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Study Disease Target CAR dose (× 106/kg) Patient No. Efficacy Survival/duration CRS Maude et al. 2014 R/R B-ALL CD19 0.76–20.6 30 CR 90% 6 m EFS 67%, 6 m OS 78% 27% (severe) Lee et al. 2014 ALL/NHL CD19 0.03–3.6 21 CR/CRi 66.7% OS 51.6% at 9.7 months 76% (total) Neelapu et al. 2017 NHL CD19 2 101 CR 54% OS 52% at 18 months 13% (≥ grade 3) Fry et al. 2018 R/R B-ALL CD22 0.3–3 21 CR 57% Median duration: 6 months 76% (total) Pan et al. 2019 R/R B-ALL CD22 0.02–3.47 34 CR/CRi 70.5% 1-year LFS 71.6% 91% (total) Raje et al. 2019 MM BCMA 50–800 × 106 (total) 33 CR 45% Median PFS: 11.8 months 76% (total) Cohen et al. 2019 MM BCMA 10–500 × 106 (total) 25 OR 20%–64% Median PFS: 2.2–4.2 months 88% (total) Wang et al. 2017 HL CD30 11–21 18 OR 39% Median PFS: 6 months 11% (≥ grade 3) Ramos et al. 2017 HL/ALCL CD30 20–200 × 106/m2 9 CR 33% CR duration: 9–36 months NA Wang et al. 2020EHA T-ALL CD7 6–15 5 CR 80% NA 100% CR, complete response; CRS, cytokine release syndrome; EFS, event-free survival; OS, overall survival; OR, objective response; PFS, progression free survival.
Disease type Potential targets B cell malignancy CD19, CD20, CD22, CD79b, CXCR5… T-cell malignancy CD7, CD5, CD4, CD30, CDTRBC1… Multiple myeloma BCMA, CD38, CD138, SLAMF7, CD44v6… AML CD33, CD123, CD117, CLL-1… Hodgkin lymphoma CD30… Study NK cell infusion regimen Results In non-transplant setting In advanced AML Miller, 2014 Haplo-NK, activated with IL-2, Flu/Cy Five of 19 (26%) patients achieved CR Bachanova, 2014 Haplo-NK, depletion of Tregs, activation of IL-2, Flu/Cy Eight of 15 patients (53%) achieved remission at day 28, CR (n = 3), (CRp; n = 2), and CRi (n = 3) Cooley, 2019 Haplo-NK cells given with rhIL-15, Flu/Cy Fourteen of 40 patients (35%) achieved CR/CRi In MRD positive AML Zhao, 2020 IL-21/4-1BBL-expanded NK cellchemotherapy with Flu/Cy or anthracyclines/Cy Effective rates were 50% or 60% in Flu/Cy (n = 10) or anthracyclines/Cy (n = 10); DFS was clearly better in the NK group than in the historical group As consolidation or maintenance Jiang, 2019 IL-21/4-1BBL-expanded NK cell infusion during 4 to 7 courses of chemotherapy The 3-year LFS was better in the NK group than in the control group (65.1% vs. 43.5%, P = 0.047) Nguyen, 2019 Haplo-NK, activated with IL-2, Flu/Cy NK cells did not improve EFS (60.7% vs. 69.1%; P = 0.553) over chemotherapy alone In transplant setting Post-HSCT Choi, 2014 Donor-derived, IL-15 plus IL-21-stimulated CD3-depleted NK cells on days 14 and 21 post HSCT Post-transplantation NK cells significantly decreased leukemia progression (74% to 46%, P = 0.038) Choi, 2016 Additional donor NK-cell infusions given on days 6 and 9 in addition to 14 and 21 post HSCT Compared with the above study findings, an additional NK infusion on days 6 and 9 was not associated with less leukemia progression Pre-HSCT Lee, 2016 IL-2 activated NK cell infusion after conditioning chemotherapy and before stem cell infusion Durable CR occurred in 5 of 21 patients Ciurea, 2017 mbIL21 ex vivo expanded donor-derived NK cells on days −2, +7, and +28 The incidence was significantly lower in the NK group than in the control group for CMV reactivation (30.8%) (70.4%, P = 0.01) CRp, CR without platelet recovery; CRi, CR with incomplete recovery.
Study Disease No. (HID vs. ISD) Protocol in HIDs Survival and relapse Wang, 2015 AML in CR1 231 vs. 219 G-CSF and ATG 3-year DFS 74% vs. 78% (P = 0.34); relapse 15% vs. 15% (P = 0.98) Wang, 2016 ALL in CR1 103 vs. 83 G-CSF and ATG 3-year DFS 61% vs. 60%, (P = 0.91), relapse 18% vs. 24% (P = 0.30) Wang, 2016 MDS 226 vs. 228 G-CSF and ATG 4-year RFS 58% (HLA 3/6) vs. 63% (HLA 4–5/6) vs. 71% (ISD) (P = 0.14) Ghosh, 2016 Lymphoma 180 vs. 807 PT-Cy based 3-year PFS 48% vs. 48% (P = 0.96), disease progression (37% vs. 40%, P = 0.51) Chang, 2017 AML MRD+ 56 vs. 20# G-CSF and ATG 4-year LFS 80% vs. 48% (P = 0.007), relapse 13% vs. 36% (P = 0.017) Chang, 2020 ALL MRD+ 169 vs. 39 G-CSF and ATG 3-year LFS 65% vs. 43% (P = 0.023), relapse 23% vs. 47% (P = 0.006) Yu, 2019 High-risk AML 83 vs. 106 G-CSF and ATG 3-year RFS 63% vs. 43% (P = 0.035), relapse 14% vs. 24% (P = 0.101) #Extracted from the prospective cohort. The bold values refer to “P <0.05” with significance.
Clinical indications Disadvantages needed to be improved CAR-T-cell therapy 1. This therapy elicits rapid and high response in refractory cases 1. This therapy has non-durable efficacy 2. CAR-T therapy may be an effective way to induce remission and serve as a “bridge to transplant” 2. Suitable targets as effective as CD19 in non-B-cell malignancies are lacking 3. Toxicity is unavoidable and unpredictable NK cell-based therapy 1. NK cells provide an “off-the-shelf” product and could be readily available for immediate clinical use 1. The efficacy of adoptively transferred allogeneic NK cell infusion is relatively limited 2. NK cell-based therapy could be applied in refractory, MRD positive, or remission cases in non- transplant settings, and could complement HSCT 2. CAR-modified NK cell therapy is largely in the preclinical phase Allo-HSCT This therapy is currently the only curative option for hematologic malignancy 1. There is a certain incidence of transplant related mortality 2. GvHD might affect quality of life
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