A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant

Naoka Murakami¹, Patrick Mulvaney², Melissa Danesh², Ala Abudayyeh³, Adi Diab⁴, Noha Abdel-Wahab⁵, Maen Abdelrahim⁶, Pascale Khairallah⁷, Shayan Shirazian⁷, Aleksandra Kukla⁸, Itunu O Owoyemi⁸, Tarek Alhamad⁹, Samir Husami⁹, Madhav Menon¹⁰, Andrew Santeusanio¹⁰, Christopher D Blosser¹¹, Sandra Carias Zuniga¹¹, Maria Jose Soler¹², Francesc Moreso¹², Zain Mithani¹³, David Ortiz-Melo¹⁴, Edgar A Jaimes¹⁵, Victoria Gutgarts¹⁵, Erik Lum¹⁶, Gabriel M Danovitch¹⁶, Francesca Cardarelli¹⁷, Reed E Drews¹⁸, Claude Bassil¹⁹, Jennifer L Swank¹⁹, Scott Westphal²⁰, Roslyn B Mannon²⁰, Keisuke Shirai²¹, Abhijat Kitchlu²², Song Ong²³, Shana M Machado²³, Suraj S Mothi²⁴, Patrick A Ott²⁵, Osama Rahma²⁵, F Stephen Hodi²⁵, Meghan E Sise²⁶, Shruti Gupta²⁴, David E Leaf²⁴, Craig E Devoe²⁷, Rimda Wanchoo²⁸, Vinay V Nair²⁸, Chrysalyne D Schmults², Glenn J Hanna²⁵, Ben Sprangers²⁹, Leonardo V Riella³⁰, Kenar D Jhaveri³¹; Immune Checkpoint Inhibitors in Solid Organ Transplant Consortium

Affiliations

¹ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: nmurakami1@bwh.harvard.edu.
² Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
³ Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴ Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁵ Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of General Internal Medicine, Section of Rheumatology and Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt.
⁶ Institute for Academic Medicine and Weill Cornell Medical College, Houston Methodist Cancer Center, Houston, Texas, USA.
⁷ Division of Nephrology, Columbia University Medical Center, New York, New York, USA.
⁸ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
⁹ Division of Nephrology, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁰ Division of Nephrology, Recanati Millar Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Divison of Nephrology, University of Washington, Seattle, Washington, USA.
¹² Nephrology Department, Vall d'Hebron Hospital Universitari, Barcelona, Spain.
¹³ Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida, USA.
¹⁴ Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
¹⁵ Renal Service, Memorial Sloan Kettering Cancer Center and Weil Cornell Medical College, New York, New York, USA.
¹⁶ Division of Nephrology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
¹⁷ Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
¹⁸ Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Division of Nephrology and Hypertension, University of South Florida, Tampa, Florida; Renal Service, H. Lee Moffitt Cancer Center, Tampa, Florida, USA.
²⁰ Division of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
²¹ Department of Hematology-Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
²² Division of Nephrology, University Health Network, University of Toronto, Ontario, Canada.
²³ Division of Nephrology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁴ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
²⁶ Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁷ Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, New York, USA.
²⁸ Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
²⁹ Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Belgium; Department of Nephrology, University Hospitals Leuven, Leuven, Belgium.
³⁰ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
³¹ Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA. Electronic address: Kjhaveri@northwell.edu.

PMID: 33359528
PMCID: PMC8222056
DOI: 10.1016/j.kint.2020.12.015

Multicenter Study

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant

Naoka Murakami et al. Kidney Int. 2021 Jul.

. 2021 Jul;100(1):196-205.

doi: 10.1016/j.kint.2020.12.015. Epub 2020 Dec 24.

