Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients

Mirjam Fässler; Stefan Diem; Joanna Mangana; Omar Hasan Ali; Fiamma Berner; David Bomze; Sandra Ring; Rebekka Niederer; Cristina Del Carmen Gil Cruz; Christian Ivan Pérez Shibayama; Michal Krolik; Marco Siano; Markus Joerger; Mike Recher; Lorenz Risch; Sabine Güsewell; Martin Risch; Daniel E Speiser; Burkhard Ludewig; Mitchell P Levesque; Reinhard Dummer; Lukas Flatz

doi:10.1186/s40425-019-0523-2

Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients

J Immunother Cancer. 2019 Feb 20;7(1):50. doi: 10.1186/s40425-019-0523-2.

Authors

Mirjam Fässler^{1

2}, Stefan Diem^{1

3

4}, Joanna Mangana⁵, Omar Hasan Ali^{1

5}, Fiamma Berner¹, David Bomze¹, Sandra Ring¹, Rebekka Niederer¹, Cristina Del Carmen Gil Cruz¹, Christian Ivan Pérez Shibayama¹, Michal Krolik¹, Marco Siano³, Markus Joerger³, Mike Recher⁶, Lorenz Risch^{7

8

9}, Sabine Güsewell¹⁰, Martin Risch^{7

11}, Daniel E Speiser¹², Burkhard Ludewig¹, Mitchell P Levesque⁵, Reinhard Dummer⁵, Lukas Flatz^{13

14

15

16

17}

Affiliations

¹ Institute of Immunobiology, Kantonsspital St.Gallen, Rorschacherstrasse 95, 9007, St. Gallen, Switzerland.
² Department of Dermatology, Allergology and Venerology, Kantonsspital St.Gallen, Rorschacher Str. 95, 9007, St. Gallen, Switzerland.
³ Department of Oncology/Hematology, Kantonsspital St.Gallen, Rorschacher Str. 95, 9007, St. Gallen, Switzerland.
⁴ Department of Oncology/Hematology, Spital Grabs, Spitalstrasse 44, 9472, Grabs, Switzerland.
⁵ Department of Dermatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.
⁶ Clinic for Primary Immunodeficiency, Medical Outpatient Unit and Immunodeficiency Laboratory, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4067, Basel, Switzerland.
⁷ Labormedizinisches Zentrum Dr. Risch Ostschweiz AG, Brauerstrasse 95, 9016, St. Gallen, Switzerland.
⁸ Center of Laboratory Medicine, University Institute of Clinical Chemistry, University of Bern, Inselspital, INO-F, 3010, Bern, Switzerland.
⁹ Private University Triesen, Dorfstrasse 24, 9495, Triesen, Liechtenstein.
¹⁰ Clinical Trials Unit, Kantonsspital St.Gallen, Bedastrasse 1, 9000, St. Gallen, Switzerland.
¹¹ Department of Laboratory Medicine, Kantonsspital Graubünden, Loestrasse 170, 7000, Chur, Switzerland.
¹² Ludwig Cancer Research, University of Lausanne, Chemin des Boveresses 155, 1066 Épalinges, Lausanne, Switzerland.
¹³ Institute of Immunobiology, Kantonsspital St.Gallen, Rorschacherstrasse 95, 9007, St. Gallen, Switzerland. [email protected].
¹⁴ Department of Dermatology, Allergology and Venerology, Kantonsspital St.Gallen, Rorschacher Str. 95, 9007, St. Gallen, Switzerland. [email protected].
¹⁵ Department of Oncology/Hematology, Kantonsspital St.Gallen, Rorschacher Str. 95, 9007, St. Gallen, Switzerland. [email protected].
¹⁶ Department of Dermatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland. [email protected].
¹⁷ Clinical Trials Unit, Kantonsspital St.Gallen, Bedastrasse 1, 9000, St. Gallen, Switzerland. [email protected].

Abstract

Background: Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs). Reliable biomarkers to predict response and clinical outcome are needed.

Methods: We investigated the role of melanoma-associated antibodies as predictive markers for CI therapy in two independent cohorts. In cohort 1, a prospective study, we measured specific antibodies before treatment, after one week and after six to nine weeks of treatment. Cohort 2 consisted of serum samples prior to CI therapy initiation. ELISA assays were performed to quantify specific IgG directed against melanocyte differentiation antigens tyrosinase-related proteins 1 and 2 (TRP1/TYRP1 and TRP2/TYRP2), glycoprotein 100 (gp100), MelanA/MART1, and the cancer-testis antigen NY-ESO-1. Response was defined as either complete or partial remission on CT scan according to RECIST 1.1.

Results: In cohort 1, baseline levels of these antibodies were higher in the responder group, although statistical significance was only reached for NY-ESO-1 (p = 0.007). In cohort 2, significantly higher antibody baseline levels for MelanA/MART1 (p = 0.003) and gp100 (p = 0.029) were found. After pooling the results from both cohorts, higher levels of MelanA/MART1 (p = 0.013), TRP1/TYRP1 (p = 0.048), TRP2/TYRP2 (p = 0.047) and NY-ESO-1 (p = 0.005) specific antibodies at baseline were independently associated with response.

Conclusions: Melanoma-associated antibodies may be candidate biomarkers for response and survival in metastatic melanoma patients being treated with CIs. These markers may be used to complement patient assessment, in combination with PD-L1 status, tumor-infiltrating lymphocytes and tumor mutational burden, with the aim to predict outcome of CI treatment in patients with metastatic melanoma.

Trial registration: Ethikkommission Ostschweiz, EKOS 16/079 https://ongoingprojects.swissethics.ch/runningProjects_list.php?q=%28BASECID~contains~2016-00998%29&orderby=dBASECID .

Keywords: Antibodies; Biomarker; Cancer/testis antigens; Checkpoint inhibitors; Immune response; MART1; Melanocyte differentiation antigens; Metastatic melanoma; NY-ESO-1; TRP1; TRP2; gp100.

Publication types

Controlled Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized / therapeutic use*
Antibodies, Neoplasm / blood*
Antineoplastic Agents, Immunological / therapeutic use*
Biomarkers
Female
Humans
Immunoglobulin G / blood
Ipilimumab / therapeutic use*
Male
Melanoma / blood*
Melanoma / drug therapy
Melanoma / immunology
Middle Aged
Nivolumab / therapeutic use*

Substances

Antibodies, Monoclonal, Humanized
Antibodies, Neoplasm
Antineoplastic Agents, Immunological
Biomarkers
Immunoglobulin G
Ipilimumab
Nivolumab
pembrolizumab