Table 3.

Clinical data for BCMA-targeted CAR-modified T-cell therapies.

Name (sponsor)	Structure	Study design/patient population	Efficacya	Safety
NIH CAR-BCMA, also referred to as anti-BCMA CAR or CAR-BCMA (NCI) [26, 27]	• Murine anti-BCMA scFv, CD28 costimulatory domain, CD8α hinge and transmembrane regions • Culture/Activation medium: anti-CD3 mAb and IL-2 • Transduction method: γ-retroviral vector	• Phase 1 dose-escalation trial (NCT02215967) • Lymphodepletion regimenb before NIH CAR-BCMA infusion • Dose levels: 0.3, 1, 3, 9 × 106 cells/kg • Measurable MM with uniform BCMA expression • 24 pts treated (16 pts received highest dose) • Median of 9.5 prior lines, 63% refractory to last treatment (at highest dose level) • 40% of evaluable pts at highest dose had high-risk cytogenetics	• ORR (9 × 106/kg): 81% • MRD–(9 × 106 kg, 11 evaluated ptsc): 100% • Median event-free survival (9 × 106/kg): 31 weeks • Peak CAR T-cell expansion occurred between 7 and 14 days post infusion for all pts • ≥1 blood CAR+ cells/μL detected between 26 and 57 days post infusion in 11 of 14 monitored pts	• Mild toxicity at lower doses • CRS-related toxicity substantial at 9 × 106/kg • 38% of pts treated at 9 × 106/kg required vasopressors for hypotension
Anti-BCMA CAR T cells with truncated EGFR safety switch (Henan University) [72]	• 4-1BB costimulatory domain, truncated EGFR as safety switch • Transduction: γ-retroviral vector	• Phase 1 triald (NCT03093168) • Lymphodepletion regimenb before CAR T-cell infusion (9 × 106 cells/kg) • RRMM (≥3 prior treatment regimens) • 20% BCMA expression on PCs	• ORR (7 evaluable pts): 86% (2 sCR, 2 VGPR) • 2 MRD–responses (both VGPR) • CAR T-cell expansion and persistence were consistently observed	• No grade > 1 neurotoxicity or CRS observed at cutoff date
bb2121 [34] (Celgene)	• 4-1BB costimulatory domain • CD8α hinge and transmembrane domains • Culture/Activation medium: anti-CD3 and anti-CD28, OKT3 • Transduction: lentiviral vector	• Phase 1 two-part triald (NCT02658929) • Part 1: dose escalation (RRMM, ≥3 prior lines; ≥50% BCMA expression on PCs) • Part 2: dose-expansion (daratumumab experienced and refractory to last therapy, no BCMA expression required) • Lymphodepletion regimenb before single bb2121 infusion • Dose levels: 50, 150, 450, 800 × 106 cells • Median age: 60 years • Median prior lines of therapy: 7 • 45% of pts had high-risk cytogenetics	• ORR: 85% • Median DOR: 10.9 months • MRD–(18 evaluable pts): 89% • MRD–(16 evaluable responders): 100% • Median PFS: 11.8 months • 96%, 86%, 57%, and 20% of pts had detectable CAR T cells at 1, 3, 6, and 12 months, respectively	• Grade ≥ 3 AEs in 97% of pts • 76% of pts experienced CRS (6% grade 3) • Median time to CRS onset: 2 days • Median CRS duration: 5 days • 42% of pts experienced neurotoxicity, including 1 grade 4 event
bb21217 [40] (bluebird bio)	bb2121 structure with ex vivo culture addition of PI3K inhibitor bb007 to increase memory-like T-cell phenotype	• Phase 1 two-part triald (NCT03274219) • RRMM (≥3 lines of therapy, ≥50% BCMA expression on PCs) • Lymphodepletion regimenb before bb21217 infusion • Planned dose levels: 150, 450, 800, 1200 × 106 cells • Median age: 64 years • Median of 9 prior lines of therapy • 50% had high-risk cytogenetics	• ORR (7 evaluable pts): 86% (1 sCR, 3 VGPR, 2 PR) • MRD–(3 evaluable responders): 100% • 2/2 pts evaluable at 6 months had detectable CAR vector copies	• 5 of 8 pts experienced CRS (1 grade 3) • 1 pt experienced DLTs (grade 3 CRS, grade 4 encephalopathy with signs of PRES)