Authors

Affiliations

¹ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: nmurakami1@bwh.harvard.edu.
² Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
³ Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴ Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁵ Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of General Internal Medicine, Section of Rheumatology and Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt.
⁶ Institute for Academic Medicine and Weill Cornell Medical College, Houston Methodist Cancer Center, Houston, Texas, USA.
⁷ Division of Nephrology, Columbia University Medical Center, New York, New York, USA.
⁸ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
⁹ Division of Nephrology, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁰ Division of Nephrology, Recanati Millar Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Divison of Nephrology, University of Washington, Seattle, Washington, USA.
¹² Nephrology Department, Vall d'Hebron Hospital Universitari, Barcelona, Spain.
¹³ Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida, USA.
¹⁴ Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
¹⁵ Renal Service, Memorial Sloan Kettering Cancer Center and Weil Cornell Medical College, New York, New York, USA.
¹⁶ Division of Nephrology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
¹⁷ Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
¹⁸ Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Division of Nephrology and Hypertension, University of South Florida, Tampa, Florida; Renal Service, H. Lee Moffitt Cancer Center, Tampa, Florida, USA.
²⁰ Division of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
²¹ Department of Hematology-Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
²² Division of Nephrology, University Health Network, University of Toronto, Ontario, Canada.
²³ Division of Nephrology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁴ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
²⁶ Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁷ Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, New York, USA.
²⁸ Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
²⁹ Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Belgium; Department of Nephrology, University Hospitals Leuven, Leuven, Belgium.
³⁰ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
³¹ Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA. Electronic address: Kjhaveri@northwell.edu.

PMID: 33359528
PMCID: PMC8222056
DOI: 10.1016/j.kint.2020.12.015

Abstract

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

Keywords: immune checkpoint inhibitors; kidney transplant; onconephrology; rejection.

PubMed Disclaimer

Figures

**Figure 1:. Characteristics of graft rejection Time to graft rejection.**
A. Characteristics of graft rejection. Data are shown as median (IQR) and n (%). *biopsy proven. ICI; immune checkpoint inhibitor, PD-1; programmed cell death protein 1, CTLA-4; cytotoxic T-lymphocyte-associated protein 4, TCMR; T-cell mediated rejection, ABMR; antibody mediated rejection, IVIg; intravenous immunoglobulin. B. Distribution of timing between ICI initiation and graft rejection, and cumulative rate of events is shown.

**Figure 2:. Risk factors of allograft rejection.**
Univariate and multivariate analyses of allograft rejection. Odds ratio (OR) and 95% confidence interval (CI) are shown. Cr; serum creatinine, Ref; reference, IS; immunosuppressant, LUKT; living unrelated kidney transplant, LRKTx; living related kidney transplant; DDKTx; deceased kidney transplant.

**Figure 3:. Rejection rate and tumor response of cSCC subgroup.**
Allograft rejection rate (A) and objective response rate (ORR, B), stratified by the number of immunosuppressants. In ICI group, cancer response in 2 patients were undetermined and excluded from analysis of ORR. cSCC; cutaneous squamous cell carcinoma

**Figure 4:. Rejection rate and tumor response of melanoma subgroup.**
Allograft rejection rate (A) and objective response rate (ORR, B), stratified by the number of immunosuppressants. In ICI group, cancer response in 2 patients were undetermined and excluded from the analysis of ORR. In panel B, Anti-PD-1 indicates ORR of patients who received pembrolizumab or nivolumab monotherapy.

See this image and copyright information in PMC

References

1. Saran R, Robinson B, Abbott KC, et al.: US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 73:A7–A8, 2019 - PMC - PubMed
1. Chapman JR, Webster AC, Wong G: Cancer in the transplant recipient. Cold Spring Harb Perspect Med 3, 2013 - PMC - PubMed
1. Engels EA: Epidemiologic perspectives on immunosuppressed populations and the immunosurveillance and immunocontainment of cancer. Am J Transplant 19:3223–3232, 2019 - PMC - PubMed
1. Sharma P, Allison JP: The future of immune checkpoint therapy. Science 348:56–61, 2015 - PubMed
1. Lipson EJ, Bodell MA, Kraus ES, et al.: Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol 32:e69–71, 2014 - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant

Affiliations

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous