TY - JOUR
T1 - Clinical activity of single-dose systemic oncolytic VSV virotherapy in patients with relapsed refractory T-cell lymphoma
AU - Cook, Joselle
AU - Peng, Kah Whye
AU - Witzig, Thomas E.
AU - Broski, Stephen M.
AU - Villasboas, Jose C.
AU - Paludo, Jonas
AU - Patnaik, Mrinal
AU - Rajkumar, Vincent
AU - Dispenzieri, Angela
AU - Leung, Nelson
AU - Buadi, Francis
AU - Bennani, Nora
AU - Ansell, Stephen M.
AU - Zhang, Lianwen
AU - Packiriswamy, Nandakumar
AU - Balakrishnan, Baskar
AU - Brunton, Bethany
AU - Giers, Marissa
AU - Ginos, Brenda
AU - Dueck, Amylou C.
AU - Geyer, Susan
AU - Gertz, Morie A.
AU - Warsame, Rahma
AU - Go, Ronald S.
AU - Hayman, Suzanne R.
AU - Dingli, David
AU - Kumar, Shaji
AU - Bergsagel, Leif
AU - Munoz, Javier L.
AU - Gonsalves, Wilson
AU - Kourelis, Taxiarchis
AU - Muchtar, Eli
AU - Kapoor, Prashant
AU - Kyle, Robert A.
AU - Lin, Yi
AU - Siddiqui, Mustaqeem
AU - Fonder, Amie
AU - Hobbs, Miriam
AU - Hwa, Lisa
AU - Naik, Shruthi
AU - Russell, Stephen J.
AU - Lacy, Martha Q.
N1 - Funding Information:
This study was funded by the National Cancer Institute, National Institutes of Health, Mayo Clinic Multiple Myeloma SPORE (grant P50CA186781), the David F. and Margaret T. Grohne Foundation, the Lu Family Foundation, and the Philips Foundation.
Funding Information:
Conflict-of-interest disclosure: S.J.R., K.-W.P., and S.N. own equity in Vyriad, an oncolytic virotherapy company. J.L.M. served as a consultant for Pharmacyclics/AbbVie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier, Novartis, Morphosys/ Incyte, and Lilly; received research funding from Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacy-clics, Seattle Genetics, Janssen, and Millennium; received honoraria from Targeted Oncology, OncView, Curio, Kyowa, Physicians' Education Resource, and Seattle Genetics; and served on the speaker’s bureau of Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Jans-sen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, and Genentech/Roche. N.B. served on the advisory board of Verastem, Purdue Pharma, Daichii Sankyo, Kyowa Kirin, Vividion, Kymera, and Secura Bio and was an invited speaker for Medscape. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2022 by The American Society of Hematology.
PY - 2022/6/14
Y1 - 2022/6/14
N2 - Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-b (IFN-b) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNb-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 3 1011 TCID50), and 6 were treated at DL4 (1.7 3 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-b, a biomarker of VSV-IFNb-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-b of 18 213 pg/mL, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNb-NIS as a single agent was effective in patients with TCL, resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. This trial is registered at www.clinicaltrials.gov as #NCT03017820.
AB - Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-b (IFN-b) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNb-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 3 1011 TCID50), and 6 were treated at DL4 (1.7 3 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-b, a biomarker of VSV-IFNb-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-b of 18 213 pg/mL, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNb-NIS as a single agent was effective in patients with TCL, resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. This trial is registered at www.clinicaltrials.gov as #NCT03017820.
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U2 - 10.1182/bloodadvances.2021006631
DO - 10.1182/bloodadvances.2021006631
M3 - Article
C2 - 35175355
AN - SCOPUS:85127354958
SN - 2473-9529
VL - 6
SP - 3268
EP - 3279
JO - Blood advances
JF - Blood advances
IS - 11
ER -