BCMA-CAR T cells [74] (Huazong University)	• Murine anti-BCMA scFv, CD8α hinge, CD28 transmembrane/costimulatory domain • Transduction: lentiviral vector	• Efficacy, safety, and tolerability trial (ChiCTR-OPC-16009113) • Lymphodepletion regimenb followed by target dose of 5.4–25.0 × 106 cells/kg • 28 pts (26 RRMM, 1 PCL, 1 POEMS)	• Strong BCMA expression (n = 22): ORR, 87% (73% CR); median DFS, 296 days • Weak BCMA expression (n = 6): ORR, 100% (33% CR or VGPR); OS, 206.5 days; median DFS, 64 days	• Grade 3 CRS occurred in 4 of 28 pts (14%)
BCMA CAR-T [105] (ShenZhen Biotechnology Company, Ltd)	Humanized alpaca anti-BCMA scFv, 4-1BB costimulatory domain	• Phase 1 trial in pts with RRMMd (NCT03661554) • Lymphodepletion regimen followed by infusion of 2–10 × 106 cells/kg • Average of 10 prior treatments	• ORR (28 days, 13 pts): 84.6% • ORR (10 weeks, 7 pts): 100% (3 sCR/CR, 1 VGPR, 3 PR) • Of 5 pts who reached 16 weeks, 4 kept remission and 1 relapsed	• 2 pts with grade 3–4 CRS (other pts had grade 0–2 CRS)
CART-19/BCMA [75] (The First Affiliated Hospital of Soochow University)	• OX40 and CD28 costimulatory domains, coinfusion with similar anti-CD19 CAR T cells • Culture/Activation medium: anti-CD3 mAb • Transduction: lentiviral vector	• Phase 1/2 triald (NCT03455972) • Pts received ASCT followed by coinfusion of CART-CD19 and CART-BCMA cells 14–20 days later • Pts with newly diagnosed stage III MM or pts who achieved ≤PR on prior therapy • All pts to date have >50% BCMA expression without CD19 expression on MM cells	• ORR (9 pts, after induction, ASCT, and CAR T-cell coinfusion): 100% (3 CR, 6 VGPR) • MRD–(post-CAR T): 66.7%	• Grade 1 or 2 CRS occurred in all 9 treated pts • No serious CRS or neurologic complications to date
CART-BCMA [37] (University of Pennsylvania–Novartis Alliance)	• Fully human anti-BCMA scFv, CD8 hinge and transmembrane domains, 4-1BB costimulatory domain • Culture/Activation medium: anti-CD3 and anti-CD28 paramagnetic beads and IL-2 • Transduction: lentiviral vector	• Phase 1 trial in 25 pts with RRMM (NCT02546167) • Cohort 1: 1–5 × 108 CAR T cells • Cohort 2: Cy 1.5 g/m2 + 1–5 × 107 CAR T cells • Cohort 3: Cy 1.5 g/m2 + 1–5 × 108 CAR T cells • Administered via split infusion (3 days) • BCMA expression assessed but not required for eligibility • Median age: 58 years • Median of 7 prior lines of therapy • 96% of pts had high-risk cytogenetics	• Cohort 1 (9 pts): 1 sCR, 2 VGPR, 1 PR • Cohort 2 (5 pts): 1 PR • Cohort 3 (11 pts): 1 CR, 3 VGPR, 3 PR • Overall ORR: 48% • Median DOR: 124.5 days • Median PFS: 125 days (cohort 3) • Median OS: 502 days • Peak CAR T-cell expansion generally occurred 10–14 days post infusion • CAR T cells remained detectable in 100% (20/20) and 82% (14/17) of pts evaluated at 3 and 6 months post infusion, respectively	• Grade ≥ 3 AEs in 96% of pts • CRS in 88% of pts (grade 3–4: 32%) • Median time to CRS onset: 4 days • Median duration of CRS: 6 days • Neurotoxicity in 32% of pts, including 3 grade 3–4 encephalopathy • 1 grade 5 AE (death)
