Puig-Saus et al. characterized the neoantigen-specific T cell response in patients with melanoma with or without a clinical response to anti-PD-1-based therapy using high-throughput tetramer screening and CRISPR-based TCR replacement. In patients with a response to anti-PD-1 therapy, neoantigen-specific T cell responses were polyclonal, targeted a limited number of immunodominant mutations despite higher mutational load, and were recurrently detected in the blood and tumor. Neoantigen-specific TCR T cells showed potent and specific cytotoxicity to patient-matched melanoma cell lines irrespective of clinical responses to immunotherapy.
Contributed by Shishir Pant
ABSTRACT: Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells(1-14). 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 technologies(15-17) 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.
Author Info: (1) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. cpuigsaus@mednet.ucla.edu. Jonsson Comprehensive Cancer Cen
Author Info: (1) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. cpuigsaus@mednet.ucla.edu. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA. cpuigsaus@mednet.ucla.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cpuigsaus@mednet.ucla.edu. Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA. cpuigsaus@mednet.ucla.edu. (2) PACT Pharma, San Francisco, CA, USA. (3) PACT Pharma, San Francisco, CA, USA. (4) PACT Pharma, San Francisco, CA, USA. (5) PACT Pharma, San Francisco, CA, USA. (6) PACT Pharma, San Francisco, CA, USA. (7) PACT Pharma, San Francisco, CA, USA. (8) PACT Pharma, San Francisco, CA, USA. (9) PACT Pharma, San Francisco, CA, USA. (10) PACT Pharma, San Francisco, CA, USA. (11) McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA. (12) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (13) PACT Pharma, San Francisco, CA, USA. (14) PACT Pharma, San Francisco, CA, USA. (15) PACT Pharma, San Francisco, CA, USA. (16) PACT Pharma, San Francisco, CA, USA. (17) PACT Pharma, San Francisco, CA, USA. (18) PACT Pharma, San Francisco, CA, USA. (19) PACT Pharma, San Francisco, CA, USA. (20) PACT Pharma, San Francisco, CA, USA. (21) PACT Pharma, San Francisco, CA, USA. (22) PACT Pharma, San Francisco, CA, USA. (23) PACT Pharma, San Francisco, CA, USA. (24) PACT Pharma, San Francisco, CA, USA. (25) PACT Pharma, San Francisco, CA, USA. (26) PACT Pharma, San Francisco, CA, USA. (27) PACT Pharma, San Francisco, CA, USA. (28) PACT Pharma, San Francisco, CA, USA. (29) PACT Pharma, San Francisco, CA, USA. (30) PACT Pharma, San Francisco, CA, USA. (31) PACT Pharma, San Francisco, CA, USA. (32) PACT Pharma, San Francisco, CA, USA. (33) PACT Pharma, San Francisco, CA, USA. (34) PACT Pharma, San Francisco, CA, USA. (35) PACT Pharma, San Francisco, CA, USA. (36) McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA. (37) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (38) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (39) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (40) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (41) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (42) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (43) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (44) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (45) McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA. (46) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA. (47) Department of Oncology, University of Lausanne, Lausanne, Switzerland. (48) PACT Pharma, San Francisco, CA, USA. (49) PACT Pharma, San Francisco, CA, USA. (50) Vall d'Hebron Institute of Oncology, Barcelona, Spain. (51) McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA. (52) McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA. (53) Institute for Systems Biology, Seattle, WA, USA. (54) PACT Pharma, San Francisco, CA, USA. (55) PACT Pharma, San Francisco, CA, USA. (56) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. aribas@mednet.ucla.edu. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA. aribas@mednet.ucla.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. aribas@mednet.ucla.edu. Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA. aribas@mednet.ucla.edu.
