Novel Approaches for Cancer Immunotherapy

In the area of cancer immunotherapy, we have developed a number of models that allow us to test the feasibility of using the immune system to fight cancer. We showed that gene therapy could be used safely and had potential to increase disease-free survival or remission times in naturally occurring melanoma of pet dogs (see Figure 1). This is the first step to develop new treatments that will help not only dogs, but also people with incurable cancers. We have extended these studies both into the realms of basic mechanisms and clinical development in a new trial to treat dogs with bone cancer.

We also have studied mechanisms that influence the immune response to tumors. A major obstacle of cancer immunotherapy is the fact that tumor cells are recognized as “self” by cells of the immune system. Various mechanisms contribute to maintain tolerance to self. In the periphery, cells receive MHC signals that support survival and can promote activation. Hence, this potentially dangerous situation is overcome by an active process of negative regulation that is enforced by MHC tuning, as well as by transcription factors such as LKLF, Tob, and NFATc2. We are working to define how to use immune effector cells in various settings to improve the outcome for cancer patients.

Figure 1. Effect of FasL gene therapy in a dog with oral melanoma. (Left) Dog #2 from a clinical trial at presentation after the tumor was surgically de-bulked, and a mass measuring 19 mm x 14 mm x 1 mm was left for administration of gene therapy. (Right) The same dog 7 days after FasL gene therapy, when the tumor measured 14 mm x 8 mm x 1 mm. The dog was subsequently treated with surgery (hemi-mandibulectomy) and radiation therapy. He eventually died from causes unrelated to his tumor. From Bianco et al, Cancer Gene Therapy 10:726, 2003.