PO.CL05.07 · 临床研究
Pre-existing T cells drive durable anti-tumor immunity after oncolytic virus therapy in glioblastoma
作者与单位
摘要 Abstract
Background: Recurrent glioblastoma (rGBM) remains refractory to immunotherapy due to sparse and suppressed T cell infiltration. We recently reported that survival correlated with immune activation signatures in rGBM patients receiving the oncolytic HSV-1 (oHSV) rQNestin34.5v.2 (CAN-3110). Here, we provide in-situ and molecular evidence that a single oncolytic virus injection can induce durable, tumor-reactive T cell immunity in rGBM.
Methods: We integrated highly multiplexed spatial proteomics (CODEX), spatial transcriptomics (Xenium) with custom probes for viral, immune and TCR targets, and bulk TCR-sequencing on paired pre- and post-treatment specimens from a phase 1 clinical trial (NCT03152318).
Results: T cell densities strongly increased after treatment, with deep infiltration into viable tumor regions persisting up to two years after a single intratumoral oHSV injection. Cytotoxic GZMB+ T cells were located in close proximity with cleaved-caspase 3+ apoptotic tumor cells, and shorter T cell-tumor distance correlated with longer-progression free survival, demonstrating ongoing anti-tumor immunity. Spatial transcriptomics identified CD8+ T cells states expressing early TCR activation (NR4A1, CD69) and tissue residency (ZNF683 [HOBIT], ITGAE [CD103]) programs enriched in the tumor bed while stem-like T cells localized within lymphoid aggregates. Bulk and spatial TCR analyses revealed in-situ expansion of pre-existing tumoral T cell clones whose amplification correlated with survival. Expanded clones featured tissue resident phenotypes and were positioned closer to tumor cells than non-expanded T cells. Viral remnants were limited to necrotic regions and did not co-localize with T cells, suggesting persistent tumor recognition rather than viral antigen.
Conclusion: These results provide in-situ evidence that a single intratumoral oncolytic virus injection can amplify pre-existing T cells clones and induce sustained T cell mediated tumor cytotoxicity even after virus clearance. This suggests that oncolytic virotherapy is as potent T cell activating strategy in rGBM.
利益披露 Disclosure
M. Meylan,
L'institut Servier ).
Y. Tian, None..
L. Wu, None..
A. L. Ling, None..
D. Kovarsky, None..
G. L. Barlow, None..
L. D. Nguyen, None..
J. Pyrdol, None..
L. Westphal, None..
M. Julius, None..
N. L. Gonzalez Castro, None..
S. D. Dumont, None..
A. Santos, None..
I. Tirosh, None.
M. L. Suva,
Immunitas Therapeutics g., Board of Directors, non-salaried role).
E. Chiocca,
Bionaut Labs g., Board of Directors, non-salaried role), Stock Option.
Seneca Therapeutics g., Board of Directors, non-salaried role), Stock Option.
Calidi Biotherapeutics g., Board of Directors, non-salaried role).
ReIgnite Therapeutics g., Board of Directors, non-salaried role), Stock Option.
Ternalys Therapeutics g., Board of Directors, non-salaried role), Stock Option.
Candel Therapeutics Other, Patents related to oHSV and CAN-3110 are under the possession of Brigham and Women’s Hospital with E.A.C. and is named as co-inventor. These patents have been licensed to Candel Therapeutics. Present and future milestone license fees and future royalty fees are distributed to Brigham and Women’s Hospital from Candel.
K. W. Wucherpfennig,
DEM BioPharma g., Board of Directors, non-salaried role).
Solu Therapeutics g., Board of Directors, non-salaried role).
D2M Biotherapeutics g., Board of Directors, non-salaried role).
DoriNano g., Board of Directors, non-salaried role).
Nextechinvest g., Board of Directors, non-salaried role).
Immunitas Therapeutics g., Board of Directors, non-salaried role), Stock.
Fate Therapeutics ).
TScan Therapeutics Stock.