patients with acute leukemia

Clinical trial.govID	Center	Disease	Antigen (scFv)	CAR signaling domain	Vector	Transplantation history	Origin	Lymphocyte depletion	Patients age
Acute lymphoid malignancies
NCT01044069	MSKCC	B-ALL	CD19	CD3ζ-CD28	γ-retrovirus	Autologous	Autologous	Chemo	≥ 18 yr
NCT01860937	MSKCC	B-ALL	CD19	CD3ζ-CD28	γ-retrovirus	Autologous	Autologous	Cy	up to 26 yr
NCT01430390	MSKCC	B-ALL	CD19 VST (EBV)	CD3ζ	Lentivirus	Relapse post-ASCT	Allogenic	Chemo	up to 19 yr
NCT01626495	CHOP	B-ALL	CD19	CD3ζ-4-1BB vs CD3ζ	Lentivirus	Relapse after ASCT	Autologous	Chemo	1-24 yr
NCT02030847	University of Pennsylvania	B-ALL	CD19	CD3ζ-4-1BB	Lentivirus	Relapse ± after ASCT	Autologous	NS	≥ 18 yr
NCT00840853	BCM	B-ALL/NHL/CLL	CD19 VST (EBV)	CD3ζ	γ-retrovirus	Post-ASCT	Allogenic	No	No limit
NCT00586391	BCM	B-ALL/NHL/CLL	CD19	CD3ζ-CD28	γ-retrovirus	No ASCT	Autologous	NS	≥ 18 yr
NCT02132624 (not open)	Uppsala University	B-ALL/NHL	CD19	CD3ζ-4-1BB-CD28	γ-retrovirus	Relapse ± after ASCT	Autologous	NS	≥ 18 yr
NCT01593696	NCI	B-ALL/NHL/CLL	CD19	CD3ζ	γ-retrovirus	Relapse ± after ASCT	Autologous	Flu/Cy	1-30 yr
NCT01087294	NCI	B-ALL/NHL/CLL	CD19 VST (EBV)	CD3ζ	γ-retrovirus	Relapse post-ASCT	Allogenic	Cy	18-75 yr
NCT01683279	Seattle Children Hospital	B-ALL	CD19 EGFRt+	CD3ζ-CD28	Lentivirus	No ASCT	Autologous	Cy	1-26 yr
NCT02028455	Seattle Children Hospital	B-ALL	CD19 EGFRt+	CD3ζ-4-1BB	Lentivirus	Relapse after ASCT vs no ASCT	Autologous	Cy/Flu/TBI	1-26 yr
NCT01865617	FHCRC	B-ALL/NHL/CLL	CD19	CD3ζ	Lentivirus	> 1st relapse	Autologous	NS	≥ 18 yr
NCT01475058	FHCRC	B-ALL/NHL/CLL	CD19 VST (CMV, EBV)	CD3ζ	Lentivirus	Post-ASCT	Allogenic	No	18-75 yr
NCT02051257	City of Hope Medical Center	B-ALL/NHL/CLL	CD19 EGFRt+	CD3ζ-CD28	Lentivirus	Post-ASCT	Autologous	Chemo	≥ 18 yr
NCT02146924 (not open)	City of Hope Medical Center	B-ALL	CD19 EGFRt+	CD3ζ-CD28	Lentivirus	Relapse/progression ± after ASCT	Autologous	Cy	≥ 18 yr
NCT01195480	London University College	B-ALL	CD19 (EBV-CTL)	CD3ζ	γ-retrovirus	Relapse after 1st ASCT	Allogenic	NS	Up to 18 yr
NCT01864889	Chinese PLA General Hospital	B-ALL/NHL/CLL	CD19	CD3ζ-4-1BB vs CD3ζ	γ-retrovirus	Relapse ± after ASCT	Autologous	NS	5-90 yr
NCT01735604	Chinese PLA General Hospital	B-ALL/NHL/CLL	CD20	CD3ζ-4-1BB vs CD3ζ	γ-retrovirus	Relapse ± after ASCT	Autologous	NS	18-90 yr
NCT01362452	MDACC	B-ALL/NHL/CLL	CD19 (cord blood derived)	CD3ζ	Transposon	Relapse post-ASCT	Allogenic	No	1-75 yr
NCT01497184	MDACC	B-ALL/NHL/CLL	CD19	CD3ζ	Transposon	Post-ASCT	Allogenic	No	1-65 yr
Acute myeloid malignancies
NCT01864902	Chinese PLA General Hospital	AML	CD33	CD3ζ-4-1BB vs CD3ζ	γ-retrovirus	Relapse ± after ASCT	Autologous/ Allogenic	NS	5-90 yr
NCT02159495	City of Hope Medical Center	AML	CD123 EGFRt+	CD3ζ-CD28	γ-retrovirus	Relapse/refractory AML	Autologous	Cy	≥ 18 yr

CAR: Chimeric antigen receptor; AML: Acute myeloid leukemia; ASCT: Allogeneic stem cell transplantation; B-ALL: B-lineage acute lymphoblastic leukemia; BCM: Baylor College of Medecine; CHOP: Children Hospital of Philadelphia; Chemo: Chemotherapy prior CAR T cells infusion; CLL: Chronic lymphoid leukemia; Cy: Cyclophosphamide; FHCRC: Fred Hutchinson Cancer Research Center; Flu: Fludarabine; MDACC: MD Anderson Cancer Center; MSKCC: Memorial Sloan-Kettering Clinical Center; NCI: National Center Institute; NS: Not specified; NHL: Non Hodgkin lymphoma; VST: Virus specific T lymphocytes; EBV: Epstein-barr virus; CTL: Cytotoxic T-cell lymphoma.

Table 2 Completed chimeric antigen receptor T cells trials including acute leukemia patients

Indications	CAR construct	Vector	Cell dose	Pre-treatment	Patients	Responses	Relapses	CAR persistence (days median)	Toxicities	Ref.
Acute lymphoid malignancies
Relapsed B-ALL ± post-ASCT	Anti-CD19 scFv 4-1BB-CD3ζ	Lentiviral	106-107 cells/kg	Cy	30	90% CR (27/30)	6 relapses (one CD19-)	145	CRS for all responding patients (fever, ARDS. MODS)	[17,97,98]
Relapsed B-ALL post-ASCT	Anti-CD19 scFv CD28-CD3ζ	γ-retroviral	106 cells/kg	Cy + flu	2	100% CR (5/5)	1 transient CR	ND	Mild CRS, no GVHD	[117]
B-ALL relapsed	Anti-CD19 scFv CD28-CD3ζ	γ-retroviral	3 × 106 cells/kg	Chemo	13 (3 Ph+ B-ALL)	85% CR (10/13)	1 NR, 1 relapse	ND	6/13 CRS	[62,94]
B-ALL relapsed without prior ASCT	Anti-CD19 scFv CD28-CD3ζ	γ-retroviral	1.5-3 × 106 cells/kg	Cy	5	100% CR (5/5)	1 relapse (no ASCT)	ND	3/5 mild CRS (MRD+ or bulk)	[63]
Relapsed B-ALL/ CLL post-ASCT	Anti-CD19 scFv CD28-CD3ζ VST (CMV, EBV, ADV)	γ-retroviral	1.5 × 107-1.2 × 108 cells/m2	No	4 (4/8)	75% CR (3/4), 25% PD (1/4)	1 relapse (no ASCT)	80	No CRS, No GVHD	[95]
Acute myeloid malignancies
Relapsed AML	Anti-LeY scFv CD28-CD3ζ	γ-retroviral	1.3 × 109 cells	Chemo	4	25% CR, 50% SD	4 relapses	14-120	Neutropenia, skin “flare” reaction, fever, rigors	[87]

CAR: Chimeric antigen receptor; ADV: Adenovirus; AML: Acute myeloid leukemia; ARDS: Acute respiratory distress syndrom; ASCT: Allogeneic stem cell transplantation; B-ALL: B-lineage acute lymphoblastic leukemia; Chemo: Chemotherapy prior CAR T cells infusion; CLL: Chronic lymphoid leukemia; CMV: Cytomegalovirus; CR: Complete remission; CRS: Cytokine release syndrome; Cy: Cyclophosphamide; EBV: Epstein Barr virus; GVHD: Graft versus host disease; MODS: Multi-organ dysfunction syndrome; ND: Not determined; NR: No response; PD: Progressive disease; SD: Stable disease; VST: Virus specific T lymphocytes.