CT053 [106] (CARsgen Therapeutics)	Human anti-BCMA scFv, 4-1BB costimulatory domain	• Multicenter investigator-initiated study in 16 pts with RRMM • Pts must have ≥50% BCMA expression on malignant cells • Lymphodepletion regimenb followed by single infusion of 0.5–1.8 × 108 cells • Median age: 55 years • Median of 4 prior lines of therapy	• ORR (13 evaluable pts): 100% • 12/13 pts achieved PR+ within 4 weeks of infusion • Durable responses at data cutoff for 12/13 pts • 11/13 pts had notable persistence of CAR T cells up to 4–6 months post infusion	• No DLTs or neurotoxicity • Most common grade ≥ 3 AEs: thrombocytopenia, leukopenia, anemia, neutropenia, fever • 3 cases of CRS (1 grade 3)
CT103A [107] (Nanjing Iaso Biotherapeutics Co, Ltd)	• Fully human anti-BCMA scFv, CD8α hinge and transmembrane region, 4-1BB costimulatory domain • Transduction: lentiviral vector	• Dose-escalation trial in 9 pts with RRMMd (ChiCTR1800018137) • 3 dose levels (1, 3, and 6 × 106 cells/kg) • Median of 4 prior lines of therapy	• ORR: 100% • 2 pts with ongoing response at 120 days post infusion (1 CR, 1 PR) • Robust CAR T-cell expansion was observed even at the lowest dosage level	• At 1 or 3 × 106 cells/kg, CRS cases were grade 0–2 • 1 DLT at 6 × 106 cells/kg
FCARH143 [73] (Fred Hutchinson Cancer Research Center)	• Fully human BCMA scFv, 4-1BB costimulatory domain • Culture/Activation medium: anti-CD3/anti-CD28 paramagnetic beads (CD8+ and CD4+ cells cultured independently) • Transduction: lentiviral vector • Product infused in 1:1 ratio of CD4+ to CD8+ CAR T cells	• Phase 1 trial in pts with RRMM with ≥5% BCMA expressiond • Pts stratified into 2 cohorts by tumor burden • Lymphodepletion regimen followed by starting dose of 5 × 107 EGFR + BCMA CAR T cells for each cohort • Median age: 63 years • Median of 8 prior regimens • All pts had ≥1 high-risk cytogenetic feature, 71% had ≥2 high-risk cytogenic features	• ORR (28 days, 6 evaluable pts): 100% • All pts surviving at median of 16 weeks of follow-up • CAR T cells remained detectable 90 days post infusion, representing ≤41.5% of CD3+ lymphocytes	• No DLTs • Grade ≤ 2 CRS in 6/7 pts • No neurotoxicity observed
JCARH125 [33] (Juno Therapeutics, Inc)	• Fully human anti-BCMA scFv, optimized spacer, CD28 transmembrane domain, optimized spacer, 4-1BB costimulatory domain • Transduction: lentiviral vector	• Phase 1/2 trial EVOLVEd (NCT03430011) • Lymphodepletion regimenb followed by JCARH125 infusion • Dose levels: 50, 150, or 450 × 106 CAR T cells • Pts with RRMM (≥3 prior regimens) • Median age: 62 years • Median of 7 prior lines of therapy • 77% of pts had high-risk cytogenetics	• ORR (44 pts): 82% (48% ≥VGPR) • MRD–(9 evaluable pts): 67% • Trend toward increased persistence 2 months post infusion for doses ≥ 150 × 106 CAR T cells	• CRS occurred in 80% of pts (grade ≥ 3: 9% of pts) • Median time to CRS onset: 3 days • Median duration of CRS: 5 days • Neurologic events in 25% of pts (grade ≥ 3: 7% of pts)
