Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma

Nirmish Singla; Thomas R. Nirschl; Aleksandar Z. Obradovic; Eugene Shenderov; Kara Lombardo; Xiaopu Liu; Alice Pons; Jelani C. Zarif; Steven P. Rowe; Bruce J. Trock; Hans J. Hammers; Trinity J. Bivalacqua; Phillip M. Pierorazio; Julie S. Deutsch; Tamara L. Lotan; Janis M. Taube; Yasser M.A. Ged; Michael A. Gorin; Mohamad E. Allaf; Charles G. Drake

doi:10.1038/s41598-024-51889-9

Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma

Nirmish Singla, Thomas R. Nirschl, Aleksandar Z. Obradovic, Eugene Shenderov, Kara Lombardo, Xiaopu Liu, Alice Pons, Jelani C. Zarif, Steven P. Rowe, Bruce J. Trock, Hans J. Hammers, Trinity J. Bivalacqua, Phillip M. Pierorazio, Julie S. Deutsch, Tamara L. Lotan, Janis M. Taube, Yasser M.A. Ged, Michael A. Gorin, Mohamad E. Allaf, Charles G. Drake

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Abstract

Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.

Original language	English (US)
Article number	1458
Journal	Scientific reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-51889-9
State	Published - Dec 2024

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Singla, N., Nirschl, T. R., Obradovic, A. Z., Shenderov, E., Lombardo, K., Liu, X., Pons, A., Zarif, J. C., Rowe, S. P., Trock, B. J., Hammers, H. J., Bivalacqua, T. J., Pierorazio, P. M., Deutsch, J. S., Lotan, T. L., Taube, J. M., Ged, Y. M. A., Gorin, M. A., Allaf, M. E., & Drake, C. G. (2024). Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma. Scientific reports, 14(1), Article 1458. https://doi.org/10.1038/s41598-024-51889-9

Singla, N, Nirschl, TR, Obradovic, AZ, Shenderov, E, Lombardo, K, Liu, X, Pons, A, Zarif, JC, Rowe, SP, Trock, BJ, Hammers, HJ, Bivalacqua, TJ, Pierorazio, PM, Deutsch, JS, Lotan, TL, Taube, JM, Ged, YMA, Gorin, MA, Allaf, ME & Drake, CG 2024, 'Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma', Scientific reports, vol. 14, no. 1, 1458. https://doi.org/10.1038/s41598-024-51889-9

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title = "Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma",

abstract = "Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.",

author = "Nirmish Singla and Nirschl, {Thomas R.} and Obradovic, {Aleksandar Z.} and Eugene Shenderov and Kara Lombardo and Xiaopu Liu and Alice Pons and Zarif, {Jelani C.} and Rowe, {Steven P.} and Trock, {Bruce J.} and Hammers, {Hans J.} and Bivalacqua, {Trinity J.} and Pierorazio, {Phillip M.} and Deutsch, {Julie S.} and Lotan, {Tamara L.} and Taube, {Janis M.} and Ged, {Yasser M.A.} and Gorin, {Michael A.} and Allaf, {Mohamad E.} and Drake, {Charles G.}",

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AU - Shenderov, Eugene

AU - Lombardo, Kara

AU - Liu, Xiaopu

AU - Pons, Alice

AU - Zarif, Jelani C.

AU - Rowe, Steven P.

AU - Trock, Bruce J.

AU - Hammers, Hans J.

AU - Bivalacqua, Trinity J.

AU - Pierorazio, Phillip M.

AU - Deutsch, Julie S.

AU - Lotan, Tamara L.

AU - Taube, Janis M.

AU - Ged, Yasser M.A.

AU - Gorin, Michael A.

AU - Allaf, Mohamad E.

AU - Drake, Charles G.

PY - 2024/12

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N2 - Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.

AB - Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.

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Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma

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