Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy

Cristina Puig-Saus (), Barbara Sennino, Songming Peng, Clifford L. Wang, Zheng Pan, Benjamin Yuen, Bhamini Purandare, Duo An, Boi B. Quach, Diana Nguyen, Huiming Xia, Sameeha Jilani, Kevin Shao, Claire McHugh, John Greer, Phillip Peabody, Saparya Nayak, Jonathan Hoover, Sara Said, Kyle Jacoby, Olivier Dalmas, Susan P. Foy, Andrew Conroy, Michael C. Yi, Christine Shieh, William Lu, Katharine Heeringa, Yan Ma, Shahab Chizari, Melissa J. Pilling, Marc Ting, Ramya Tunuguntla, Salemiz Sandoval, Robert Moot, Theresa Hunter, Sidi Zhao, Justin D. Saco, Ivan Perez-Garcilazo, Egmidio Medina, Agustin Vega-Crespo, Ignacio Baselga-Carretero, Gabriel Abril-Rodriguez, Grace Cherry, Deborah J. Wong, Jasreet Hundal, Bartosz Chmielowski, Daniel E. Speiser, Michael T. Bethune, Xiaoyan R. Bao, Alena Gros, Obi L. Griffith, Malachi Griffith, James R. Heath, Alex Franzusoff, Stefanie J. Mandl and Antoni Ribas ()
Additional contact information
Cristina Puig-Saus: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Barbara Sennino: PACT Pharma
Songming Peng: PACT Pharma
Clifford L. Wang: PACT Pharma
Zheng Pan: PACT Pharma
Benjamin Yuen: PACT Pharma
Bhamini Purandare: PACT Pharma
Duo An: PACT Pharma
Boi B. Quach: PACT Pharma
Diana Nguyen: PACT Pharma
Huiming Xia: McDonnell Genome Institute, Washington University School of Medicine
Sameeha Jilani: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Kevin Shao: PACT Pharma
Claire McHugh: PACT Pharma
John Greer: PACT Pharma
Phillip Peabody: PACT Pharma
Saparya Nayak: PACT Pharma
Jonathan Hoover: PACT Pharma
Sara Said: PACT Pharma
Kyle Jacoby: PACT Pharma
Olivier Dalmas: PACT Pharma
Susan P. Foy: PACT Pharma
Andrew Conroy: PACT Pharma
Michael C. Yi: PACT Pharma
Christine Shieh: PACT Pharma
William Lu: PACT Pharma
Katharine Heeringa: PACT Pharma
Yan Ma: PACT Pharma
Shahab Chizari: PACT Pharma
Melissa J. Pilling: PACT Pharma
Marc Ting: PACT Pharma
Ramya Tunuguntla: PACT Pharma
Salemiz Sandoval: PACT Pharma
Robert Moot: PACT Pharma
Theresa Hunter: PACT Pharma
Sidi Zhao: McDonnell Genome Institute, Washington University School of Medicine
Justin D. Saco: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Ivan Perez-Garcilazo: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Egmidio Medina: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Agustin Vega-Crespo: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Ignacio Baselga-Carretero: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Gabriel Abril-Rodriguez: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Grace Cherry: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Deborah J. Wong: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Jasreet Hundal: McDonnell Genome Institute, Washington University School of Medicine
Bartosz Chmielowski: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles
Daniel E. Speiser: Department of Oncology, University of Lausanne
Michael T. Bethune: PACT Pharma
Xiaoyan R. Bao: PACT Pharma
Alena Gros: Vall d’Hebron Institute of Oncology
Obi L. Griffith: McDonnell Genome Institute, Washington University School of Medicine
Malachi Griffith: McDonnell Genome Institute, Washington University School of Medicine
James R. Heath: Institute for Systems Biology
Alex Franzusoff: PACT Pharma
Stefanie J. Mandl: PACT Pharma
Antoni Ribas: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles

Nature, 2023, vol. 615, issue 7953, 697-704

Abstract: Abstract Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1–14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15–17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen–HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR–Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Date: 2023
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DOI: 10.1038/s41586-023-05787-1

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