Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer.
To protect viral particles from neutralization, sequestration, nonspecific adhesion, and mislocalization following systemic delivery, we have previously exploited the natural tumor-homing properties of antigen-specific CD8+ T cells. Thus, OT-I T cells, preloaded in vitro with the oncolytic vesicular stomatitis virus (VSV), can deliver virus to established B16ova tumors to generate significantly better therapy than that achievable with OT-I T cells, or systemically delivered VSV, alone. Here, we demonstrate that preconditioning immune-competent mice with Treg depletion and interleukin-2 (IL-2), before adoptive T-cell therapy with OT-I T cells loaded with VSV, leads to further highly significant increases in antitumor therapy. Therapy was associated with antitumor immune memory, but with no detectable toxicities associated with IL-2, Treg depletion, or systemic dissemination of the oncolytic virus. Efficacy was contributed by multiple factors, including improved persistence of T cells; enhanced delivery of VSV to tumors; increased persistence of OT-I cells in vivo resulting from tumor oncolysis; and activation of NK cells, which acquire potent antitumor and proviral activities. By controlling the levels of virus loaded onto the OT-I cells, adoptive therapy was still effective in mice preimmune to the virus, indicating that therapy with virus-loaded T cells may be useful even in virus-immune patients. Taken together, our data show that it is possible to combine adoptive T-cell therapy, with biological therapy (Treg depletion+IL-2), and VSV virotherapy, to treat established tumors under conditions where none of the individual modalities alone is successful.
Kottke
Timothy
T
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Diaz
Rosa M
RM
Kaluza
Karen
K
Pulido
Jose
J
Galivo
Feorillo
F
Wongthida
Phonphimon
P
Thompson
Jill
J
Willmon
Candice
C
Barber
Glen N
GN
Chester
John
J
Selby
Peter
P
Strome
Scott
S
Harrington
Kevin
K
Melcher
Alan
A
Vile
Richard G
RG
D000220:Adaptation, Biological / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000941:Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D007156:Immunologic Memory / Q000276:immunology; D007167:Immunotherapy; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D050130:Oncolytic Virotherapy; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018116:Vesiculovirus / Q000235:genetics
D000906:Antibodies; D000941:Antigens; D007376:Interleukin-2