Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer

Matthew D. Galsky; Xiangnan Guan; Deepali Rishipathak; Aaron S. Rapaport; Hesham M. Shehata; Romain Banchereau; Kobe Yuen; Eugene Varfolomeev; Ruozhen Hu; Chia Jung Han; Haocheng Li; Yuxin Liang; Domagoj Vucic; Li Wang; Jun Zhu; Haocheng Yu; Rebecca H. Herbst; Emma Hajaj; Evgeny Kiner; Aristotelis Bamias; Maria De Santis; Ian D. Davis; José Ángel Arranz; Eiji Kikuchi; Sandrine Bernhard; Patrick Williams; Chooi Lee; Ira Mellman; Shomyseh Sanjabi; Robert Johnston; Peter C. Black; Enrique Grande; Sanjeev Mariathasan

doi:10.1016/j.xcrm.2024.101393

Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer

Matthew D. Galsky, Xiangnan Guan, Deepali Rishipathak, Aaron S. Rapaport, Hesham M. Shehata, Romain Banchereau, Kobe Yuen, Eugene Varfolomeev, Ruozhen Hu, Chia Jung Han, Haocheng Li, Yuxin Liang, Domagoj Vucic, Li Wang, Jun Zhu, Haocheng Yu, Rebecca H. Herbst, Emma Hajaj, Evgeny Kiner, Aristotelis BamiasMaria De Santis, Ian D. Davis, José Ángel Arranz, Eiji Kikuchi, Sandrine Bernhard, Patrick Williams, Chooi Lee, Ira Mellman, Shomyseh Sanjabi, Robert Johnston, Peter C. Black, Enrique Grande, Sanjeev Mariathasan

Eastern Health Clinical School

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

52 Citations (Scopus)

Abstract

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

Original language	English
Article number	101393
Number of pages	21
Journal	Cell Reports Medicine
Volume	5
Issue number	2
DOIs	https://doi.org/10.1016/j.xcrm.2024.101393
Publication status	Published - 20 Feb 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

bladder cancer
carboplatin
chemotherapy
cisplatin
immune checkpoint blockade
immunogenic cell death
PD-1 blockade
PD-L1 blockade
single cell RNA sequencing
urothelial cancer

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Galsky, M. D., Guan, X., Rishipathak, D., Rapaport, A. S., Shehata, H. M., Banchereau, R., Yuen, K., Varfolomeev, E., Hu, R., Han, C. J., Li, H., Liang, Y., Vucic, D., Wang, L., Zhu, J., Yu, H., Herbst, R. H., Hajaj, E., Kiner, E., ... Mariathasan, S. (2024). Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer. Cell Reports Medicine, 5(2), Article 101393. https://doi.org/10.1016/j.xcrm.2024.101393

@article{bccbb528b43444d88cc957ec17467b96,

title = "Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer",

abstract = "In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.",

keywords = "bladder cancer, carboplatin, chemotherapy, cisplatin, immune checkpoint blockade, immunogenic cell death, PD-1 blockade, PD-L1 blockade, single cell RNA sequencing, urothelial cancer",

author = "Galsky, \{Matthew D.\} and Xiangnan Guan and Deepali Rishipathak and Rapaport, \{Aaron S.\} and Shehata, \{Hesham M.\} and Romain Banchereau and Kobe Yuen and Eugene Varfolomeev and Ruozhen Hu and Han, \{Chia Jung\} and Haocheng Li and Yuxin Liang and Domagoj Vucic and Li Wang and Jun Zhu and Haocheng Yu and Herbst, \{Rebecca H.\} and Emma Hajaj and Evgeny Kiner and Aristotelis Bamias and \{De Santis\}, Maria and Davis, \{Ian D.\} and Arranz, \{Jos{\'e} {\'A}ngel\} and Eiji Kikuchi and Sandrine Bernhard and Patrick Williams and Chooi Lee and Ira Mellman and Shomyseh Sanjabi and Robert Johnston and Black, \{Peter C.\} and Enrique Grande and Sanjeev Mariathasan",

note = "Funding Information: This work was supported by CA196521 (to M.D.G). This study was sponsored by F. Hoffmann-La Roche Ltd . Medical writing assistance for this manuscript was provided by Qing Yun Chong, PhD, of MediTech Media Ltd , and funded by F. Hoffmann-La Roche Ltd . Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = feb,

day = "20",

doi = "10.1016/j.xcrm.2024.101393",

language = "English",

volume = "5",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "2",

}

Galsky, MD, Guan, X, Rishipathak, D, Rapaport, AS, Shehata, HM, Banchereau, R, Yuen, K, Varfolomeev, E, Hu, R, Han, CJ, Li, H, Liang, Y, Vucic, D, Wang, L, Zhu, J, Yu, H, Herbst, RH, Hajaj, E, Kiner, E, Bamias, A, De Santis, M, Davis, ID, Arranz, JÁ, Kikuchi, E, Bernhard, S, Williams, P, Lee, C, Mellman, I, Sanjabi, S, Johnston, R, Black, PC, Grande, E & Mariathasan, S 2024, 'Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer', Cell Reports Medicine, vol. 5, no. 2, 101393. https://doi.org/10.1016/j.xcrm.2024.101393

TY - JOUR

T1 - Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer

AU - Galsky, Matthew D.

AU - Guan, Xiangnan

AU - Rishipathak, Deepali

AU - Rapaport, Aaron S.

AU - Shehata, Hesham M.

AU - Banchereau, Romain

AU - Yuen, Kobe

AU - Varfolomeev, Eugene

AU - Hu, Ruozhen

AU - Han, Chia Jung

AU - Li, Haocheng

AU - Liang, Yuxin

AU - Vucic, Domagoj

AU - Wang, Li

AU - Zhu, Jun

AU - Yu, Haocheng

AU - Herbst, Rebecca H.

AU - Hajaj, Emma

AU - Kiner, Evgeny

AU - Bamias, Aristotelis

AU - De Santis, Maria

AU - Davis, Ian D.

AU - Arranz, José Ángel

AU - Kikuchi, Eiji

AU - Bernhard, Sandrine

AU - Williams, Patrick

AU - Lee, Chooi

AU - Mellman, Ira

AU - Sanjabi, Shomyseh

AU - Johnston, Robert

AU - Black, Peter C.

AU - Grande, Enrique

AU - Mariathasan, Sanjeev

N1 - Funding Information: This work was supported by CA196521 (to M.D.G). This study was sponsored by F. Hoffmann-La Roche Ltd . Medical writing assistance for this manuscript was provided by Qing Yun Chong, PhD, of MediTech Media Ltd , and funded by F. Hoffmann-La Roche Ltd . Publisher Copyright: © 2024 The Authors

PY - 2024/2/20

Y1 - 2024/2/20

N2 - In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

AB - In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

KW - bladder cancer

KW - carboplatin

KW - chemotherapy

KW - cisplatin

KW - immune checkpoint blockade

KW - immunogenic cell death

KW - PD-1 blockade

KW - PD-L1 blockade

KW - single cell RNA sequencing

KW - urothelial cancer

UR - https://www.scopus.com/pages/publications/85184769865

U2 - 10.1016/j.xcrm.2024.101393

DO - 10.1016/j.xcrm.2024.101393

M3 - Article

C2 - 38280376

AN - SCOPUS:85184769865

SN - 2666-3791

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 2

M1 - 101393

ER -

Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer

Abstract

UN SDGs

Keywords

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