Interleukin-2 gene-modified allogeneic melanoma cell vaccines can induce cross-protection against syngeneic tumors in mice

Abstract

Vaccination using well-characterized allogeneic tumor cell lines expressing standardized doses of immunostimulatory cytokines is an attractive alternative for autologous gene-transfected tumor cell vaccines. In the present study, we show that vaccination with irradiated allogeneic K1735 (H-2 k ) or B16F10 (H-2 b ) melanoma cells induces a moderate degree of cross-protection against the M-3 melanoma (H-2 d ) in DBA/2 mice. Cross-protection against the syngeneic tumor was markedly improved when the allogeneic vaccines were transfected with the interleukin-2 (IL-2) gene. The IL-2 gene-modified allogeneic vaccines were effective for prophylactic vaccination against subsequent tumor challenge and for therapeutic vaccination against pre-existing tumor deposits, with efficacies that were comparable with that of the IL-2 gene-modified syngeneic vaccines. Cross-protection correlated with the cytotoxic activity of splenocytes against M-3 targets. Allogeneic vaccination was not effective in another model, against the B16F10 melanoma in C57BL/6 mice, irrespective of genetic modification with the IL-2 or granulocyte-macrophage colony-stimulating factor genes. Cancer Gene Therapy (2000) 7, 870 -878

The transferrin receptor and the targeted delivery of therapeutic agents against cancer

“…When used as allogeneic melanoma cell vaccines in animal models, murine melanoma cells transfected with AVET complexes carrying the murine IL-2 gene induced cross protection against syngeneic melanoma tumors in DBA/2 mice [217]. This vaccine strategy was effective in both a prophylactic vaccination setting where protection was observed from subsequent tumor challenge as well as in a therapeutic vaccination setting against pre-existing tumor deposits [217].…”

“…This vaccine strategy was effective in both a prophylactic vaccination setting where protection was observed from subsequent tumor challenge as well as in a therapeutic vaccination setting against pre-existing tumor deposits [217]. In a Phase I clinical trial, these AVET complexes were used to exogenously transfect human melanoma cells with the human IL-2 gene for the use as an autologous vaccination strategy in patients with advanced disease [218].…”

Cancer immunotherapy

“…A variety of different cancer vaccines has been studied, such as tumor-associated polypeptides or proteins (such as HER2/neu [27] or MAGE-3 [28]), tumor cell lysates [29], irradiated autologous tumor cells or allogenic tumor cell lines with or without transfection of genes encoding for viral antigens or cytokines, such as granulocyte macrophage-colony stimulating factor (GM-CSF) or IL-2 [30][31][32][33][34][35], which are intended to induce a tumor-specific immune response. In most approaches the immunization antigens have to be combined with strong adjuvants (e.g., BCG [36] or QS-21 [37]) or cytokines (IL-2, GM-CSF or IL-12) [30][31][32][33][34][35] to induce a strong immune response. Particulate substances, such as Al(OH) 3 , onto which the immunization antigen is adsorbed to may exhibit an adjuvant effect [38].…”

“…In particular, cytokine gene-modified tumor cells have been broadly explored for induction of systemic immune responses against the wild-type tumor [30,31,34,35]. The logistic challenges in preparing patient-specific autologous therapies, however, have motivated the exploration of allogenic tumor cell lines [32,33], utilizing the expression of shared tumor antigens, and processing by host DCs through cross-priming [25]. While proof of principle for cancer vaccines has been demonstrated with therapeutic efficacy shown at least in murine tumor models using gene-modified whole cell vaccines, molecularly defined synthetic vaccines (combining defined target antigens with a synchronized cytokine pattern and being amenable to large scale pharmaceutical manufacturing process) are warranted for vaccine development [43].…”

Granulocyte-Macrophage Colony-Stimulating Factor-Based Melanoma Cell Vaccines Immunize Syngeneic and Allogeneic Recipients via Host Dendritic Cells

“…Originally, it was thought that the modified cancer cells themselves activate the immune response by directly interacting with T lymphocytes (11,12). This notion was challenged by the observation that the administration of genetically modified MHC class II-negative cancer cells results in the activation of tumor-specific, class II-restricted T lymphocytes and by the ability of allogeneic cancer cell vaccines to induce a tumor-specific T cell response which is restricted by the MHC type of host and capable of protecting against the growth of histogenetically identical syngeneic cancer cells (13)(14)(15). These and other data led to the conclusion that the specific T cells are activated indirectly, i.e., by host APC (16).…”