Tumor-infiltrating lymphocytes (TILs) and natural killer (NK) adoptive cell therapies have shown promising results in advanced-stage melanoma and haematological malignancies, respectively. However, their limited persistence in vivo in absence of an exogenous source of IL-2, and migration to neoplastic sites have impaired their effectiveness in immunosuppressive tumor microenvironments, such as ovarian cancer. Here, we propose the use of an engineered oncolytic adenovirus encoding a vIL-2 cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), to improve said cell therapies. Oncolytic adenoviruses are immunogenic agents that lyse infected cancer cells and recruit immune cells to the neoplastic site. Moreover, the vIL-2 virus continuously expresses a vIL-2 cytokine that preferentially stimulates effector lymphocyte proliferation over T regulatory cells.
Fragments of resected human ovarian cancer tumors were received and processed into single-cell suspensions. Autologous TILs were expanded from said sample fragments, while PBMC cells from healthy donors were used as the source of allogeneic NK cells. To evaluate cancer cell killing, ovarian cancer ex vivo tumor cultures were co-cultured either with autologous TILs or with allogeneic NK cells in the presence or absence of the vIL-2 virus. Additionally, in vivo combination therapies efficacy was assessed with a patient-derived xenograft (PDX) ovarian cancer model. Immune cell profiling was performed following patient sample co-cultures and PDX tumor treatments.
The addition of vIL-2 virus to the ovarian cancer ex vivo tumor cultures improved both TIL and NK cell therapies efficacy in vitro. Similarly, significantly better tumor control was achieved when the vIL-2 virus was given in conjunction with cell therapies compared to their respective controls. Mechanistically, vIL-2 virus treatment enhanced cell cytotoxicity of adoptively transferred TILs and NK cells in PDX tumors, and in ovarian cancer tumor cultures.
Ad5/3-E2F-d24-vIL2 virus treatment seems to be a promising immunotherapeutic candidate to improve the response of adoptive cell therapies in human immunosuppressive solid tumors.
Cancer Gene Therapy Group (CGTG), Translational Immunology Research Program, University of Helsinki.
TILT Biotherapeutics.
J.M. Santos, J. Clubb, R. Havunen, V. Cervera-Carrascon: Financial Interests, Personal and Institutional, Stocks/Shares: TILT Biotherapeutics. A. Hemminki: Financial Interests, Personal and Institutional, Stocks/Shares: TILT Biotherapeutics; Financial Interests, Personal, Stocks/Shares: Targovax ASA. All other authors have declared no conflicts of interest.