Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma

Niccolò Rossi; Karla A Lee; Maria V Bermudez; Alessia Visconti; Andrew Maltez Thomas; Laura A Bolte; Johannes R Björk; Laura Kist de Ruijter; Julia Newton-Bishop; Mark Harland; Heather M Shaw; Mark Harries; Joseph Sacco; Ruth Board; Paul Lorigan; Elisabeth G E de Vries; Nicola Segata; Leonie Taams; Sophie Papa; Tim D Spector; Paul Nathan; Rinse K Weersma; Geke A P Hospers; Rudolf S N Fehrmann; Veronique Bataille; Mario Falchi

doi:10.1016/j.ebiom.2022.104235

Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma

Niccolò Rossi, Karla A Lee, Maria V Bermudez, Alessia Visconti, Andrew Maltez Thomas, Laura A Bolte, Johannes R Björk, Laura Kist de Ruijter, Julia Newton-Bishop, Mark Harland, Heather M Shaw, Mark Harries, Joseph Sacco, Ruth Board, Paul Lorigan, Elisabeth G E de Vries, Nicola Segata, Leonie Taams, Sophie Papa, Tim D SpectorPaul Nathan, Rinse K Weersma, Geke A P Hospers, Rudolf S N Fehrmann, Veronique Bataille, Mario Falchi

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma.

METHODS: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival.

FINDINGS: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10-4, 2.29 × 10-4, and 1.02 × 10-3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10-2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10-3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response.

INTERPRETATION: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy.

FUNDING: This work was supported by the Seerave Foundation and Dutch Cancer Society.

Original language	English
Article number	104235
Pages (from-to)	104235
Journal	EBioMedicine
Volume	83
Early online date	22 Aug 2022
DOIs	https://doi.org/10.1016/j.ebiom.2022.104235
Publication status	Published - Sept 2022

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10.1016/j.ebiom.2022.104235

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Rossi, N., Lee, K. A., Bermudez, M. V., Visconti, A., Thomas, A. M., Bolte, L. A., Björk, J. R., de Ruijter, L. K., Newton-Bishop, J., Harland, M., Shaw, H. M., Harries, M., Sacco, J., Board, R., Lorigan, P., de Vries, E. G. E., Segata, N., Taams, L., Papa, S., ... Falchi, M. (2022). Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma. EBioMedicine, 83, 104235. Article 104235. https://doi.org/10.1016/j.ebiom.2022.104235

@article{7554cc7d78cd42819f593afb2511433c,

title = "Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma",

abstract = "BACKGROUND: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma.METHODS: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival.FINDINGS: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10-4, 2.29 × 10-4, and 1.02 × 10-3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10-2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10-3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response.INTERPRETATION: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy.FUNDING: This work was supported by the Seerave Foundation and Dutch Cancer Society.",

author = "Niccol{\`o} Rossi and Lee, {Karla A} and Bermudez, {Maria V} and Alessia Visconti and Thomas, {Andrew Maltez} and Bolte, {Laura A} and Bj{\"o}rk, {Johannes R} and {de Ruijter}, {Laura Kist} and Julia Newton-Bishop and Mark Harland and Shaw, {Heather M} and Mark Harries and Joseph Sacco and Ruth Board and Paul Lorigan and {de Vries}, {Elisabeth G E} and Nicola Segata and Leonie Taams and Sophie Papa and Spector, {Tim D} and Paul Nathan and Weersma, {Rinse K} and Hospers, {Geke A P} and Fehrmann, {Rudolf S N} and Veronique Bataille and Mario Falchi",

