Transfusion Medicine Reviews 33 (2019) 98–110

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Transfusion Medicine Reviews

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Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

in Cancer: A Systematic Review and Meta-Analysis☆
Emma J.M. Grigor a,b,c,1, Dean Fergusson b,c,f,1, Natasha Kekre d, Joshua Montroy b,c, Harold Atkins d,e,
Matthew D. Seftel j, Mads Daugaard k,l, Justin Presseau b,c, Kednapa Thavorn b,c,o, Brian Hutton c,g,
Robert A. Holt i,m,n, Manoj M. Lalu a,b,h,⁎,1
a
Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
b
Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
c
School of Epidemiology and Pubic Health, University of Ottawa, Ottawa, Ontario, Canada
d
Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, Ontario, Canada
e
Cancer Therapeutic Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
f
Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada
g
Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
h
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
i
Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
j
Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba
k
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
l
Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
m
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
n
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
o
Institute for Clinical Evaluative Sciences, Ottawa, Ontario, Canada

a r t i c l e i n f o a b s t r a c t

Available online 14 February 2019 Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety con-
siderations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in pa-
Keywords: tients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane
CAR-T cell therapy Register of Controlled Trials (inception – November 21, 2017). Interventional studies investigating CAR-T cell
Systematic review
therapy in patients with malignancies were included. Our primary outcome of interest was complete response
Cancer
(defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed
Hematologic
risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy
studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients,
54.4% [95% CI, 42.5%-65.9%] experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65
evaluable hematologic patients, 24.4% [95% CI, 9.4%-50.3%] experienced complete response in seven non-CD19
CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% [95% CI, 40.3%-69.4%] of pa-
tients and neurotoxicity 37.2% [95% CI, 28.6%-46.8%] of patients with hematologic malignancies. Of 86 evaluable
solid tumor patients, 4.1% [95% CI, 1.6%-10.6%] experienced complete response in eight CAR-T cell therapy stud-
ies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There
was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no
overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and
other stakeholders of the benefits and risks associated with CAR-T cell therapy.
© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BioCanRx, Biotherapeutics for Cancer Treatment; CAR-T, chimeric antigen receptor T cell; CD, cluster of
differentiation; CLL, chronic lymphocytic leukemia; DistillerSR, Distiller Systematic Review; GRADE, grading of recommendations, assessment, development and evaluations; IHE, Institute
of Health Economics; NHL, non-Hodgkin's lymphoma; RECIST, response evaluation criteria in solid tumors.
☆ Systematic review registration: PROSPERO CRD42017075331.
⁎ Corresponding author at: Manoj M Lalu, MD, PhD, 501 Smyth Road, PO Box 201B, Ottawa, ON, K1H 8L6, Canada.
E-mail addresses: manojlalu@gmail.com, mlalu@toh.ca (M.M. Lalu).
@manojlalu (M.M. Lalu).
1
Authors contributed equally to work.

https://doi.org/10.1016/j.tmrv.2019.01.005
0887-7963/© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110 99

Contents

Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Data sources and searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Data extraction and quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Data synthesis and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Declaration of Interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Chimeric antigen receptor (CAR) T cell therapy is a cell-based gene
therapy that has been used to treat patients with relapsed or refractory
malignancies in several phase I and phase II clinical trials. This individu-
alized patient therapy harnesses the natural function of the body's T
lymphocytes. T cells from either a donor or the recipient are genetically
engineered to express a specific CAR (eg, using a retrovirus) designed to
recognize a specific tumor associated antigen; this allows the T-cells to ac-
tively target and selectively kill cells expressing that antigen (eg, CD19,
HER-2). Early clinical trials that investigated anti-CD19 CAR-T cells in he-
matologic malignancies have demonstrated continued remission in pa-
tients with late stage disease [1-5]. CAR-T cell therapy investigating
different cancer-specific targets have also shown some potential in stud-
ies of non-hematopoietic malignancies [6]. These promising results have
been tempered by safety considerations, including cytokine release syn-
drome, neurotoxicity, and other rare and uncommon adverse events [7,8].
We present a comprehensive, up-to-date and methodologically rig-
orous systematic review and meta-analysis summarizing the benefits
and risks of CAR-T cell therapy in patients with relapsed or refractory
hematological malignancies and solid tumors from all published clinical
trials. This summary will help inform decisions by patients, clinicians
and other stakeholders.
Methods
This systematic review and meta-analysis follows the Preferred
Reporting Items for Systematic Reviews and Meta-analyses guidelines,
as shown in the appendix (Appendix 1) [9]. The protocol is available
in the International Prospective Register of Systematic Reviews
(CRD42017075331). The protocol has been previously published [10].

