Antiproliferative Effects of 111 In- or 177 Lu-DOTATOC on Cells Exposed to Low Multiplicity-of-Infection Double-Deleted Vaccinia Virus Encoding Somatostatin Subtype-2 Receptor

Abstract

Oncolytic viruses may be limited in their ability to infect and lyse tumor cells because of penetration barriers and viral elimination by the immune system. Combining virotherapy with targeted radiotherapy that uses ¹¹¹In- or ¹⁷⁷Lu-DOTATOC may address such issues by spatially enhancing antitumor effects through bystander and/or cross-fire phenomena. In this study, a double-deleted vaccinia virus (vvDD) encoding the gene for somatostatin subtype-2 receptor (sstr-2) infected MC-38 murine colon adenocarcinoma cells and increased their sstr-2 expression by 2-fold. A low multiplicity-of-infection (MOI = 0.1) of vvDD and short exposure time (48 hours) preserved MC-38 viability (>80%–90%) for up to 3 days, permitting targeting of sstr-2 by ¹¹¹In- or ¹⁷⁷Lu-DOTATOC. ¹¹¹In-DOTATOC, alone or in combination with vvDD, was less effective than ¹⁷⁷Lu-DOTATOC at decreasing the growth of sstr-2-gene-transfected human embryonic kidney (HEK)-293 cells or MC-38 cells in monolayer. However, ¹¹¹In- or ¹⁷⁷Lu-DOTATOC combined with vvDD provided equivalent growth inhibition of HEK-293 or MC-38 cells as spheroids, suggesting a bystander effect from ¹¹¹In-DOTATOC. Growth of the cells was reduced 4-fold (from 20% to <5%) at 8 days in this case. Further evaluation of low-MOI vvDD in combination with ¹¹¹In- or ¹⁷⁷Lu-DOTATOC for the treatment of MC-38 tumors in mice is planned.