note = "Funding Information: The authors would like to acknowledge the Seerave Foundation which funded this work, along with The Dutch Cancer Society grant 10034 POINTING to EGEdV. We also acknowledge and thank the MRC (grant number MR/MO19012/1) which supported JNB and the work done in Leeds. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. We would like to acknowledge Sanofi for supporting NR. Lastly, we would like to thank all the patients who selflessly took the time to donate samples for this project. Funding Information: RKW acted as a consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico, and Ferring, and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. TDS is a co-founder of Zoe Global. EGEdV reports an advisory role at Daiichi Sankyo, NSABP and Sanofi (paid to University Medical Center Groningen), and research funding from Amgen, AstraZeneca, Bayer, Crescendo, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon (paid to University Medical Center Groningen). SP received speaker fees from Almirall, BMS, ISDIN, La Roche Posay, Leo Pharma, Regeneron, Roche, Sanofi, and acted as an advisory board for Almirall, ISDIN, La Roche Posay, Pfizer, Roche, Regeneron, Sanofi, Sunpharma and research funding from Abbie, AMGEN, ISDIN, La Roche Posay, Leo Pharma, Novartis. SP is also an employee of Enara Bio. RB has received honoraria from, and sits on advisory boards of, Novartis, BMS and MSD. PN has received honoraria in the last 2 years for advisory board membership for AztraZeneca, Esai, BMS, Immunocore, Ipsen, Merck, MSD, Novartis, Pfizer, 4SC. HS has received honoraria for consulting/advisory board membership and speaker's bureau from Novartis, BMS, Sanofi and MSD, along with honoraria for consulting/advisory board membership from Immunocore, Idera, Iovance, Genmab, Genzyme/Regeneron, Macrogenics and Roche. JS received a grant to his institution to fund investigator led research from Immunocore, along with personal fees and institution fees for advisory roles and presentations at meetings from Immunocore. JS also declares a grant for an investigator sponsored trial, personal fees for advisory board attendance and support in attending conferences along with institutional support to run BMS sponsored trials from BMS. JS has received a grant to fund investigator sponsored trials from AstraZeneca, funding from Replimune to his institution to fund Replimune sponsored research and honoraria from Pierre-Fabre. JS has received fees from MSD for advisory board/conference attendance as well as his institution receiving funding to run MSD clinical trials. PL has received personal fees from BMS, Merck, Novartis, GSK, Amgen, Chugai, Pierre-Fabre, NeraCare, Roche and Oncology Education Canada. LT reports research funding from a Sanofi iAward. GH received a research grant from BMS, along with consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre. Funding Information: The authors would like to acknowledge the Seerave Foundation which funded this work, along with The Dutch Cancer Society grant 10034 POINTING to EGEdV. We also acknowledge and thank the MRC (grant number MR/MO19012/1) which supported JNB and the work done in Leeds. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. We would like to acknowledge Sanofi for supporting NR. Lastly, we would like to thank all the patients who selflessly took the time to donate samples for this project. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = sep,

doi = "10.1016/j.ebiom.2022.104235",

language = "English",

volume = "83",

pages = "104235",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

Rossi, N , Lee, KA, Bermudez, MV, Visconti, A, Thomas, AM, Bolte, LA, Björk, JR, de Ruijter, LK, Newton-Bishop, J, Harland, M, Shaw, HM, Harries, M, Sacco, J, Board, R, Lorigan, P, de Vries, EGE, Segata, N, Taams, L , Papa, S , Spector, TD, Nathan, P, Weersma, RK, Hospers, GAP, Fehrmann, RSN, Bataille, V & Falchi, M 2022, 'Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma', EBioMedicine, vol. 83, 104235, pp. 104235. https://doi.org/10.1016/j.ebiom.2022.104235

