Novel Approaches for Cancer Immunotherapy

FAS LIGAND GENE-BASED IMMUNOTHERAPY FOR CANINE OSTEOSARCOMA STUDY IS NOW OPEN FOR PATIENT ENROLLMENT THROUGH THE UNIVERSITY OF MINNESOTA AND THROUGH COLORADO STATE UNIVERSITY.

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.

Finally, we are interested in exploring how use of tobacco products influences the origin and progression of lymphoma and leukemia, as well as how it impacts responses to immunotherapy. Recent work from our lab using human and mouse models showed that nicotine enforces negative regulation of T cell proliferation by activating NFATc2. Further exploration of this phenomenon using siRNA to eliminate expression of selected cholinergic receptors in T cells suggests that tonic signaling through nicotinic receptors contributes to T cell survival, and that these receptors are also necessary for calcium flux generated by ligation of the TCR. Nicotinic receptors appear to be similarly involved in survival of myeloid cells. As tobacco use is a major risk factor for development of cancers of the lung and other organs, we are studying the possible role of anti-apoptotic effects of nicotine and nicotine receptors both in the immune response against cancer and in the pathogenesis of these diseases.

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.

Selected Results from Our Laboratory

Below is a list of selected publications from our laboratory on cancer immunology and immunotherapy. For more extensive details please see our list of publications. You can also contact our laboratory staff if you have questions or requests for more specific information.

Review and Opinion Articles
Modiano JF, Johnson LDS, Bellgrau D. (2008). Negative regulators in homeostasis of naïve peripheral T cells. Immunol Res, 41(2), 137-153.

Modiano JF, Breen M, Lana SE, Ehrhart N, Fosmire SP, Thomas R, Jubala CM, Lamerato-Kozicki AR, Ehrhart EJ, Schaack J, Duke RC, Cutter GC, Bellgrau D. (2006). Naturally occurring translational models for development of cancer gene therapy. Gene Ther Mol Biol, 10, 31-40.

Modiano JF, Lamerato-Kozicki AR, Jubala CM, Coffey D, Borakove M, Schaack J, Bellgrau D. (2004). Fas ligand gene transfer for cancer therapy. Cancer Therapy, 2, 561-570.

Chitko-McKown CG and Modiano JF. (1997). Clues to immune function and oncogenesis provided by events that activate the cell cycle machinery in normal human T cells. J Leukocyte Biol 62, 430-437.

Research Articles
Jubala CM, Lamerato AR, Borakove M, Lang J, Gardner L, Coffey D, Helm KM, Schaack J, Baier M, Cutter GR, Bellgrau D, Modiano JF. (2009) MHC-dependent desensitization of intrinsic anti-self reactivity. Cancer Immunol Immunother, 58(2), 171-185. (Epub 2008 Jun 4 DOI 10.1007/s00262-008-0535-0)

Evidence for links between MHC-dependent signals and mechanisms that prevent spontaneous or inappropriate activation of self-reactive T cells.

Modiano JF, Sun J, Lang J, Vacano G, Patterson D, Chan D, Franzusoff A, Giannini R, Meech SJ, Duke R, Bellgrau D. (2004). Fas ligand-dependent suppression of autoimmunity via recruitment and subsequent termination of activated T cells. Clin Immunol, 112, 54-65.

Documentation of Fas-dependent T cell recruitment to areas of inflammation, and its impact for cancer immunotherapy and treatment of autoimmune disease.

Frazer-Abel AA, Baksh S, Fosmire SP, Willis D, Pierce AM, Meylemans H, Linthicum DS, Coons T, Burakoff SJ, Bellgrau D, Modiano JF. (2004). Nicotine activates NFATc2 and prevents cell cycle entry in T cells. J Pharmacol Exp Ther, 311, 758-769.

Identification of NFAT activation in lymphocytes and endothelial cells by nicotine and description of how nicotine co-opts a major mechanism that enforces T cell negative regulation.

Bianco SR, Sun J, Fosmire SP, Hance K, Padilla M, Ritt MG, Getzy D, Duke RC, Withrow S, Lana S, Matthiesen DT, Dow S, Bellgrau D, Cutter G, Helfand SC, Modiano JF. (2003). Enhancing anti-melanoma immune responses through apoptosis. Cancer Gene Ther, 10, 726-736.

Documentation of priming in antigen presenting cells by uptake of apoptotic cells, and the possibility to harness this in cancer immunotherapy.

Baksh S, Widlund HR, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, DeCaprio JA, Modiano JF, Burakoff SJ. (2002). NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol Cell, 10, 1071-1081.

Characterization of a major mechanism that controls quiescence and enforces tolerance in T cells.