Human tumors actively suppress and inhibit effective immunity. Work from our group, and others, has shown that MHC class II restricted, CD4+ IFN-gamma secreting Th1 cells may be essential for tumor rejection. A major goal of the TVG is the development of vaccines that specifically elicit and expand Type I T-cells to treat and prevent cancer. Our therapeutic and prophylactic DNA and peptide-based vaccines target multiple tumor associated proteins thought to drive transformation, growth and metastasis. We have discovered immune dominant protein segments called ‘epitopes,’ that preferentially stimulate anti-tumor IFN-gamma/Th1 responses and other epitopes within self proteins that may suppress Type I immunity. Our studies have shown that including immune stimulatory epitopes, while excluding immune suppressive segments, will create optimum anti-cancer vaccines. Our multi-antigen, multi-epitope approach aims at heading off tumor escape by avoiding immune suppression and targeting multiple tumor growth pathways.
Our group has identified a growing number of novel, tumor-associated vaccine targets that include cell cycle regulatory or growth factor receptor proteins that are over-expressed in cancer patients, immunogenic and associated with poor clinical outcomes. We have also indentified genetic changes that may occur at the earliest stages of a cancer and identified the encoded proteins as immunogenic. Many antigens are also cancer stem cell proteins associated with an epithelial to mesenchymal transformation phenotype. Targeting cancer stem cells may be a particularly effective strategy to prevent cancer, prevent relapse and/or restore sensitivity to chemotherapy. Further, we work on adjuvant systems that may serve to enhance immunity against tumor antigens elicited with vaccination.
Vaccines from the Laboratory to the Clinic
- We have identified the HER2 oncoprotein as a tumor antigen and demonstrated in animal models that immunity against HER2 can result in inhibition of tumor growth.
- We have shown that Class II specific peptide based vaccines can stimulate tumor specific CD4 T helper (Th) immunity and that immune response achieved after vaccination can be of the same magnitude as an infectious disease vaccine and can persist for years.
- Peptide based vaccines can generate high levels of tumor specific effector memory T cells.
- Eliciting CD4 tumor antigen specific T cell immunity results in the co-generation of CTL specific of the tumor.
- Vaccines can be given concurrently with standard therapy in cancer patients to prevent relapse.
- DNA based vaccines can be developed which encode multiple proteins and stimulate Type I immunity.
- Early data suggests that vaccines may result in a survival benefit and that survival is associated with the development of epitope spreading. High levels of tumor specific Th1 cells homing to the tumor microenvironment modulate immune suppression in the tumor bed.
- Targeting biologically relevant antigens via vaccination, in animal models, has resulted in both tumor inhibition and modulation of the biology of the tumor to make cancer more amenable to standard treatments.
- Prophylactic cancer vaccines have been developed for breast and ovarian cancer and show efficacy in pre-clinical models of genetically engineered mice.
The TVG is actively developing a multi-antigen vaccine targeting some of the most common tumor types. Vaccine technologies are an area of active interest; the development of an inexpensive, easily transportable vaccine is our goal. We have an intensive program in assessing vaccine adjuvant which may further augment immunity generated with active immunization. We are evaluating, in a series of Phase I and II clinical trial, the immunogenicity, safety, and efficacy of tumor antigen specific vaccines. We continue to assess the phenotype of immunity generated with vaccination and the clinical parameters which may influence vaccine efficacy.