1637 Solid cancer records identified through 1674 Blood cancer records identified through
database searching database searching

1356 = Solid 1381 = Blood

1518 Solid cancer records screened after 1492 Blood cancer records screened after
cancer cancer
duplicates removed duplicates removed
excluded excluded
reports at reports at
title/abstract title/abstract

144 Solid cancer excluded 162 Solid cancer full-text reports assessed 69 Blood cancer excluded reports
reports
111 Blood cancer full-text reports assessed 39 commentary, editorials,
96 pre-clinical or animal or letters, or reviews
manufacturer studies 5 Duplicate
41 commentary, editorials, 2 Partial duplicate
letters, or reviews 4 pre-clinical or animal or
3 Duplicates manufacturer studies
3 other 4 abstract
1 Abstract 3 did not report outcomes of
interest
12 other (including protocols)

18 Solid cancer studies were included

42 Blood cancer studies were included

Fig 1. PRISMA diagram summarizing screening and selection of studies included in review.
100 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110

Table 1
Characteristics of the included studies and participants

First author (year) Country Trial Phase Patients evaluated Age, years mean (range) Cancer type(s) Follow-up
n (% male)

Hematologic malignancies
Till 2008 [25] United States I 9 (89) 60.2 (43–77) NHL NP
Kalos 2011 [26] United States I 3 (100) 68.7 (64–77) ALL 15 m
Brentjens 2011 [27] United States I 8 (80) 63.9 (51–73) ALL, CLL NP
Till 2012 [28] United States I 4 (100) 59.2 (28–80) NHL NP
Kochenderfer 2012 [29] United States I/II 8 (NP) 55.8 (47–63) NHL, CLL NP
Brentjens 2013 [30] United States I 5 (80) 52.4 (23–66) ALL NP
Cruz 2013 [31] United States I 8 (63) 38.5 (9–59) ALL, CLL NP
Kochenderfer 2013 [32] United States I 10 (80) 52.4 (44–66) NHL, CLL NP
Ritchie 2013 [33] Australia I 5 (33) 70.6 (64–78) AML NP
Davila 2014 [4] United States I 16 (75) 50 (NP)b ALL NP
Maude 2014 [23] United States I/IIa 30 (60) 8.7 (8–12) ALL NP
Wang 2014 [34] China I/II 7 (85) 62.4 (37–85) NHL 14 m
Dai 2015 [35] China NP 9 (44) 38.9 (15–65) ALL NP
Lee 2015 [3] United States I 21 (66) 14.7 (5–27) NHL, ALL NP
Porter 2015 [36] United States I 14 (85) 66 (51–78)b CLL 19 m (6–53)
Wang 2015 [37] China I/II 1 (100) 41 (NP) AML NP
Brudno 2016 [38] United States I 20 (55) 48 (20–68) NHL, ALL, CLL 6m
Cai 2016 [39] China I 1 (0) 71 (NP) ALL 31 d
Hu 2016 [40] China NP 1 (0) 43 (NP) ALL 32 w
Kebriaei 2016 [41] United States I 26 (NP) 40 (21–61) NHL, ALL NP
Locke 2016 [42] United States I 7 (NP) NP NHL NP
Prudent 2016 [43] United States NP 2 (50) 29 (25–33) ALL NP
Turtle 2016a [44] United States I/II 30 (NP) 40 (20–73)b ALL NP
Turtle 2016b [45] United States I 32 (84) 57 (22–70) NHL NP
Wang 2016 [46] United States I 16 (56) 60 (23–75) NHL 25.8 m (24–37)
Zhu 2016 [47] China NP 2 (50) 34 (29–39) ALL NP
Chen 2017 [48] China I/II 6 (17) 26.5 (8–44) ALL 14 m
Fitzgerald 2017 [49] United States I/IIa 39 (51) 11 (5–22)b ALL 28 d
Fry 2017 [50] United States I 21 (62) 19 (7–30)b ALL 21 m
Gardner 2017 [51] United States I 45 (51) 12.2 (1.3–25.3)b ALL 9.6 m (2–28)
Hay 2017 [52] United States I/II 133 (70) 54 (20–73)b CLL, ALL, NHL 30 d
Kochenderfer 2017 [53] United States I/II 22 (NP) 47.4 (38–64) NHL 26 m
Lai 2017 [54] China NP 1 (NP) NP ALL 80 d
Neelapu 2017 [55] United States II 28 (64) 58 (23–76) NHL 15.4 m
Pan 2017 [56] China NP 51 (63) 2–68 ALL 206 d (45–427)
Qasim 2017 [57] United Kingdom 0 2 (0) 1.1 (0.9–1.3) ALL 15 m (12–18)
Ramos 2017 [58] United States I 9 (67) 34.6 (20–65) Hodgkin lymphoma 15 m
Rossig 2017 [59] Germany I/II 11 (83) 9 (2–12) ALL 12 m (1–37)
Schuster 2017 [60] United States II 92 (61) 25–77 NHL 28.6 m (3.5–3.79)
Smith 2017 [61] United States NP 1 (100) 21 (NP) ALL 28 d
Wang 2017 [62] China I 18 (72) 33 (13–77)b NHL ≥2m
Zahid 2017 [63] United States NP 1 (100) 65 (NP) NHL 17 m

Solid malignancies
Morgan 2010 [64] United States I/II 1 (0) 39 Colon cancer NP
Maus 2013 [8] United States I 3 (NP) NP Pancreatic exceadenocarcinoma NP
Ahmed 2015 [65] United States I/II 19 (47) 17 (7.7–29.6)b Sarcoma, neuroectodermal tumor, DSRCT 10.2 m (1.1–37)
Brown 2015 [66] United States I 3 (NP) NP Glioblastoma NP
Katz 2015 [67] United States I 6 (67) 57 (51–66) Liver metastases NP
Brown 2016 [68] United States I 1 (100) 50 Glioblastoma 298 d
Feng 2016 [69] China I 11 (45) 58 (40–66)b NSCLC NP
Junghans 2016 [70] United States I 5 (100) 61 (51–75)b Prostate cancer NP
Lamers 2016 [71] The Netherlands I/II 12 (NP) NP MRCC 9.5 m
You 2016 [72] United States I 1 (100) NP Metastatic seminal vesicle cancer NP
Feng 2017a [73] China I 1 (0) 52 Advanced cholangio-carcinoma NP
Feng 2017b [74] China I 11 (82) 60.5 (50–75) Biliary tract and pancreatic cancers 4.8 m (1.5–8.3)
Hege 2017 [75] United States I 23 (NP) NP colorectal cancer 20 d
O'Rourke 2017 [76] United States I 10 (50) 59.5 (45–76)b Glioblastoma NP
Tanyi 2017 [77] United States NP 1 (0) 52 (NP) ovarian cancer 29 d
Tchou 2017 [78] United Kingdom 0 6 (0) 55.3 (44–64) metastatic breast cancer 10 m (3–28)
Thistlethwaite 2017 [79] United Kingdom I 14 (57) 47.7 (36–66) CEA+ tumors of GI tract 56 m
Zhang 2017 [80] United States I 10 (70) 58 (48.8–67)b metastatic colorectal cancer 77 m

Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CEA, carcinoembryonic antigen; CLL, chronic lymphocytic leukemia; d, days; DSRCT, desmoplastic small
round cell tumor; GI, gastrointestinal; mo, months; n, number; NHL, non-Hodgkin's lymphoma; NP, not provided; MRCC, metastatic renal cell carcinoma; NSCLC, non-small cell lung can-
cer; w, weeks; y, year.

Data sources and searches
Uncontrolled or controlled interventional studies that investigated
CAR-T cell therapy in patients with refractory or relapsed hematologic
or solid malignancies were considered. Only studies that reported out-
comes of interest were included. Gray literature, commentaries, letters,
and abstracts were excluded. MEDLINE (OVID interface, including In-
Process and Epub Ahead of Print) Embase (OVID interface), and the
Cochrane Central Register of Controlled Trials (Wiley interface) data-
bases were search from inception to November 21, 2017. Two separate
search strategies were developed for hematological malignancies and
solid tumors using key words related to CAR-T cell therapy (search
 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110 101

Table 2
Chimeric Antigen Receptor T-cell Therapy Characteristics of the Included Studies

First author T-cell Transfection/ CAR-T dose Previous treatments Lymphodepletion Co-stim CAR antigen
(year) origin transduction method (cells/m2 or cells/kg) domain target

Hematologic malignancies
Till 2008 [25] Auto Electroporation 1×108–3.3×108/m2 Chemo Chemo NC CD20
Kalos 2011 [26] Auto Retrovirus 1.46×105–1.6×107/kg Biologic, chemo Chemo (Cy, Fl, Pen, Be, Le), 4-1BB CD19
biologic (All, Ri)
Brentjens 2011 Auto NP 1.2×107–3×107/kg Chemo Chemo (Cy) CD28 CD19
[27]
6 7
Till 2012 [28] Auto Retrovirus 3×10 -3×10 /kg NP Chemo (Cy, Fl) CD28 CD19
Kochenderfer Allo Lentivirus 2.5×105–3.3×109/m2 Chemo Chemo (Cy) CD28, CD20
2012 [29] 4-1BB
Brentjens 2013 Auto Gammaretrovirus 1.5×106-3×106/kg Chemo Chemo (Cy, Mi) CD28 CD19
[30]
Cruz 2013 [31] Allo Retrovirus 1.5×107–1.2×108/m2 SC None CD28 CD19
Kochenderfer Allo Gammaretrovirus 1×106/kg SC None CD28 CD19
2013 [32]
Ritchie 2013 [33] Auto Retrovirus 1.64×109–2.65×109/kg NP Chemo (Cyt, Fl) CD28 LeY
Davila 2014 [4] Auto Retrovirus 3×106/kg NP Chemo (Cy) CD28 CD19
Maude 2014 [23] Auto Lentivirus 7.6×105–2.06×107/kg SC, chemo NP 4-1BB CD19
Wang 2014 [34] Auto Lentivirus 1×107/kg Chemo Chemo (Cy, Ca, De, Et, Vi) 4-1BB LeY
Dai 2015 [35] Allo, Au Lentivirus NP Chemo Chemo (Cy) 4-1BB CD19
Lee 2015 [3] Auto Retrovirus 1×106-3×106/kg SC Chemo (Cy, Fl) CD28 CD19
Porter 2015 [36] Auto Lentivirus 1.4×107–1.1×107/kg Chemo Chemo (Cy, Fl, Pen, Be) 4-1BB CD19
Wang 2015 [37] Auto Lentivirus 1×107/kg Chemo NP 4-1BB CD33
Brudno 2016 [38] Allo Gammaretrovirus 1×106–1×107/kg SC None CD28 CD19
Cai 2016 [39] Auto NP 1.5×107/kg Chemo Chemo 4-1BB CD19
Hu 2016 [40] Auto Retrovirus NP NP Chemo (Cy, Fl) 4-1BB CD19
Kebriaei 2016 Auto Electroporation 1×108/m2 NP Radiation CD28 CD19
[41]
Locke 2016 [42] Auto Retrovirus 2×106/kg SC, biologic, chemo Chemo (Cy or Cy + Fl) CD28 CD19
Prudent 2016 [43] Allo NP NP Chemo, radiation Chemo (Cy, Fl) NP CD19
Turtle 2016a [44] Auto Lentivirus 2×105–2×107/kg SC, chemo Chemo (Cy, Fl) 4-1BB CD19
Turtle 2016b [45] Auto Lentivirus 2×105–2×107/kg SC, chemo Chemo (Cy, Fl) 4-1BB CD19
Wang 2016 [46] Auto Lentivirus 5×107–8×108/kg SC Radiation, biologic (Ri) CD28 CD19
Zhu 2016 [47] Auto Lentivirus 1.19×106–1×106/kg NP Chemo (Cy) 4-1BB CD19
Chen 2017 [48] Allo NP 0.38–4.19×108/kg SC Chemo (Cy, Fl) NP CD19
Fitzgerald 2017 Auto NP NP NP NP 4-1BB CD19
[49]
Fry 2017 [50] Auto Lentivirus 1×106/kg SC, biologic Chemo 4-1BB CD22
Gardner 2017 [51] Auto Lentivirus 0.5×106–1×107/kg SC Chemo (Cy or Cy + Fl) 4-1BB CD19
Hay 2017 [52] Auto Lentivirus 2×105–2×107/kg SC Chemo (Cy, Fl) 4-1BB CD19
Kochenderfer Allo Retrovirus 1-6×106/kg SC Chemo (Cy, Fl) CD28 CD19
2017 [53]
Lai 2017 [54] Auto Lentivirus 5×104/kg NP Chemo (Cy, Fl) CD28 CD19
Neelapu 2017 Auto NP 1.79–5×108/kg SC Chemo CD28 CD19
[55]
Pan 2017 [56] NP Lentivirus 1×105/kg NP Chemo (Cy, Fl) 4-1BB CD19
Qasim 2017 [57] Auto Lentivirus 4×106–4.6×106/kg SC Chemo (Cy, Fl), biologic (Al) CD28, CD19
4-1BB
Ramos 2017 [58] Auto Lentivirus 0.2–2×108/m2 NA NA CD28 CD30
Rossig 2017 [59] Auto Retrovirus 2×108/m2 SC Chemo (Fl, Tr, Th) CD28 CD19
Schuster 2017 Auto Retrovirus 2×108/kg SC, biologic NP 4-1BB CD19
[60]
Smith 2017 [61] NP NP NP NP NP NP CD19
Wang 2017 [62] Auto NP 1.1–2.1×107/kg Chemo Chemo (Cy, Fl) 4-1BB CD30
Zahid 2017 [63] NP NP NP SC, chemo, radiation, Chemo (Cyt, Fl) NP CD19
biologic