TY - JOUR

T1 - Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma

AU - Rossi, Niccolò

AU - Lee, Karla A

AU - Bermudez, Maria V

AU - Visconti, Alessia

AU - Thomas, Andrew Maltez

AU - Bolte, Laura A

AU - Björk, Johannes R

AU - de Ruijter, Laura Kist

AU - Newton-Bishop, Julia

AU - Harland, Mark

AU - Shaw, Heather M

AU - Harries, Mark

AU - Sacco, Joseph

AU - Board, Ruth

AU - Lorigan, Paul

AU - de Vries, Elisabeth G E

AU - Segata, Nicola

AU - Taams, Leonie

AU - Papa, Sophie

AU - Spector, Tim D

AU - Nathan, Paul

AU - Weersma, Rinse K

AU - Hospers, Geke A P

AU - Fehrmann, Rudolf S N

AU - Bataille, Veronique

AU - Falchi, Mario

N1 - Funding Information: The authors would like to acknowledge the Seerave Foundation which funded this work, along with The Dutch Cancer Society grant 10034 POINTING to EGEdV. We also acknowledge and thank the MRC (grant number MR/MO19012/1) which supported JNB and the work done in Leeds. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. We would like to acknowledge Sanofi for supporting NR. Lastly, we would like to thank all the patients who selflessly took the time to donate samples for this project. Funding Information: RKW acted as a consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico, and Ferring, and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. TDS is a co-founder of Zoe Global. EGEdV reports an advisory role at Daiichi Sankyo, NSABP and Sanofi (paid to University Medical Center Groningen), and research funding from Amgen, AstraZeneca, Bayer, Crescendo, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon (paid to University Medical Center Groningen). SP received speaker fees from Almirall, BMS, ISDIN, La Roche Posay, Leo Pharma, Regeneron, Roche, Sanofi, and acted as an advisory board for Almirall, ISDIN, La Roche Posay, Pfizer, Roche, Regeneron, Sanofi, Sunpharma and research funding from Abbie, AMGEN, ISDIN, La Roche Posay, Leo Pharma, Novartis. SP is also an employee of Enara Bio. RB has received honoraria from, and sits on advisory boards of, Novartis, BMS and MSD. PN has received honoraria in the last 2 years for advisory board membership for AztraZeneca, Esai, BMS, Immunocore, Ipsen, Merck, MSD, Novartis, Pfizer, 4SC. HS has received honoraria for consulting/advisory board membership and speaker's bureau from Novartis, BMS, Sanofi and MSD, along with honoraria for consulting/advisory board membership from Immunocore, Idera, Iovance, Genmab, Genzyme/Regeneron, Macrogenics and Roche. JS received a grant to his institution to fund investigator led research from Immunocore, along with personal fees and institution fees for advisory roles and presentations at meetings from Immunocore. JS also declares a grant for an investigator sponsored trial, personal fees for advisory board attendance and support in attending conferences along with institutional support to run BMS sponsored trials from BMS. JS has received a grant to fund investigator sponsored trials from AstraZeneca, funding from Replimune to his institution to fund Replimune sponsored research and honoraria from Pierre-Fabre. JS has received fees from MSD for advisory board/conference attendance as well as his institution receiving funding to run MSD clinical trials. PL has received personal fees from BMS, Merck, Novartis, GSK, Amgen, Chugai, Pierre-Fabre, NeraCare, Roche and Oncology Education Canada. LT reports research funding from a Sanofi iAward. GH received a research grant from BMS, along with consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre. Funding Information: The authors would like to acknowledge the Seerave Foundation which funded this work, along with The Dutch Cancer Society grant 10034 POINTING to EGEdV. We also acknowledge and thank the MRC (grant number MR/MO19012/1) which supported JNB and the work done in Leeds. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. We would like to acknowledge Sanofi for supporting NR. Lastly, we would like to thank all the patients who selflessly took the time to donate samples for this project. Publisher Copyright: © 2022 The Author(s)

PY - 2022/9

Y1 - 2022/9

N2 - BACKGROUND: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma.METHODS: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival.FINDINGS: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10-4, 2.29 × 10-4, and 1.02 × 10-3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10-2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10-3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response.INTERPRETATION: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy.FUNDING: This work was supported by the Seerave Foundation and Dutch Cancer Society.

AB - BACKGROUND: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma.METHODS: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival.FINDINGS: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10-4, 2.29 × 10-4, and 1.02 × 10-3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10-2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10-3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response.INTERPRETATION: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy.FUNDING: This work was supported by the Seerave Foundation and Dutch Cancer Society.

UR - http://www.scopus.com/inward/record.url?scp=85136473914&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2022.104235

DO - 10.1016/j.ebiom.2022.104235

M3 - Article

C2 - 36007304

SN - 2352-3964

VL - 83

SP - 104235

JO - EBioMedicine

JF - EBioMedicine

M1 - 104235

ER -

Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma

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