LCAR-B38M [32] (Nanjing Legend Biotech Co)	• 2 bispecific anti-BCMA variable fragments of llama heavy-chain murine Ab fused to 4-1BB signaling domain, CD8α hinge and transmembrane region • Culture/Activation medium: IL-2 • Transduction: lentiviral vector	• Phase 1 trial LEGEND-2 (NCT03090659) • Lymphodepletion regimen (cy alone) followed by LCAR-B38M (split into 3 infusions over 7 days) • Median LCAR-B38M dose: 0.5 × 106 cells/kg • Pts with RRMM (median of 3 prior lines of therapy) • Median age: 54 years	• ORR (57 pts): 88% (39 CR, 3 VGPR, 8 PR) • MRD–(57 pts): 63% • Median PFS: 15 months • Median DOR: 14 months • Median OS: not reached	• Most common AEs: pyrexia (91%), CRS (90%), thrombocytopenia (49%), leukopenia (47%) • Most common grade ≥ 3 AEs: leukopenia (30%), thrombocytopenia (23%), AST increases (21%) • Median time to CRS onset: 9 days • Median duration of CRS: 9 days
MCARH171 [68, 77] (Poseida Therapeutics, Inc)	• Human-derived, 4-1BB costimulatory domain, CD8α hinge and transmembrane region, truncated EGFR safety system • Culture/Activation medium: phytohemagglutinin or CD3/CD28 beads in presence of IL-2 • Transduction: retroviral vector	• Phase 1 dose-escalation triald • Lymphodepletion regimenb followed by MCARH171 infusion in 1–2 split doses • Mean doses (by cohort): 72 × 106, 137 × 106, 475 × 106, or 818 × 106 cells • Pts with RRMM (median of 6 prior lines of therapy) • 82% of pts had high-risk cytogenetics	• ORR (11 pts): 64% • ORR (dose 450 × 106 cells, 5 pts): 100% • Median DOR: 106 days • Expansion and persistence of CAR T cells were dose dependent	• No DLTs reported • CRS occurred in 60% of evaluable pts (grade 3 in 20% of pts) • No grade ≥ 3 neurotoxicity
P-BCMA-101 [78] (Poseida Therapeutics, Inc)	• Anti-BCMA Centyrin™ fused to CD3ζ/4-1BB signaling domain, safety switch and selection gene • Transduction: piggyBac™ DNA modification system	• Phase 1 dose-escalation triald (NCT03288493) • Lymphodepletion regimenb followed by P-BCMA-101 infusion • Dose range: 48–430 × 106 cells (across 3 cohorts) • Pts with RRMM (≥3 prior lines) • 64% of pts had high-risk cytogenetics	• ORR (6 pts treated above cohort 1 doses): 83% (3 PR, 1 VGPR, 1 sCR) • CAR T-cell expansion peaked at 2–3 weeks and remained detectable at 3 months in all 3 evaluable pts	• No neurotoxicity or DLTs related to treatment • 1 pt (8%) developed grade 2 CRS • Most common grade ≥ 3 AEs: cytopenia, febrile neutropenia

Ab antibody, AE adverse event, ASCT autologous stem cell transplantation, BCMA B-cell maturation antigen, CAR chimeric antigen receptor, CR complete response, CRS cytokine release syndrome, cy cyclophosphamide, DFS disease-free survival, DLT dose-limiting toxicity, DOR duration of response, EGFR epidermal growth factor receptor, IL interleukin, IV intravenous, mAb monoclonal Ab, MM multiple myeloma, MR minimal response, MRD minimal residual disease, ORR objective response rate, PC plasma cell, PCL PC leukemia, PD progressive disease, PFS progression-free survival, PI proteasome inhibitor, POEMS polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes, PR partial response, PRES posterior reversible encephalopathy syndrome, pt patient, Q3W once every 3 weeks, RRMM relapsed/refractory MM, scFv single-chain variable fragment, sCR stringent CR, SD stable disease, VGPR very good PR.

^aMRD data highlighted in bold.

^bLymphodepletion regimen consisted of cy and fludarabine.

^cFive patients not evaluated for MRD (three because of clinical lack of response, one because of baseline MRD negativity, one because of patient noncompliance).

^dData are from preliminary analyses of ongoing clinical trials.