Solid malignancies
Morgan 2010 [64] Auto Retrovirus 1×1010 cells Chemo Chemo (Fl, Cy) CD28, ERRB2
4-1BB
Maus 2013 [8] Auto Electroporation 1×108 cells Chemo No lymphodepletion 4-1BB mesothelin
Ahmed 2015 [65] Auto Retrovirus 1×108/m2 Chemo, radiation No lymphodepletion CD28 HER-2
Brown 2015 [66] Auto NP 1×108 cells Chemo, radiation, No lymphodepletion NC IL13-zetakine
biologic
Katz 2015 [67] Auto Retrovirus 1×1010 cells Chemo, radiation No lymphodepletion CD28 CEA
Brown 2016 [68] Auto Lentivirus 1×107 cells Chemo, radiation No lymphodepletion 4-1BB IL13Rα2
Feng 2016 [69] Auto Lentivirus 9.7×106/kg Chemo, radiation Chemo (Cy, Pem, Ci, Do) 4-1BB EGFR
Junghans 2016 Auto Retrovirus 1×1010 cells Chemo, radiation Chemo (Fl, Cy) NC PSMA
[70]
Lamers 2016 [71] Auto Retrovirus 2×109 cells NP No lymphodepletion NC CAIX
You 2016 [72] Auto Lentivirus 5×105/kg NP No lymphodepletion CD28, CAIX
4-1BB
Feng 2017a [73] Auto NP 2.2×106/kg Chemo, radiation No lymphodepletion 4-1BB EGFR
Feng 2017b [74] Auto Lentivirus 2.1×106/kg NP Chemo (Nab-paclitaxel, Cy) 4-1BB HER-2
Hege 2017 [75] Auto Retrovirus 1×108–1010 cells NP No lymphodepleting NP TAG-72
chemotherapy
(continued on next page)
102 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110
Table 2 (continued)
First author T-cell Transfection/ CAR-T dose
(year) origin transduction method (cells/m2 or cells/kg)
O'Rourke 2017 Auto Lentivirus 5×108/kg
[76]
Tanyi 2017 [77] Auto Lentivirus 4.65×107 cells
Tchou 2017 [78] Auto Electroporation 3×107–3×108 cells
Thistlethwaite Auto Retrovirus 1×109–5×1010 cells
2017 [79]
Zhang 2017 [80] Auto Lentivirus 1.5×105–1×108/kg
Abbreviations: Al, alemtuzumab; Allo, allogeneic; Auto, autologous; Be, bendamustine; Ca, carboplatin; Chemo, chemotherapy; Ci, cisplatin; Co-stim, co-stimulatory domain; Cy, cyclophos-
phamide; Cyt, cytarabine; De, dexamethasone; Do, docetaxel; Et, etoposide; Fl, fludarabine; Le, lenalidomide; Mi, mitoxantrone; NC, no costimulatory domains; Pen, pentostatin; Pem,
pemetrexed; Ri, rituximab; SC, stem cell therapy; Tr, treosulpha; Th, thiotepa; Vi, vincristine.
strategy presented in Appendix 2). A peer review of the electronic
search strategy was performed [11].
Study selection
Search results and full-text articles meeting full eligibility criteria
were reviewed independently and in duplicate (EG, JM) using Distiller
Systematic Review Software (DistillerSR, Evidence Partners, Ottawa,
Canada). Disagreement was settled through discussion with a third re-
viewer (DF, HA, ML, NK). Efficacy outcomes of interest included com-
plete response (primary outcome), overall or objective response,
relapse, and overall survival. Complete response was defined as the ab-
sence of detectable cancer following treatment with CAR-T cell therapy.
Overall response was defined as the total sum of complete and partial
responses. Both complete response and overall or objective response
outcomes excluded patients with continued responses (where patients
were enrolled while in remission from a previous therapy) after receiv-
ing CAR-T cell therapy. These patients were included in the other effi-
cacy and safety outcomes (eg, relapse, overall survival). Safety
outcomes of interest included cytokine release syndrome, neurotoxic-
ity, infection, and graft versus host disease (GVHD). Patient reported
outcomes including quality of life and healthy utility measures were
also extracted.
Data extraction and quality assessment
Patient characteristics, CAR-T treatment-specific details, and effi-
cacy/safety outcomes were extracted. Studies were assessed for meth-
odological quality using the Institute of Health Economics (IHE) risk of
bias tool [12,13]. We presented in a risk of bias graph using Review
Manager 5.3 (London, UK). Data extraction and risk of bias assessments
were performed independently and in duplicate. Disagreements were
settled through discussion with a third reviewer (DF, HA, ML, NK).
Data synthesis and analysis
Dichotomous data (eg, complete response) was analyzed and re-
ported as a proportion with 95% confidence intervals (CI, truncated at
0 and 1) from the data extracted. Included study results were stratified
by CD19 and non-CD19 CAR-T cell constructs for hematologic and solid
malignancies. A random effects model was employed using the
