LICR Melanoma & Ovarian Cancer Initiatives Meeting Report
New York, September 17 & 18
Despite many years of intense research, current treatments for both melanoma and ovarian cancer mainly rely on early detection and removal of the tumor followed by chemo- and radiotherapy; treatments that are associated with drug resistance and severe side effects. There is a great expectation that novel cancer therapies—designed to selectively target metastasis, harness the immune system’s potential to attack tumors, or both—will offer considerable advantages for these highly metastatic tumor types. Accordingly, a group of LICR investigators, Affiliates and collaborators gathered recently for a joint Melanoma & Ovarian Cancer Initiative meeting, with the common thread being the LICR focus on the development of therapeutic cancer vaccines for these diseases.
An ideal cancer vaccine would induce a strong and sustained immune response against an antigen that is expressed only by cancer cells. A diverse class of genes, here named Cancer/Testis (CT) genes, provides a vast source of potentially useful antigens since their expression is normally restricted to the germ line, but re-emerges in tumor cells. More than 100 CT genes are known to date, with new genes continuing to be discovered. Dr. Brian Stevenson (Lausanne Branch) described a genomic approach to characterize the more than 70 known families of CT genes and identify new family members. This characterization includes both human and non-human CT genes and has generated solid clues to the evolution and function of CT gene families. Another computational method for identifying novel CT genes was presented by Dr. AnaMaria Camargo, who, with her colleagues at the São Paulo Branch, is using EST database mining to uncover genes that are expressed exclusively in germ line and tumor cells. An approach for identifying CT antigens at the protein level was described by LICR Affiliate Dr. Boquan Jin (Fourth Military Medical University, Xi’an) who screened a collection of monoclonal antibodies against potential CT antigens using immunohistochemistry. As new CT genes are being discovered continuously—with a wealth of clinical and biological knowledge mounting around some of them—there is a need for systematic organization and comprehensive interpretation of these data. The development of a public CT gene database, the CTpedia, is ongoing as a coordinated effort of several of the Institute’s Branches and collaborators, and was presented by Affiliate Dr. Ana Tereza Vasconcelos (National Laboratory of Scientific Computation, Petropolis) whose group is constructing the database.
It recently emerged that expression of certain CT antigens correlates with advanced disease and poor outcome in cancer patients. However, the involvement of CT antigens in tumorigenesis is largely unknown. Dr. Otavia Caballero (New York Branch) and Dr. Jack Longley (University of Wisconsin, Madison) both addressed the biological function of CT genes by presenting studies of CT antigens in melanoma cell lines. The impact of their discoveries is emphasized by the fact that CT antigens, on account of their restricted expression pattern, are attractive candidates for targeting drug therapy. The cell biology of melanoma was discussed further by Dr. Colin Goding (Marie Curie Research Institute, London). Using two complementary model systems—differentiating melanocytes and melanoma tumors—his group has uncovered routes of transcriptional regulation and cell signaling that seem to underlie the progression of metastasis and drug resistance; findings of significant value for the development of novel therapeutic strategies.
Although immunotherapy based on cancer vaccines is a promising strategy for cancer treatment, it is complicated by the variety of immune responses observed in patients after vaccination. Melanoma, unlike ovarian cancer and many other cancer types, is regularly diagnosed at early stages and thus provides a model for studying the full progression of anti-tumor immunity. The meeting conveyed a range of experience from clinical investigations of cancer vaccines in melanoma patients. Dr. Jonathan Cebon (Melbourne Center) discussed spontaneous and vaccine-induced immune responses observed in patient trials, highlighting that the disease stage is an important factor to consider when designing strategies for anti-tumor vaccination. He also shared new insights into the biological role of the CT antigen NY-ESO-1 from studies in melanoma cell lines. Dr. Pedro Romero (Lausanne Branch) discussed how to optimize the composition of vaccines based on synthetic peptides to elicit specific immune responses against tumors. A series of cancer vaccine trials in patients with melanoma and other types of cancer were presented by Dr. Sylvia Adams, who together with Dr. Nina Bhardwaj (both LICR Affiliates at the NYU School of Medicine, New York) are exploring different strategies of inducing anti-tumor immunity by activation of dendritic cells.
Two presentations from the Brussels Branch illuminated fundamental aspects of anti-tumor immunity and prospects to augment current strategies of vaccine-based immunotherapy. Dr. Benoît Van den Eynde described exceptional modes of intra-cellular protein processing whereby peptide fragments are generated for antigen presentation, and presented preliminary studies of anti-tumor immune responses in a mouse melanoma model with inducible expression of specific tumor antigens. He also discussed a mechanism whereby tumors can suppress anti-tumor immune responses by inducing metabolic changes in T cells, and the possibility of designing therapeutic approaches to overcome such tumor resistance. Dr. Pierre van der Bruggen revealed pioneering discoveries indicating the existence of a separate mechanism that may limit immune responses against tumors by making cytolytic T cells lose their ability of tumor recognition upon antigen stimulation.
Technology advancements with promise for cancer research and therapeutics were described by two of the Institute’s collaborators. Dr. Robert Strausberg (J. Craig Venter Institute, Maryland) presented a multi-institutional sequencing project aimed to characterize somatic mutations in ovarian cancer, and discussed proceedings to advance genomic analysis of tumors. Dr. Richard Jove (City of Hope Comprehensive Cancer Center, California) described the principles behind the development of therapies that rely on delivery of small interfering RNAs (siRNAs) to tumor cells.
The last session of the meeting focused on ovarian cancer. Affiliate Dr. Kunle Odunsi (Roswell Park Cancer Institute, New York) introduced a familial ovarian cancer databank and a collection of patient samples that are available to investigators within the Ovarian Cancer Initiative. He also presented discoveries from a cancer vaccine trial in patients with epithelial ovarian cancer, exploring individual and co-ordinate expression of CT antigens and distinct immune responses. Finally, Dr. Tanja Pejovic (Oregon Health Sciences University, Oregon) discussed the association of Fanconi anemia, an inherited cancer predisposition syndrome, with ovarian cancer. Dr. Pejovic and her colleagues found that suppression of the FA-associated gene FANCD2 may correlate with sensitivity to DNA damage and high risk of ovarian cancer development.
In his concluding remarks, Dr. Andy Simpson (Scientific Director) expressed optimism that LICR’s newly established Initiatives, by organizing research around individual tumor types, will advance the implementation of innovative therapeutic strategies into clinical practice. The sharing of patient samples, resources, and discoveries from laboratories and clinics is a key part in the effort to further our understanding of melanoma and ovarian cancer—and to develop means of controlling their metastasis.
The Melanoma & Ovarian Cancer Initiative meeting brought together 42 participants from five Branches (Brussels, Lausanne, London, New York and São Paulo), the Melbourne Center, five Affiliates and two collaborating institutions (City of Hope Comprehensive Cancer Center, California, and the J. Craig Venter Institute, Maryland, USA).
Drs Pierre van der Bruggen (Brussels Branch), left, and Sacha Gnjatic (New York Branch)