PMID- 34772758
OWN - NLM
STAT- MEDLINE
DCOM- 20220111
LR  - 20220111
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 9
IP  - 11
DP  - 2021 Nov
TI  - Combining CTLA-4 and angiopoietin-2 blockade in patients with advanced melanoma: 
      a phase I trial.
LID - 10.1136/jitc-2021-003318 [doi]
LID - e003318
AB  - BACKGROUND: Angiogenic factors promote the growth of tumor vasculature, modulate 
      lymphocyte trafficking into tumors, and inhibit maturation of dendritic cells. We 
      hypothesized that MEDI3617, a human IgG1 kappa monoclonal antibody directed 
      against human angiopoietin-2, in combination with tremelimumab (treme), an IgG2 
      monoclonal antibody blocking cytotoxic T-lymphocyte-associated protein- (CTLA-4), 
      is safe in patients with advanced melanoma. METHODS: In a phase I, 3+3 dose 
      escalation trial, patients with metastatic or unresectable melanoma received 
      treme in combination with MEDI3617. The primary objectives of the study were 
      safety and determination of recommended phase II dose (RP2D). The secondary 
      objectives included determination of 6-month and 1-year overall survival and best 
      overall response rate. Immune cell populations and soluble factors were assessed 
      in peripheral blood and metastatic tumors using Fluorescence activated cell 
      sorting (FACS), Luminex, and multiplexed immunofluorescence. RESULTS: Fifteen 
      patients (median age: 62) were enrolled in the study (3 patients in cohort 1: 
      treme at 10 mg/kg and MEDI3617 at 200 mg; and 12 patients in cohort 2: treme at 
      10 mg/kg and MEDI3617 at 600 mg). The most common all-grade treatment-related 
      adverse events were rash, pruritus, fatigue, and extremity edema. No 
      dose-limiting toxicities were observed. Cohort 2 was determined to be the RP2D. 
      There were no patients with confirmed immune-related complete response or 
      immune-related partial response. Six of 15 patients had immune-related stable 
      disease, resulting in a disease control rate of 0.40 (95% CI 0.16 to 0.68). An 
      increase in frequencies of circulating inducible T-cell costimulator (ICOS)(+) 
      and human leukocyte antigen (HLA)-DR(+) CD4(+) and CD8(+) T cells and production 
      of Interleukin-2 and Interleukin-10 was observed post therapy. CONCLUSIONS: 
      Tremelimumab in combination with MEDI3617 is safe in patients with advanced 
      melanoma. Angiopoietin-2 inhibition in combination with immune checkpoint 
      inhibition warrants further exploration. TRIAL REGISTRATION NUMBER: NCT02141542.
CI  - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Ott, Patrick A
AU  - Ott PA
AUID- ORCID: 0000-0002-4253-943X
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA Patrick_Ott@dfci.harvard.edu.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
AD  - Harvard Medical School, Boston, Massachusetts, USA.
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
FAU - Nazzaro, Matthew
AU  - Nazzaro M
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA.
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
FAU - Pfaff, Kathleen L
AU  - Pfaff KL
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 
      USA.
FAU - Gjini, Evisa
AU  - Gjini E
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 
      USA.
FAU - Felt, Kristen D
AU  - Felt KD
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 
      USA.
FAU - Wolff, Jacquelyn O
AU  - Wolff JO
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 
      USA.
FAU - Buchbinder, Elizabeth I
AU  - Buchbinder EI
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
AD  - Harvard Medical School, Boston, Massachusetts, USA.
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
FAU - Haq, Rizwan
AU  - Haq R
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
AD  - Harvard Medical School, Boston, Massachusetts, USA.
FAU - Sullivan, Ryan J
AU  - Sullivan RJ
AUID- ORCID: 0000-0001-5344-6645
AD  - Harvard Medical School, Boston, Massachusetts, USA.
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
FAU - Lawrence, Donald P
AU  - Lawrence DP
AD  - Harvard Medical School, Boston, Massachusetts, USA.
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
FAU - McDermott, David F
AU  - McDermott DF
AD  - Harvard Medical School, Boston, Massachusetts, USA.
AD  - Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
FAU - Severgnini, Mariano
AU  - Severgnini M
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA.
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
FAU - Giobbie-Hurder, Anita
AU  - Giobbie-Hurder A
AD  - Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer 
      Institute, Boston, Massachusetts, USA.