DerSimonian and Laird random effects method in order to pool outcome
event rates using Comprehensive Meta-Analysis (version 3; Biostat Inc,
USA). Statistical heterogeneity between summary data was assessed
using the Cochrane I2 statistic. N-of-1 studies were narratively described
and not included in the final meta-analysis.
We performed subgroup analyses based on type of cancer, age group
(pediatric and adult), T-cell origin (autologous versus allogeneic), and
construct type (eg, CD19 and non-CD19, co-stimulatory domain
types). A post hoc subgroup analysis was performed to assess the effect
of chemotherapeutic preconditioning, as well as the trial phase. A post
hoc random effects meta-regression analysis was performed using the
Previous treatments Lymphodepletion Co-stim CAR antigen
domain target
Chemo, radiation, vaccine No lymphodepletion 4-1BB EGFRvIII
Surgery, chemo, biologic No lymphodepletion 4-1BB mesothelin
NP NP NP c-met
Surgery, chemo, Chemo (Fl, Cy) NP CEACAM5
radiation, biologic
Chemo Chemo (Fl or Cy + Fl) CD28 CEA
method of moments approach to investigate potential underlying rela-
tionships that may explain some of the variability in response rates. In
addition, we also performed a post hoc analysis by plotting complete re-
sponse rate against prevalence of cytokine release syndrome to investi-
gate a potential linear relationship. We assessed publication bias using
an alternative funnel plot designed for single arm studies [14]. Grading
of Recommendations, Assessment, Development and Evaluations
(GRADE) was used to assess the quality of the evidence [15].
Role of the funding source
The funder of the study had no role in study design, data collection,
data analysis, data interpretation, or writing of the report. The corre-
sponding author had full access to all the data in the study and had
final responsibility for the decision to submit for publication.
Results
The systematic searches returned 3311 citations. Following
deduplication and screening by title/abstract and full manuscript, a
total of 42 hematologic cancer studies (775 patients) and 18 solid can-
cer studies (138 patients) met our full eligibility criteria (Fig 1). Follow-
ing screening and de-duplication, there were eight studies that reported
patient data that was fully duplicated [5,16-22] and two studies partially
duplicated [23,24].
The characteristics of the included studies are listed in Table 1. All in-
cluded studies administered CAR-T cell interventions to patients with
relapsed or refractory malignancies without control groups. Studies
were published between 2008 and 2017, with sample sizes ranging
from one to 133 participants. 19 (32%) studies investigated acute lym-
phocytic leukemia (ALL), 18 (30.0%) solid malignancies (eg, liver metas-
tases, glioblastoma), 11 (18%) non-Hodgkin's lymphoma (NHL), two
(3%) acute myeloid leukemia, one (2%) chronic lymphocytic leukemia
(CLL), one (2%) Hodgkin's lymphoma and eight (13%) included patients
with more than one type of hematologic cancer. Thirty-four trials were
reported as phase I studies (57%), 13 were phase I/II (22%), two were
phase II studies (3%), and two were reported as being phase 0 (3%).
Study phase was not reported in 9 studies (15%). Follow-up periods
were highly variable (range: 20 days to 77 months). There was no re-
port of loss to follow-up in any of the included studies. The majority of
studies were performed in either the United States (41 studies, 68%)
or China (13 studies, 22%).
The CAR-T cell intervention characteristics are listed in Table 2. A
total of 34 studies (57%) investigated CD19 and 26 (43%) targeted alter-
native tumor associated antigens. There were 49 studies (82%) that in-
vestigated autologous CAR-T cells, seven (12%) allogeneic, one (2%)
mixed, and three (5%) did not report cell type. CAR-T cell therapies
were defined as autologous regardless of the source of previous stem
cell transplant treatments received (eg, autologous or allogenic). The
CAR-T cell dose that was administered to patients varied considerably
(2×10 5-1×10 10 cells/kg). There were 25 studies (41.7%) that investi-
gated CAR-T cells with a 4-1BB co-stimulatory domain, 20 studies
 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110 103

