Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer

Author:

Tsimberidou Apostolia M.1ORCID,Alayli Farah A.2ORCID,Okrah Kwame2ORCID,Drakaki Alexandra3ORCID,Khalil Danny N.4ORCID,Kummar Shivaani5ORCID,Khan Saad A.5ORCID,Hodi F. Stephen67ORCID,Oh David Y.8ORCID,Cabanski Christopher R.2ORCID,Gautam Shikha2ORCID,Meier Stefanie L.25ORCID,Amouzgar Meelad2ORCID,Pfeiffer Shannon M.2ORCID,Kageyama Robin2ORCID,Yang EnJun2ORCID,Spasic Marko2ORCID,Tetzlaff Michael T.9ORCID,Foo Wai Chin9ORCID,Hollmann Travis J.410ORCID,Li Yanyun4ORCID,Adamow Matthew4ORCID,Wong Phillip4ORCID,Moore Jonni S.11ORCID,Velichko Sharlene12ORCID,Chen Richard O.13ORCID,Kumar Dinesh2ORCID,Bucktrout Samantha2ORCID,Ibrahim Ramy2ORCID,Dugan Ute2ORCID,Salvador Lisa10ORCID,Hubbard-Lucey Vanessa M.14ORCID,O’Donnell-Tormey Jill14ORCID,Santulli-Marotto Sandra2ORCID,Butterfield Lisa H.2ORCID,Da Silva Diane M.2ORCID,Fairchild Justin2ORCID,LaVallee Theresa M.2ORCID,Padrón Lacey J.2ORCID,Sharma Padmanee15161718ORCID

Affiliation:

1. The University of Texas MD Anderson Cancer Center 1 Department of Investigational Cancer Therapeutics, , Houston, TX, USA

2. Parker Institute for Cancer Immunotherapy 2 , San Francisco, CA, USA

3. University of California, Los Angeles 3 , Los Angeles, CA, USA

4. Memorial Sloan Kettering Cancer Center 4 , New York, NY, USA

5. Stanford University 5 , Stanford, CA, USA

6. Dana-Farber Cancer Institute 6 , Boston, MA, USA

7. Parker Institute for Cancer Immunotherapy, Dana-Farber Cancer Institute 7 , Boston, MA, USA

8. University of California, San Francisco 8 , San Francisco, CA, USA

9. The University of Texas MD Anderson Cancer Center 9 Department of Pathology, , Houston, TX, USA

10. Bristol Myers Squibb 13 , New York, NY, USA

11. University of Pennsylvania 10 , Philadelphia, PA, USA

12. Natera Inc. 11 , Austin, TX, USA

13. Personalis Inc. 12 , Fremont, CA, USA

14. Cancer Research Institute 14 , New York, NY, USA

15. The University of Texas MD Anderson Cancer Center 15 Department of Immunology, , Houston, TX, USA

16. James P. Allison Institute, The University of Texas MD Anderson Cancer Center 16 , Houston, TX, USA

17. James P. Allison Institute, The University of Texas MD Anderson Cancer Center 17 Immunotherapy Platform, , Houston, TX, USA

18. The University of Texas MD Anderson Cancer Center 18 Department of Genitourinary Medical Oncology, , Houston, TX, USA

Abstract

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

Funder

Parker Institute for Cancer Immunotherapy

Bristol Myers Squibb

Cancer Research Institute

Publisher

Rockefeller University Press

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