To enlist effector memory, CMV-specific, CD8+ T cells shown in cancer patients, Millar et al. created tumor-targeting antibodies conjugated with immunodominant CMV peptides made releasable by tumor-associated metalloproteases for loading onto empty HLA-1 molecules. Conjugates did not target antigen-expressing healthy cells for CTL recognition (in absence of exogenous protease or free peptide) or enlist Tregs, but enabled efficacy against established human tumors in immunodeficient mice that were reconstituted with human CMV-specific CTLs, and syngeneic tumors in immunocompetent mice depleted of immunosuppressive MDSCs.
Contributed by Paula Hochman
ABSTRACT: Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8(+) T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.
Author Info: (1) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Steele Laboratories, Department of Radiation Oncology, Har
Author Info: (1) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (3) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (4) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (5) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (6) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (7) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (8) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (9) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (10) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (11) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (12) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (13) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (14) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (15) Medical Research Council Centre for Immune Regulation and Clinical Immunology Service, School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, UK. (16) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (17) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (18) Medical Research Council Centre for Immune Regulation and Clinical Immunology Service, School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, UK. (19) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (20) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (21) Massachusetts General Hospital, Boston, MA, USA. (22) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (23) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (24) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. (25) Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (26) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (27) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (28) Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA. (29) Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. mcobbold@mgh.harvard.edu.