Fig 2. Complete response event rate for patients with hematologic (A-B) and solid malignancies (C). The diamond indicates the pooled summary estimate for each subgroup and the
overall weighted effect estimate where the gray vertical line reflects this pooled summary effect. A random effects model was employed using the DerSimonian and Laird random
effects method.

(33.3%) with a CD28 co-stimulatory domain, seven studies (11.7%) with
no co-stimulatory domain reported, four studies (6.7%) with no co-
stimulatory domain and four studies (6.7%) with a CD28 and 4-1BB
co-stimulatory domain.
We excluded seven solid cancer patients who received surgical re-
section of their solid tumor prior to CAR-T cell treatment and 30 hema-
tologic cancer patients who were in continued complete response at the
start of CAR-T cell treatment from complete and overall or objective re-
sponse outcomes.
The overall risk of bias results from the quality assessment are pre-
sented in the appendix (Appendix 3). All studies lacked an independent,
blinded assessor and demonstrated high risk of bias with regards to pa-
tient recruitment. The majority of studies were also single center trials.
The symmetry observed in the modified funnel plot was not suggestive
of overt publication bias (Appendix 4).
Complete response was reported in 27 CD19 CAR-T cell therapy he-
matologic cancer studies (486 evaluable patients) and seven non-CD19
CAR-T cell therapy studies (65 evaluable patients) as shown in Figure 2A
and B, respectively. A pooled prevalence of 54.4% [95% CI, 42.5-65.9; I2
69.9%] was demonstrated among patients treated with CD19-targeted
CAR-T cell therapy. Among the patients that experienced a complete re-
sponse, 52.5% were reported to have achieved absence of minimal resid-
ual disease; however it was only reported in three trials (MRD). The
sensitivity of the MRD tests performed ranged from 0.01 to 0.08%
[39,45,60]. A pooled prevalence of 24.4% [95% CI, 9.4-50.3; I 2 55.8%]
was demonstrated among patients treated with non-CD19 targeted
CAR-T cell therapy. Subgroup analysis of CD19+ hematologic cancer
types demonstrated that patients with ALL had the highest response
when compared to CLL and lymphoma. Among the ALL patients, there
was a complete response rate of 77.1% [95% CI, 62.8%-87.1%; I 2 58.5%]
104 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110

Fig 3. Overall response for patients with hematologic (A-B) and solid tumor malignancies (C). The diamond indicates the pooled summary estimate for each subgroup and the overall
weighted effect estimate where the gray vertical line reflects this pooled summary effect. A random effects model was employed using the DerSimonian and Laird random effects method.

compared to CLL and NHL with rates of 25.5% [95% CI, 13.9%-42.1%; I 2
0%] and 44.4% [95% CI, 34.1%-55.2%; I2 35.3%], respectively.
Among the CD19+ hematologic cancer studies, subgroup analy-
ses of T-cell origin categorized by autologous and allogeneic CAR-T
cell therapies and age subgrouped by pediatric versus adult revealed
non-significant differences in complete response. In addition, there
was no difference in response rates observed in our subgroup analy-
sis by trial phase. In our subgroup analysis of complete response by
co-stimulatory domain type comparing 4-1BB versus CD28, a higher
response rate was observed with the 4-1BB construct (P b .05) even
after controlling for disease type. Patients who received chemother-
apeutic preconditioning had significantly higher response rates com-
pared to those who did not (Appendix 5–10). Meta-regression was
performed among CD19+ hematologic cancer studies to investigate
potential underlying relationships that may explain some of the het-
erogeneity (Appendix 11). Multiple meta-regression demonstrated
that ALL patients demonstrated a higher complete response rate
than CLL and NHL patients after controlling for T-cell origin and co-
stimulatory domain type (P b .001). Post-hoc analysis using a scatter
plot to visually investigate a possible relationship between cytokine
 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110
Fig 4. Relapse for patients with hematologic malignancies. The diamond indicates the pooled summary estimate for each subgroup and the overall weighted effect estimate where the gray
vertical line reflects this pooled summary effect. A random effects model was employed using the DerSimonian and Laird random effects method.
release syndrome and complete response demonstrated no relation-
ship (Appendix 12).
Overall response was reported in 27 CD19 CAR-T cell therapy hemato-
logic cancer studies (486 evaluable patients) and seven non-CD19 CAR-T
cell therapy studies (65 evaluable patients) as shown in Figure 3A and B, re-
spectively. A pooled prevalence of 66.5% [95% CI, 56%-75.5%; I2 61.9%] was
demonstrated among patients treated with CD19 targeted CAR-T cell ther-
apy. A pooled prevalence of 47.5% [95% CI, 32.2%-63.2%; I2 23.0%] was dem-
onstrated among patients treated with non-CD19 CAR-T cell therapy.
Relapse was reported in 19 CD19 CAR-T cell therapy hematologic
cancer studies (241 evaluable patients) and five non-CD19 CAR-T cell
therapy studies (32 evaluable patients) as shown in Figure 4. A pooled
prevalence of 37.0% [95% CI, 29.4%-45.4%; I 2 23.7%] was demonstrated
among patients treated with CD19 targeted CAR-T cell therapy. A
pooled prevalence of 75.6% [95% CI, 56.4%-88.2%; I 2 0%] was demon-
strated among patients treated with non-CD19 CAR-T cell therapy.
Overall survival was reported in 24 CD19 CAR-T cell therapy hema-
tologic cancer studies (460 evaluable patients) and six non-CD19 CAR-
T cell therapy studies (48 evaluable patients) as shown in Figure 5A
and B. A pooled analysis was not performed due to the considerable var-
iability in reported follow-up time between trials. Over all CD-19 CAR-T
cell studies, the survival ranged from 5% to 95%. In non-CD-19 hemato-
logic studies, survival ranged from 74% to 97%. In solid malignancy stud-
ies, survival ranged from 7% to 92%.
Cytokine release syndrome was reported in 18 hematologic cancer
studies (594 evaluable patients) as shown in Figure 6A. A pooled prev-
alence of 55.3% [95% CI, 40.3%-69.4%; I 2 86.6%] was demonstrated
among patients treated with CAR-T cell therapy. Grading of cytokine
release syndrome severity was not consistently reported between
studies. In post hoc subgroup analyses, the prevalence of CRS did not
differ between cancer types, co-stimulatory domains, or trial phase
(Appendix 13–15).
Neurotoxicity was reported in 14 hematologic cancer studies (296
evaluable patients) as shown in Figure 6A. A pooled prevalence of
37.2% [95% CI, 28.6%-46.8%; I2 72.6%] was demonstrated among patients
105
treated with CAR-T cell therapy. In post hoc subgroup analyses, the
prevalence of neurotoxicity did not differ between cancer types, co-
stimulatory domains, or trial phase (Appendices 13–15).
Infection was reported in 14 hematologic cancer studies (272
evaluable patients) as shown in Figure 6A. A pooled prevalence of
12.2% [95% CI, 8.1%-18.0%; I 2 9.9%] was demonstrated among patients
treated with CAR-T cell therapy.
Graft versus host disease (GVHD) was reported in three of the seven
hematologic cancer studies that administered an allogeneic product (44
evaluable patients) as shown in Figure 6A. A pooled prevalence of GVHD
was 23.4% [95% CI, 8.6%-49.8%; I2 49.7%] was demonstrated among pa-
tients treated with CAR-T cell therapy.
B-cell aplasia was measured and reported in seven of the CD19
CAR-T cell therapy hematologic cancer studies and one non-CD19
CAR-T cell therapy hematologic cancer study reviewed. The B-cell
aplasia persistence ranged from 1 month to 4 years among these
studies [3,22,23,26,46,80].
Five N-of-1 hematologic cancer studies were of patients treated with
CAR-T cell therapy. In four studies that reported on complete response
and overall response, three patients reported a complete and overall re-
sponse. In three studies that reported on survival to last follow-up, all
patients survived. In three studies that reported on cytokine release
syndrome, all patients experienced cytokine release syndrome. In
three studies that reported on neurotoxicity, all patients experienced
neurotoxic events. In the one study that reported on GVHD, one patient
experienced GVHD. None of the studies reported relapse. Summaries of
the N-of-1 reports can be found in appendix (Appendix 16).
Complete response was reported in eight solid cancer studies
(86 evaluable patients) as shown in Figure 2C. A pooled prevalence of
4.1% [95% CI, 1.6%-10.6%; I 2 0%] was demonstrated among patients
treated with non-CD19 CAR-T cell therapy.
Objective response was reported in ten solid cancer studies (112
evaluable patients) as shown in Figure 3C. The overall objective re-
sponse rate among studies investigating solid tumors was 10.0% [95%
CI, 5.1%-18.9%; I2 0%].
106 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110
Fig 5. Overall survival for patients with hematologic (A-B) and solid malignancies (C). A random effects model was employed using the DerSimonian and Laird random effects method.
Relapse was reported in one solid cancer study (three evaluable
patients). All patients in this study experienced a relapse [66].
Overall survival was reported in nine solid cancer studies (83
evaluable patients) as shown in Figure 5C. The overall survival rate
among studies investigating solid tumors was 34.2% [95% CI, 16.4%-
57.8%; I2 60.6%].
Cytokine release syndrome was reported in two solid cancer studies
(17 evaluable patients) as shown in Figure 6B. A pooled prevalence of
5.4% [95% CI, 0.8%-30.2%; I 2 0%] was demonstrated among patients
treated with CAR-T cell therapy.
Neurotoxicity was assessed in three solid cancer studies (27
evaluable patients) as shown in Figure 6B. A pooled prevalence of
12.1% [95% CI, 3.3%-35.7%; I2 3.7%] was determined.
Infection was assessed in two solid cancer studies (24 evaluable pa-
tients) as shown in Figure 6B. A pooled prevalence of 13.6% [95% CI,
0.7%-79.0%; I 2 72.8%] was demonstrated among patients treated with
CAR-T cell therapy.
Five N-of-1 solid tumor studies were reports of patients treated with
CAR-T cell therapy. In three studies that reported complete response,
one patient experienced complete response. In four studies that
reported objective responses, two patients experienced an objective re-
sponse. In two studies that reported on cytokine release syndrome, both
patients experienced cytokine release syndrome. In two studies that re-
ported on survival to last follow-up, both patients experienced mortal-
ity. Summaries of N-of-1 reports can be found in the appendix
(Appendix 16).
Patient-reported outcomes, including health-related quality of life,
health utility measures, and patient experience, were not reported in
any of the reviewed studies.
The quality of evidence for the complete response and overall re-
sponse outcomes was assessed as very low due serious risk of bias and
inconsistency (i.e. heterogeneity) in the results (refer to Appendix 17).
This should be interpreted with caution however, as all included trials
were single-arm and early-phase in nature.
Discussion
We conducted a systematic review of the efficacy and safety of CAR-
T cell therapy based on 60 interventional studies that included 913 par-
ticipants. Meta-analysis demonstrated a strong signal of efficacy for
 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110 107

Fig 6. Safety outcomes for patients with hematologic (A) and solid malignancies (B). The diamond indicates the pooled summary estimate for each subgroup and the overall weighted
effect estimate where the gray vertical line reflects this pooled summary effect. A random effects model was employed using the DerSimonian and Laird random effects method.
108 E.JM. Grigor et al. / Transfusion Medicine Reviews 33 (2019) 98–110
CD19-targeted CAR-T cell therapy for patients with hematologic malig-
nancies. There was significant variability and a lower signal for efficacy
among the non-CD19 targeted CAR-T cell therapy studies. There was no
complete response reported among studies investigating CAR-T cell
therapy of solid tumors.
Our review also demonstrated a substantial level of heterogeneity for the
complete response outcome among the pooled CD19 targeted CAR-T cell
therapy studies. Meta-regression of the complete response outcome demon-
strated that cancer type was a significant source of heterogeneity in the
pooled results after controlling for T-cell origin and co-stimulatory domain
type. In particular, patients with ALL hematologic cancer had a significantly
higher rate of complete response compared to patients with CLL and NHL.
Cytokine release syndrome and neurotoxicity were the most com-
monly reported adverse events from CAR-T cell therapy among the he-
matologic cancer studies. These are unique and often serious side effects
of CAR-T cell therapy, however included studies rarely provided grading
of adverse events (which ranged from simple fever, to organ failure),
which limited further analysis around the severity of side effects. It
has been speculated that the development of cytokine release syndrome
is associated with efficacy; however, in our analysis of trial level of data
no association was demonstrated between this adverse event and com-
plete response. This relationship will need to be further explored using
individual patient level data. Novel CAR technologies (eg, universal
CARs for multiplexed and logical control of T cell responses) may de-
crease these issues of toxicity.
Our review has identified gaps in our current knowledge of CAR-T
cell therapy. More complete reporting is needed. For example, MRD is
inconsistently reported, making the level of remission unclear. MRD
can only be measured in ALL and CLL as there are no routine measures
available in diffuse large B-cell lymphoma or solid tumors, thus limiting
our assessment of levels of remission. The outcome ascertainment win-
dow was also highly variable between studies and frequently limited.
These short follow-up durations limited conclusions on the durability
of response to CAR-T cell therapy. In addition, there was an absence of
reporting on the safety of CAR-T cell therapy among solid tumor studies,
where only a few studies reported safety outcomes of interest (eg, infec-
tion, neurotoxicity). It was also shown in the present review that no
studies investigating CAR-T cell therapy have investigated patient-
reported outcomes (eg, patient experience, quality of life). Ultimately,
this data will be needed to demonstrate that CAR-T cell therapy im-
proves both the duration and quality of life [81]. Finally, the lack of effect
in solid tumors suggests that essential issues need to be addressed by
research teams (eg, antigen selection) developing future CAR therapies.
This systematic review and meta-analysis provides the largest
synthesis of the clinical results for CAR-T cell therapy in patients with
relapsed or refractory malignancies to date. Despite limitations associ-
ated with single arm studies, there is a strong signal of efficacy for
CD19-targeted CAR-T cell therapy among hematologic malignancies.
These results support currently approved treatments, and also identify
knowledge gaps to be addressed by future trials. Our review will help
to better inform patients and other stakeholders of the risks and bene-
fits of CAR-T cell therapy.
Contributors
Dr. Lalu had full access to all the data in the study and takes full respon-
sibility for the integrity. of the data and the accuracy of the data analysis.
Concept and design: DF, EJMG, ML, NK, HA.
Acquisition of data: EJMG, JM, ML.
Analysis or interpretation of data: DF, EJMG, ML, JM, NK, HA, RH.
Drafting of the manuscript: EJMG, ML.
Critical revision of the manuscript: All authors.
Statistical analysis: DF, EJMG, JM.
Obtained funding: DF, ML.
Administrative, technical, or material support: All authors.
Supervision: DF, ML.
Declaration of Interests
All authors have completed the ICMJE uniform disclosure form at
www.icmje.org/coi_disclosure.pdf and declare: no support from any or-
ganization for the submitted work; no financial relationships with any
organizations that might have an interest in the submitted work in
the previous three years; no other relationships or activities that could
appear to have influenced the submitted work.
Acknowledgments
Biotherapeutics for Cancer Treatment (BioCanRx) supported the
conduct of this study by a grant (Grant reference number: FY17/
CSEI4). BioCanRx is a Government of Canada funded Networks of Cen-
tres of Excellence and was not involved in any other aspect of the pro-
ject, such as the design of the project's protocol and analysis plan, the
collection of data and analyses.
ML is supported by The Ottawa Hospital Anesthesia Alternate Funds
Association and the Scholarship Protected Time Program, Department
of Anesthesiology and Pain Medicine, uOttawa.
Funding Source
BioCanRx a Government of Canada funded Networks of Centres of
Excellence.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.tmrv.2019.01.005.
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