Ling et al. treated 41 patients with recurrent high-grade glioma, including glioblastoma, (rHGG/GBM) with a single intralesional injection of an oncolytic herpes virus, CAN-3110. CAN-3110 retained the neurovirulence gene, ICP34.5, under the control of the nestin promoter, overexpressed in HGG/GBM but not in healthy tissue. Particularly in patients who were seropositive for HSV1 or who seroconverted, an enrichment of the TME with TILs, induction of defined changes in the peripheral and tumor T cell repertoires, and intratumoral immune activation gene signatures were observed and associated with improved survival. Dose-limiting toxicities or HSV1 encephalitis/meningitis were not induced.
Contributed by Ute Burkhardt
ABSTRACT: Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)(1,2). Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)(3). In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue(4). These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).
Author Info: (1) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (2) Department of Pathology, Brigham and Women's Hospital
Author Info: (1) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (2) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (4) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (5) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (6) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (8) Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. (10) Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. (11) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (12) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (13) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (14) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (15) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (16) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (17) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (18) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (19) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (20) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (21) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (22) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (23) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (24) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (25) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (26) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (27) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (28) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (29) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (30) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (31) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (32) Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (33) Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (34) Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (35) Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (36) Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. (37) Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (38) Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. (39) ClearPoint Neuro, Solana Beach, CA, USA. (40) BostonGene, Waltham, MA, USA. (41) BostonGene, Waltham, MA, USA. (42) BostonGene, Waltham, MA, USA. (43) BostonGene, Waltham, MA, USA. (44) BostonGene, Waltham, MA, USA. (45) BostonGene, Waltham, MA, USA. (46) BostonGene, Waltham, MA, USA. (47) Candel Therapeutics, Needham, MA, USA. (48) Candel Therapeutics, Needham, MA, USA. (49) Candel Therapeutics, Needham, MA, USA. (50) Candel Therapeutics, Needham, MA, USA. (51) Candel Therapeutics, Needham, MA, USA. (52) Candel Therapeutics, Needham, MA, USA. (53) Candel Therapeutics, Needham, MA, USA. (54) Candel Therapeutics, Needham, MA, USA. (55) Department of Molecular Cell Biology, Weizmann Institute of Medical Sciences, Tel Aviv, Israel. (56) Department of Molecular Cell Biology, Weizmann Institute of Medical Sciences, Tel Aviv, Israel. (57) Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (58) Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, MA, USA. (59) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (60) Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (61) Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. eachiocca@bwh.harvard.edu.
