Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab

Tyler J Alban; Nadeem Riaz; Prerana Parthasarathy; Vladimir Makarov; Sviatoslav Kendall; Seong-Keun Yoo; Rachna Shah; Nils Weinhold; Raghvendra Srivastava; Xiaoxiao Ma; Chirag Krishna; Juk Yee Mok; Wim J E van Esch; Edward Garon; Wallace Akerley; Benjamin Creelan; Nivedita Aanur; Diego Chowell; William J Geese; Naiyer A Rizvi; Timothy A Chan

doi:10.1038/s41591-024-03240-y

Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab

Nat Med. 2024 Sep 30. doi: 10.1038/s41591-024-03240-y. Online ahead of print.

Authors

Tyler J Alban^#^{1

2}, Nadeem Riaz^#³, Prerana Parthasarathy^{1

2}, Vladimir Makarov^{1

2}, Sviatoslav Kendall³, Seong-Keun Yoo¹, Rachna Shah³, Nils Weinhold³, Raghvendra Srivastava^{1

2}, Xiaoxiao Ma^{1

2}, Chirag Krishna⁴, Juk Yee Mok⁵, Wim J E van Esch⁵, Edward Garon⁶, Wallace Akerley⁷, Benjamin Creelan⁸, Nivedita Aanur⁹, Diego Chowell¹⁰, William J Geese⁹, Naiyer A Rizvi^{11

12}, Timothy A Chan^{13

14

15

16}

Affiliations

¹ Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
² Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
³ Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Sanquin 1006 AN, Amsterdam, the Netherlands.
⁶ Department of Thoracic Medical Oncology, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
⁸ Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA.
⁹ Bristol Myers Squibb, Princeton, NJ, USA.
¹⁰ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Synthekine, Menlo Park, CA, USA.
¹² Thoracic Oncology, Columbia University, New York, NY, USA.
¹³ Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA. [email protected].
¹⁴ Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. [email protected].
¹⁵ Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. [email protected].
¹⁶ National Center for Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA. [email protected].

^# Contributed equally.

PMID: 39349627
DOI: 10.1038/s41591-024-03240-y

Abstract

Neoantigen immunoediting drives immune checkpoint blockade efficacy, yet the molecular features of neoantigens and how neoantigen immunogenicity shapes treatment response remain poorly understood. To address these questions, 80 patients with non-small cell lung cancer were enrolled in the biomarker cohort of CheckMate 153 (CA209-153), which collected radiographic guided biopsy samples before treatment and during treatment with nivolumab. Early loss of mutations and neoantigens during therapy are both associated with clinical benefit. We examined 1,453 candidate neoantigens, including many of which that had reduced cancer cell fraction after treatment with nivolumab, and identified 196 neopeptides that were recognized by T cells. Mapping these neoantigens to clonal dynamics, evolutionary trajectories and clinical response revealed a strong selection against immunogenic neoantigen-harboring clones. We identified position-specific amino acid and physiochemical features related to immunogenicity and developed an immunogenicity score. Nivolumab-induced microenvironmental evolution in non-small cell lung cancer shared some similarities with melanoma, yet critical differences were apparent. This study provides unprecedented molecular portraits of neoantigen landscapes underlying nivolumab's mechanism of action.

Abstract

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