Table 1.

Adoptive cellular therapies used to treat B-ALL in clinical trials.

Cell Type	Ag Targeted	Manufacturing Method	Pt #	Disease Status	Treatment Associated Toxicities	Disease Outcome	Notes	Clinical Trial #/ (Reference)
CAR-T cell	CD19	-Autologous T cell source -2nd gen CD28z CAR -Expansion with CD3/CD28 dynabeads	53	-Relapsed and refractory -Patients were all heavily pre-treated, third line treatment for 68% of patients	-CRS (n = 45, 85%) -Severe CRS (n = 14, 26%) -Neurotoxicity (n = 23, 43%)	-CR = 83% -Median EFS = 6.1 months -Median OS = 12.9 months	-Patients with high initial disease burden (>5% BM blasts) had higher incidence of AE and lower EFS and OS rates -CD19 negative relapse observed in 4 patients -Median time of T cell detectability = 14 days	NCT01044069 [10]
CAR-T cell	CD19	-Autologous T cell source -2nd gen 4-1BBz CAR -Expansion with CD3/CD28 dynabeads	75	-Relapsed and refractory, average 3 previous treatments -46% received previous alloHSCT	-CRS in 77% -Neurotoxicity in 40% -All responders had B cell aplasia	-ORR = 81% -EFS rate @ 6 and 12 months = 73% and 50% -OS rate @ 6 and 12 months = 90% and 76%	-96% of patients received pre-conditioning lymphodepletion -Median time to max expansion of T cells was 10 days	NCT02435849 [11]
CAR-T cell	CD19	-Allogeneic T cell source (batches from 3 different HD used) -2nd gen 4-1BBz CAR, rituximab mediated depletion epitope added for safety purposes -Genome-edited CAR-T cells, knocked out for TCRα chain and CD52 to prevent GvHD	21	-Relapsed and refractory, average 4 previous treatments -62% received previous alloHSCT -Median initial BM tumor burden = 8% blasts	-CRS (n = 19, 91%) -Neurotoxicity (n = 8, 38%) -GvHD (n = 2, 10%)	-CR = 67% -Median duration of response = 4.1 months -EFS rate @ 6 months = 27% -OS rate @ 6 months = 55%	-All patients received pre-conditioning lymphodepletion -3 patients saw CAR-T persistence beyond 42 days	NCT02808442 and NCT02746952 [19]
CAR-NK cell	CD19	-Allogeneic HLA-mismatched NK cell source (cord blood derived) -4th gen CAR that included inducible IL-15 secretion domain and caspase 9 safety switch -Expansion in presence of K562 feeder cells and IL-2	11	-Relapsed and refractory, all patients had 3 or more previous lines of therapy -All adult/elderly patients -Patients had lymphoma or CLL (CD19 targeting means results expected to be translatable to B-ALL patients)	-No AE -No GvHD -No increase in levels of inflammatory cytokines	-73% of patients had a response (n = 8) -CR = 64% (n = 7) -Response duration difficult to assess due to several patients receiving various post-remission therapies	-CAR-NK cells persisted at low levels for at least 12 months -All patients received pre-condition lymphodepletion -3 patients experienced disease relapse or progression	NCT03056339 [20]
CAR-T cell	CD19/CD22	-Autologous T cell source -Bispecific 2nd gen CAR, OX40 costim paired with CD19 and 4-1BB costim paired with CD22 -Semi-automated manufacturing process	10	-Relapsed and refractory, high-risk patients -All pediatric patients	-CRS (n = 9, 90%) -Neurotoxicity (n = 1, 10%) -Patients in ongoing CR maintain B cell aplasia -No patients required ICU admission	-CR = 100%, all MRD negative -3 patients relapsed within post treatment 1 year -Longer follow-up result updates still need to be reported	-All patients received pre-condition lymphodepletion -1 of the 3 relapses had CD19 negative/CD22 low relapse -180 days median persistence of CAR-T cells in blood	NCT03289455 [21,22]

AE = adverse events; Ag = Antigen; alloHSCT = allogeneic hematopoietic stem cell transplant; BM = bone marrow; CAR = chimeric antigen receptor; CR = complete remission; CRS = cytokine release syndrome; EFS = event free survival; GvHD = graft versus host disease; HD = healthy donor; HLA = human leukocyte antigen; ICU = intensive care unit; NK = natural killer; ORR = overall remission rate; OS = overall survival; Pt = patient; TCR = T cell receptor.