Investigating why patients with frameshifting CALRMUT myeloproliferative neoplasms (MPNs) with many predicted immunogenic peptides rarely show signs of CALRMUT-specific T cell responses, Gigoux et al. found that these patients were less likely to carry MHC-I alleles capable of presenting CALRMUT neoepitopes with high affinity, possibly representing a mechanism of immune escape. To rescue activity against native, weaker-binding peptides, heteroclitic variants (optimized for strong MHC binding affinity) of CALRMUT peptides were designed, and could effectively stimulate CD8+ T cells that were cross-reactive with the native peptides in vitro and in mice.
Contributed by Lauren Hitchings
ABSTRACT: The majority of JAK2(V617F)-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALR(MUT)), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALR(MUT)-specific T cells are rare in patients with CALR(MUT) MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALR(MUT) MPN from two independent cohorts. We observed that MHC-I alleles that present CALR(MUT) neoepitopes with high affinity are underrepresented in patients with CALR(MUT) MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALR(MUT) MPN would not efficiently respond to a CALR(MUT) fragment cancer vaccine but would when immunized with a modified CALR(MUT) heteroclitic peptide vaccine approach. We found that heteroclitic CALR(MUT) peptides specifically designed for the MHC-I alleles of patients with CALR(MUT) MPN efficiently elicited a CALR(MUT) cross-reactive CD8(+) T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALR(MUT) native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8(+) T cell response to the CALR(MUT) fragment upon immunization with a CALR(MUT) heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALR(MUT) MPN.
Author Info: (1) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Onc
Author Info: (1) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Department of Oncology, National Center for Cancer Immune Therapy, Herlev Hospital, Herlev 2730, Denmark. Department of Immunology and Microbiology, Copenhagen University Hospital, Herlev 2730, Denmark. (3) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA. (4) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (5) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (8) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Division of Regenerative Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY 10065, USA. (9) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (10) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (11) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (12) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (13) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (14) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (15) Weill Cornell Medicine, New York, NY 10065, USA. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (17) Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (18) Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (19) Broad Institute, Cambridge, MA 02142, USA. (20) Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. (22) Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (23) Department of Hematology, Zealand University Hospital, Roskilde 4000, Denmark. (24) Department of Hematology, Zealand University Hospital, Roskilde 4000, Denmark. (25) Department of Hematology, Zealand University Hospital, Roskilde 4000, Denmark. (26) Department of Hematology, Odense University Hospital, Odense 5000, Denmark. (27) Department of Hematology, Odense University Hospital, Odense 5000, Denmark. (28) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. (29) Department of Hematology, Zealand University Hospital, Roskilde 4000, Denmark. (30) Department of Oncology, National Center for Cancer Immune Therapy, Herlev Hospital, Herlev 2730, Denmark. Department of Immunology and Microbiology, Copenhagen University Hospital, Herlev 2730, Denmark. (31) Department of Oncology, National Center for Cancer Immune Therapy, Herlev Hospital, Herlev 2730, Denmark. Department of Immunology and Microbiology, Copenhagen University Hospital, Herlev 2730, Denmark. (32) Department of Oncology, National Center for Cancer Immune Therapy, Herlev Hospital, Herlev 2730, Denmark. Department of Immunology and Microbiology, Copenhagen University Hospital, Herlev 2730, Denmark. (33) Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19002, USA. (34) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medicine, Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY 10065, USA. (35) Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19002, USA. (36) Weill Cornell Medical College, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (37) Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (38) Department of Oncology, National Center for Cancer Immune Therapy, Herlev Hospital, Herlev 2730, Denmark. Department of Immunology and Microbiology, Copenhagen University Hospital, Herlev 2730, Denmark. (39) Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (40) Parker Institute for Cancer Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (41) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (42) Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Broad Institute, Cambridge, MA 02142, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. (43) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA.
