Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors

Victoria Roulstone, Khurum Khan, Hardev S. Pandha, Sarah Rudman, Matt Coffey, George M. Gill, Alan A. Melcher, Richard Geoffrey Vile, Kevin J. Harrington, Johann De Bono, James Spicer

Research output: Contribution to journalArticle

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Abstract

Purpose: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. Experimental design: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25-1,000 mg/m<sup>2</sup> through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. Results: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m<sup>2</sup> combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a prede fined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. Conclusions: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.

Original languageEnglish (US)
Pages (from-to)1305-1312
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number6
DOIs
StatePublished - Mar 15 2015

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Neutralizing Antibodies
Cyclophosphamide
Mammalian orthoreovirus 3
Neoplasms
Oncolytic Viruses
Maximum Tolerated Dose
Immunomodulation
T-Lymphocyte Subsets
Immunosuppressive Agents
Antiviral Agents
Blood Cells
Research Design
Viruses
Injections

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors. / Roulstone, Victoria; Khan, Khurum; Pandha, Hardev S.; Rudman, Sarah; Coffey, Matt; Gill, George M.; Melcher, Alan A.; Vile, Richard Geoffrey; Harrington, Kevin J.; De Bono, Johann; Spicer, James.

In: Clinical Cancer Research, Vol. 21, No. 6, 15.03.2015, p. 1305-1312.

Research output: Contribution to journalArticle

Roulstone, V, Khan, K, Pandha, HS, Rudman, S, Coffey, M, Gill, GM, Melcher, AA, Vile, RG, Harrington, KJ, De Bono, J & Spicer, J 2015, 'Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors', Clinical Cancer Research, vol. 21, no. 6, pp. 1305-1312. https://doi.org/10.1158/1078-0432.CCR-14-1770
Roulstone, Victoria ; Khan, Khurum ; Pandha, Hardev S. ; Rudman, Sarah ; Coffey, Matt ; Gill, George M. ; Melcher, Alan A. ; Vile, Richard Geoffrey ; Harrington, Kevin J. ; De Bono, Johann ; Spicer, James. / Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 6. pp. 1305-1312.
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abstract = "Purpose: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. Experimental design: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25-1,000 mg/m2 through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. Results: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m2 combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a prede fined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14{\%} of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. Conclusions: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.",
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T1 - Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors

AU - Roulstone, Victoria

AU - Khan, Khurum

AU - Pandha, Hardev S.

AU - Rudman, Sarah

AU - Coffey, Matt

AU - Gill, George M.

AU - Melcher, Alan A.

AU - Vile, Richard Geoffrey

AU - Harrington, Kevin J.

AU - De Bono, Johann

AU - Spicer, James

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N2 - Purpose: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. Experimental design: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25-1,000 mg/m2 through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. Results: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m2 combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a prede fined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. Conclusions: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.

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