Combining CTLA-4 and angiopoietin-2 blockade in patients with advanced melanoma: a phase I trial

Abstract

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.

Keywords: CTLA-4 antigen; T-lymphocytes; combination; drug therapy; melanoma.

Conflict of interest statement

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.

© 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.

Figures

Figure 1

Kaplan-Meier estimates of progression-free survival and recurrence-free survival.

Figure 2

Immune cell populations and soluble factors in the peripheral blood in relation to treatment with tremelimumab and MEDI3617. (A) Peripheral CD4+human leukocyte antigen (HLA)-DR+ and CD8+HLA-DR+ T cell and CD4+Inducible T-cell costimulator (ICOS)+ and CD8+ICOS+ T cell populations over time assessed by flow cytometry (see the Methods section). Each line represents an individual patient. (B) Changes in quantities of cytokine and chemokine levels in plasma at 2 months post-treatment as measured by Luminex (see the Methods section). Different blue shades represent fold changes normalized to pretreatment levels (scale on the right vertical axis). Different cytokines and chemokines are denoted on the left vertical axis, and individual patients are denoted on the horizontal axis. Hatched boxes: below limit of quantification.

Figure 3

Immune cell populations in metastatic tumors prior to treatment with tremelimumab and MEDI3617 at baseline. CD4+ and CD4+programmed death (PD)-1+, CD8+ and CD8+PD-1+, CD68+, CD68+CD163+ (M2), CD68+CD163− (M1), and inducible T-cell costimulator (ICOS)+, CD8+ICOS+, and CD4+ICOS+ T cell populations were assessed by multiplex immunofluorescence (see the Methods section). Bars indicate cell density per square millimeter of the respective immune populations in tumors obtained prior to study treatment in individual patients.

Figure 4

Immune cell populations in metastatic tumors prior to treatment and on treatment with tremelimumab and MEDI3617. CD4+ and CD8+, inducible T-cell costimulator (ICOS)+, CD4+ICOS+, CD8+ICOS+, CD68+, and CD68+CD163+ T cell populations were assessed by multiplex immunofluorescence (see the Methods section). Bars indicate cell density per square millimeter of the respective immune populations in tumors obtained pretreatment and post-treatment in individual patients. Tx: treatment