Direct in situ introduction of exogenous genes into proliferating tumors could provide an effective therapeutic approach for treatment of localized tumors. Rats with a cerebral glioma were given an intratumoral stereotaxic injection of murine fibroblasts that were producing a retroviral vector in which the herpes simplex thymidine kinase (HS-tk) gene had been inserted. After 5 days during which the HS-tk retroviral vectors that were produced in situ transduced the neighboring proliferating glioma cells, the rats were treated with the anti-herpes drug ganciclovir. Gliomas in the ganciclovir- and vector-treated rats regressed completely both macroscopically and microscopically. This technique exploits what was previously considered to be a disadvantage of retroviral vectors--that is, their inability to transfer genes into nondividing cells. Instead, this feature of retroviruses is used to target gene delivery to dividing tumor cells and to spare nondividing neural tissue.

In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors

The mixture of cytokines that is produced in the tumour microenvironment has an important role in cancer pathogenesis. Cytokines that are released in response to infection, inflammation and immunity can function to inhibit tumour development and progression. Alternatively, cancer cells can respond to host-derived cytokines that promote growth, attenuate apoptosis and facilitate invasion and metastasis. A more detailed understanding of cytokine–tumour-cell interactions provides new opportunities for improving cancer immunotherapy.

Cytokines in cancer pathogenesis and cancer therapy

A variety of tumors are potentially immunogenic but do not stimulate an effective anti-tumor immune response in vivo. Tumors may be capable of delivering antigen-specific signals to T cells, but may not deliver the costimulatory signals necessary for full activation of T cells. Expression of the costimulatory ligand B7 on melanoma cells was found to induce the rejection of a murine melanoma in vivo. This rejection was mediated by CD8+ T cells; CD4+ T cells were not required. These results suggest that B7 expression renders tumor cells capable of effective antigen presentation, leading to their eradication in vivo.

http://science.sciencemag.org/content/sci/259/5093/368.full.pdf

Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells

Many tumors express tumor-specific antigens capable of being presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules. Antigen presentation models predict that the tumor cell itself should present these antigens to T cells. However, when conditions for the priming of tumor-specific responses were examined in mice, no detectable presentation of MHC class I-restricted tumor antigens by the tumor itself was found. Rather, tumor antigens were exclusively presented by host bone marrow-derived cells. Thus, MHC class I-restricted antigens are efficiently transferred in vivo to bone marrow-derived antigen-presenting cells, which suggests that human leukocyte antigen matching may be less critical in the application of tumor vaccines than previously thought.

https://science.sciencemag.org/content/sci/264/5161/961.full.pdf

Toshiuki Itaya

Papers

Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response