Clinical trial links oncolytic immunoactivation to survival in glioblastoma

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

doi:10.1038/s41586-023-06623-2

Clinical trial links oncolytic immunoactivation to survival in glioblastoma

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 HalloranRaziye 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^*

^*Corresponding author for this work

Department of Molecular Cell Biology

Research output: Contribution to journal › Article › peer-review

67 Citations (Scopus)

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 tissue⁴. 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 ).

Original language	English
Pages (from-to)	157-166
Number of pages	10
Journal	Nature
Volume	623
Issue number	7985
DOIs	https://doi.org/10.1038/s41586-023-06623-2
Publication status	Published - 2 Nov 2023

Funding

All Science Journal Classification (ASJC) codes

General

Access to Document

10.1038/s41586-023-06623-2

Cite this

Ling, A. L., Solomon, I. H., Landivar, A. M., Nakashima, H., Woods, J. K., Santos, A., Masud, N., Fell, G., Mo, X., Yilmaz, A. S., Grant, J., Zhang, A., Bernstock, J. D., Torio, E., Ito, H., Liu, J., Shono, N., Nowicki, M. O., Triggs, D., ... Antonio Chiocca, E. (2023). Clinical trial links oncolytic immunoactivation to survival in glioblastoma. Nature, 623(7985), 157-166. https://doi.org/10.1038/s41586-023-06623-2

@article{cf004671c16d4a4c997a99cad0b676a6,

title = "Clinical trial links oncolytic immunoactivation to survival in glioblastoma",

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

year = "2023",

month = nov,

day = "2",

doi = "10.1038/s41586-023-06623-2",

language = "English",

volume = "623",

pages = "157--166",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7985",

}

Ling, AL, Solomon, IH, Landivar, AM, Nakashima, H, Woods, JK, Santos, A, Masud, N, Fell, G, Mo, X, Yilmaz, AS, Grant, J, Zhang, A, Bernstock, JD, Torio, E, Ito, H, Liu, J, Shono, N, Nowicki, MO, Triggs, D, Halloran, P, Piranlioglu, R, Soni, H, Stopa, B, Bi, WL, Peruzzi, P, Chen, E, Malinowski, SW, Prabhu, MC, Zeng, Y, Carlisle, A, Rodig, SJ, Wen, PY, Lee, EQ, Nayak, L, Chukwueke, U, Gonzalez Castro, LN, Dumont, SD, Batchelor, T, Kittelberger, K, Tikhonova, E, Miheecheva, N, Tabakov, D, Shin, N, Gorbacheva, A, Shumskiy, A, Frenkel, F, Aguilar-Cordova, E, Aguilar, LK, Krisky, D, Wechuck, J, Manzanera, A, Matheny, C, Tak, PP, Barone, F, Kovarsky, D , Tirosh, I, Suvà, ML, Wucherpfennig, KW, Ligon, K, Reardon, DA & Antonio Chiocca, E 2023, 'Clinical trial links oncolytic immunoactivation to survival in glioblastoma', Nature, vol. 623, no. 7985, pp. 157-166. https://doi.org/10.1038/s41586-023-06623-2

TY - JOUR

T1 - Clinical trial links oncolytic immunoactivation to survival in glioblastoma

AU - Ling, Alexander L.

AU - Solomon, Isaac H.

AU - Landivar, Ana Montalvo

AU - Nakashima, Hiroshi

AU - Woods, Jared K.

AU - Santos, Andres

AU - Masud, Nafisa

AU - Fell, Geoffrey

AU - Mo, Xiaokui

AU - Yilmaz, Ayse S.

AU - Grant, James

AU - Zhang, Abigail

AU - Bernstock, Joshua D.

AU - Torio, Erickson

AU - Ito, Hirotaka

AU - Liu, Junfeng

AU - Shono, Naoyuki

AU - Nowicki, Michal O.

AU - Triggs, Daniel

AU - Halloran, Patrick

AU - Piranlioglu, Raziye

AU - Soni, Himanshu

AU - Stopa, Brittany

AU - Bi, Wenya Linda

AU - Peruzzi, Pierpaolo

AU - Chen, Ethan

AU - Malinowski, Seth W.

AU - Prabhu, Michael C.

AU - Zeng, Yu

AU - Carlisle, Anne

AU - Rodig, Scott J.

AU - Wen, Patrick Y.

AU - Lee, Eudocia Quant

AU - Nayak, Lakshmi

AU - Chukwueke, Ugonma

AU - Gonzalez Castro, L. Nicolas

AU - Dumont, Sydney D.

AU - Batchelor, Tracy

AU - Kittelberger, Kara

AU - Tikhonova, Ekaterina

AU - Miheecheva, Natalia

AU - Tabakov, Dmitry

AU - Shin, Nara

AU - Gorbacheva, Alisa

AU - Shumskiy, Artemy

AU - Frenkel, Felix

AU - Aguilar-Cordova, Estuardo

AU - Aguilar, Laura K.

AU - Krisky, David

AU - Wechuck, James

AU - Manzanera, Andrea

AU - Matheny, Chris

AU - Tak, Paul P.

AU - Barone, Francesca

AU - Kovarsky, Daniel

AU - Tirosh, Itay

AU - Suvà, Mario L.

AU - Wucherpfennig, Kai W.

AU - Ligon, Keith

AU - Reardon, David A.

AU - Antonio Chiocca, E.

PY - 2023/11/2

Y1 - 2023/11/2

N2 - 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 ).

AB - 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 ).

UR - http://www.scopus.com/inward/record.url?scp=85174245978&partnerID=8YFLogxK

U2 - 10.1038/s41586-023-06623-2

DO - 10.1038/s41586-023-06623-2

M3 - Article

C2 - 37853118

AN - SCOPUS:85174245978

SN - 0028-0836

VL - 623

SP - 157

EP - 166

JO - Nature

JF - Nature

IS - 7985

ER -

Clinical trial links oncolytic immunoactivation to survival in glioblastoma

Abstract

Funding

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this