FAU - Rodig, Scott J
AU  - Rodig SJ
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 
      USA.
FAU - Stephen Hodi, F
AU  - Stephen Hodi F
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
AD  - Harvard Medical School, Boston, Massachusetts, USA.
AD  - Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 
      USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02141542
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Angiopoietin-2)
RN  - 0 (CTLA-4 Antigen)
SB  - IM
MH  - Angiopoietin-2/*antagonists & inhibitors
MH  - CTLA-4 Antigen/*therapeutic use
MH  - Female
MH  - Humans
MH  - Male
MH  - Melanoma/*drug therapy
MH  - Middle Aged
PMC - PMC8593712
OTO - NOTNLM
OT  - CTLA-4 antigen
OT  - T-lymphocytes
OT  - combination
OT  - drug therapy
OT  - melanoma
COIS- Competing interests: PO reports research funding from and has advised Neon 
      Therapeutics, Bristol Myers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, 
      Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences, Xencor, Oncorus, and 
      Roche/Genentech. RH reports research grant support from Novartis and consulting 
      for Tango Therapeutics. EB reports consulting as an advisory board member for 
      Novartis, Apexigen, Shionogi, and BMS, and clinical trial support from Lilly, 
      Novartis, Partner Therapeutics, Genentech, and BVD. SR reports research support 
      from Bristol Myers Squibb, Merck, Affimed, and KITE/Gilead, and scientific 
      advisory board membership for Immunitas. RS reports grant funding as well as 
      personal fees from Merck. He has received personal fees from Array Biopharma, 
      Asana Biosciences, AstraZeneca, Bristol Myers Squibb, Eisai, Iovance, Merck, 
      Novartis, OncoSec, Pfizer, and Replimune. DM reports grant funding from Bristol 
      Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, and 
      personal fees for consulting from Bristol Myers Squibb, Merck, Pfizer, Alkermes, 
      EMD Serono, Eli Lilly, Iovance, Eisai, Werewolf Therapeutics, and Calithera 
      Biosciences. FSH reports grants, personal fees, and other from Bristol Myers 
      Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal 
      fees, and other from Novartis, personal fees from Surface, personal fees from 
      Compass Therapeutics, personal fees from Apricity, personal fees from Sanofi, 
      personal fees from Pionyr, personal fees from Torque, personal fees from Rheos, 
      personal fees from Bicara, other from Pieris Pharmaceuticals, personal fees from 
      Eisai, personal fees from Checkpoint Therapeutics, personal fees from Idera, 
      personal fees from Takeda, personal fees from Genentech/Roche, personal fees from 
      Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees 
      from Trillium, and personal fees from Catalym, outside the submitted work. In 
      addition, FSH has a patent method for treating MICA-related disorders 
      (#20100111973) with royalties paid, a patent tumor antigen and uses thereof 
      (#7250291) issued, a patent angiopoiten-2 biomarkers predictive of anti-immune 
      checkpoint response (#20170248603) pending, a patent for compositions and methods 
      for identification, assessment, prevention, and treatment of melanoma using PD-L1 
      isoforms (#20160340407) pending, a patent therapeutic peptides (#20160046716, 
      #20140004112, #20170022275, #20170008962) pending, a patent therapeutic peptides 
      (#9402905) issued, a patent method of using pembrolizumab and trebananib pending, 
      a patent vaccine compositions and methods for restoring NKG2D pathway function 
      against cancers (patent number: 10279021) issued, a patent antibody that binds to 
      MHC class I polypeptide-related sequence A (patent number: 10106611), and a 
      patent antigalectin antibody biomarker predictive of anti-immune checkpoint and 
      antiangiogenesis responses (publication number: 20170343552) pending.
EDAT- 2021/11/14 06:00
MHDA- 2022/01/12 06:00
PMCR- 2021/11/12
CRDT- 2021/11/13 05:43
PHST- 2021/09/13 00:00 [accepted]
PHST- 2021/11/13 05:43 [entrez]
PHST- 2021/11/14 06:00 [pubmed]
PHST- 2022/01/12 06:00 [medline]
PHST- 2021/11/12 00:00 [pmc-release]
AID - jitc-2021-003318 [pii]
AID - 10.1136/jitc-2021-003318 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2021 Nov;9(11):e003318. doi: 10.1136/jitc-2021-003318.