PMID- 37527011
OWN - NLM
STAT- Publisher
LR  - 20231015
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 29
IP  - 20
DP  - 2023 Oct 13
TI  - Axicabtagene Ciloleucel in Combination with the 4-1BB Agonist Utomilumab in 
      Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from 
      ZUMA-11.
PG  - 4118-4127
LID - 10.1158/1078-0432.CCR-23-0916 [doi]
AB  - PURPOSE: Chimeric antigen receptor (CAR) T-cell therapies have shown clinical 
      benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), 
      yet approximately 60% of patients do not respond or eventually relapse. We 
      investigated the safety and feasibility of the CD19-directed CAR T-cell therapy 
      axicabtagene ciloleucel (axi-cel) in combination with the 4-1BB agonist antibody 
      utomilumab as an approach to improve efficacy of CAR T-cell therapy. PATIENTS AND 
      METHODS: In phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL 
      received a single axi-cel infusion (target dose, 2 x 106 cells/kg) plus 
      utomilumab 10 to 200 mg intravenously every 4 weeks for up to 6 months in a 
      dose-escalation design. The primary endpoint was incidence of dose-limiting 
      toxicities (DLT) with utomilumab. Key secondary endpoints were safety, antitumor 
      activity, pharmacokinetics, and pharmacodynamics. RESULTS: No DLTs were observed 
      among patients treated with axi-cel and utomilumab (n = 12). Grade >/=3 adverse 
      events occurred in 10 patients (83%); none were Grade >/=3 cytokine release 
      syndrome or neurologic events. The objective response rate was 75% and seven 
      patients (58%) had a complete response. Peak CAR T-cell levels increased in a 
      utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 
      100 mg had persistently increased CAR T cells on days 57 to 168 compared with 
      other dose levels. Utomilumab was associated with dose-dependent increases in 
      IL2, IFNgamma, and IL10. CONCLUSIONS: Utomilumab-mediated 4-1BB agonism combined with 
      axi-cel therapy had a manageable safety profile. Dual 4-1BB and CD28 
      costimulation is a feasible therapeutic approach that may enhance CAR T-cell 
      expansion in patients with LBCL.
CI  - (c)2023 The Authors; Published by the American Association for Cancer Research.
FAU - Jain, Michael D
AU  - Jain MD
AUID- ORCID: 0000-0002-7789-1257
AD  - Moffitt Cancer Center, Tampa, Florida.
FAU - Miklos, David B
AU  - Miklos DB
AUID- ORCID: 0000-0003-0717-4305
AD  - Stanford University, Stanford, California.
FAU - Jacobson, Caron A
AU  - Jacobson CA
AUID- ORCID: 0000-0002-0180-0654
AD  - Dana-Farber Cancer Institute, Boston, Massachusetts.
FAU - Timmerman, John M
AU  - Timmerman JM
AUID- ORCID: 0000-0003-4104-8943
AD  - University of California, Los Angeles Medical Center, Los Angeles, California.
FAU - Sun, Jennifer
AU  - Sun J
AUID- ORCID: 0009-0008-8649-3817
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Nater, Jenny
AU  - Nater J
AUID- ORCID: 0000-0001-9495-0653
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Fang, Xiang
AU  - Fang X
AUID- ORCID: 0009-0006-3958-990X
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Patel, Ankit
AU  - Patel A
AUID- ORCID: 0009-0000-2105-2262
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Davis, Madison
AU  - Davis M
AUID- ORCID: 0000-0002-1293-8974
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Heeke, Darren
AU  - Heeke D
AUID- ORCID: 0009-0006-3790-5227
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Trinh, Tan
AU  - Trinh T
AUID- ORCID: 0009-0000-8980-3579
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Mattie, Mike
AU  - Mattie M
AUID- ORCID: 0000-0003-0868-3865
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Neumann, Frank
AU  - Neumann F
AUID- ORCID: 0009-0001-0995-1537
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Kim, Jenny J
AU  - Kim JJ
AUID- ORCID: 0009-0008-6816-1499
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - To, Christina
AU  - To C
AUID- ORCID: 0000-0001-7164-8072
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Filosto, Simone
AU  - Filosto S
AUID- ORCID: 0000-0002-7854-998X
AD  - Kite, a Gilead Company, Santa Monica, California.
FAU - Reshef, Ran
AU  - Reshef R
AUID- ORCID: 0000-0003-2185-9546
AD  - Columbia University Irving Medical Center, New York, New York.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
SB  - IM
PMC - PMC10570684
EDAT- 2023/08/01 19:13
MHDA- 2023/08/01 19:13
PMCR- 2023/10/13
CRDT- 2023/08/01 12:33
PHST- 2023/03/29 00:00 [received]
PHST- 2023/06/15 00:00 [revised]
PHST- 2023/07/28 00:00 [accepted]
PHST- 2023/08/01 19:13 [pubmed]
PHST- 2023/08/01 19:13 [medline]
PHST- 2023/08/01 12:33 [entrez]
PHST- 2023/10/13 00:00 [pmc-release]
AID - 728154 [pii]
AID - CCR-23-0916 [pii]
AID - 10.1158/1078-0432.CCR-23-0916 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2023 Oct 13;29(20):4118-4127. doi: 
      10.1158/1078-0432.CCR-23-0916.