Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

in Nature by Alexander L Ling, Isaac H Solomon, Ana Montalvo Landivar, Hiroshi Nakashima, Jared K Woods, Andres Santos, Nafisa Masud, Geoffrey Fell, Xiaokui Mo, Ayse S Yilmaz, James Grant, Abigail Zhang, Joshua D Bernstock, Erickson Torio, Hirotaka Ito, Junfeng Liu, Naoyuki Shono, Michal O Nowicki, Daniel Triggs, Patrick Halloran, Raziye Piranlioglu, Himanshu Soni, Brittany Stopa, Wenya Linda Bi, Pierpaolo Peruzzi, Ethan Chen, Seth W Malinowski, Michael C Prabhu, Yu Zeng, Anne Carlisle, Scott J Rodig, Patrick Y Wen, Eudocia Quant Lee, Lakshmi Nayak, Ugonma Chukwueke, L Nicolas Gonzalez Castro, Sydney D Dumont, Tracy Batchelor, Kara Kittelberger, Ekaterina Tikhonova, Natalia Miheecheva, Dmitry Tabakov, Nara Shin, Alisa Gorbacheva, Artemy Shumskiy, Felix Frenkel, Estuardo Aguilar-Cordova, Laura K Aguilar, David Krisky, James Wechuck, Andrea Manzanera, Chris Matheny, Paul P Tak, Francesca Barone, Daniel Kovarsky, Itay Tirosh, Mario L Suvà, Kai W Wucherpfennig, Keith Ligon, David A Reardon, E Antonio Chiocca

TLDR

  • The study investigated the effectiveness of an oncolytic herpes virus (oHSV) called CAN-3110 in patients with a type of brain tumor called recurrent glioblastoma (rGBM). The virus was designed to target and destroy cancer cells while leaving healthy cells unharmed. The study found that patients who had positive HSV1 serology (meaning they had antibodies to the virus) had better survival and clearance of the virus from their tumors. Additionally, the study found that changes in the number and diversity of T cells (a type of white blood cell) in the tumor and blood were associated with improved survival and immune activation. These results suggest that oHSV therapy can enhance the immune response against cancer cells, even in immunosuppressive environments.

Abstract

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM). 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). 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. 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 ).

Overview

  • The study aims to investigate the efficacy of CAN-3110, an oncolytic herpes virus (oHSV) in patients with recurrent glioblastoma (rGBM). The study is a first-in-human phase I trial in 41 patients who were injected with CAN-3110. The virus retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter, which enhances its preferential tumour replication. The primary objective of the study is to evaluate the safety and efficacy of CAN-3110 in patients with rGBM. The study also aims to identify the immune responses elicited by CAN-3110 and their association with survival and tumour clearance. The study is registered on ClinicalTrials.gov with the identifier NCT03152318.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The results showed that positive HSV1 serology was significantly associated with improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with changes in tumour/PBMC T cell counts and clonal diversity, peripheral expansion/contraction of specific T cell clonotypes; and 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.

Implications and Future Directions

  • The study's findings suggest that intralesional oHSV treatment can enhance anticancer immune responses in patients with rGBM, even in immunosuppressive tumour microenvironments. The study also highlights the importance of HSV1 serology in predicting treatment response and survival in patients with rGBM. Future research should focus on identifying the specific T cell clonotypes and immune signatures that are associated with treatment response and survival in patients with rGBM. Additionally, future studies should investigate the use of oHSVs in combination with other immunotherapies to enhance treatment efficacy in patients with rGBM.
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