More research groups these days are trying to produce treatments for cancer by targeting known commonalities shared by all cancers or at least large classes of different types of cancer. This is good, because the cause of slow progress across the modern history of cancer research is arguably the fact that most efforts focus on approaches that can only work for a tiny fraction of cancer types. When talking about commonalities shared by all cancers, I largely mean lengthening of telomeres via telomerase or the less well understood alternative lengthening of telomeres (ALT) processes. All cancers abuse the mechanisms of telomere lengthening, normally inactive in the somatic cells making up the vast majority of tissues, in order to bypass evolved checks on uncontrolled cellular replication. Telomeres are repeated sequences of DNA at the end of chromosomes that shorten with each cell division, forming a clock of sorts. When they are too short, cells become senescent or self-destruct. If cancer cells are prevented from extending their telomeres, they die. Equally, if cancer cells can be reliably identified through the signature of their abuse of telomere lengthening, then they can be targeted for destruction via any of the selective cell killing mechanisms under development in the cancer research community:
Tumour progression, growth, and metastasis are intimately associated with both increased intratumoural angiogenesis, growth of blood vessels to supply the tumor, and increased cell proliferation. Thus, many therapeutic strategies are focused on targeting either or both of these processes. Angiogenesis, the process by which capillaries sprout from pre-existing blood vessels, is a complex multistep process that is tightly regulated by a large number of angiogenic factors. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) play pivotal roles in tumour angiogenesis.
Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase, which is silent in normal tissues but reactivated in most human cancers. TERT expression is directly correlated with tumour growth and progression and TERT serves as a universal tumour antigen in immunotherapy for cancer. Immunization against TERT may overcome tumour cell immune evasion by boosting the level of cytotoxic T cells specifically targeting the cancer. Thus, TERT is a promising immunotherapeutic candidate that should be considered for combination with anti-angiogenic therapies.
Antigen-presenting cells including dendritic cells (DCs) express mannan receptors (MR) on their surface, which can be exploited in cancer therapy by designing immune-stimulatory viruses coated with mannan-modified capsids that then bind to DCs and initiate a potent immune response. Co-immunization against tumour (TERT) and angiogenesis-specific markers (VEGFR-2) has a stronger inhibitory effect on tumour growth than single agents. Similarly, immunization of mice with a 1:1 mixture of dendritic cells transfected with VEGFR-2 and TERT mRNAs in vitro was shown to have a synergistic anti-tumour effect. Nevertheless, preparation of antigen-specific DC vaccine ex vivo is costly and time-consuming. A vaccine that directly targets DCs in vivo could be used to bypass these high costs and dependency on ex vivo manipulation.
We previously constructed a mannan-modified recombinant TERT adenovirus as a prophylactic vaccine for targeting DCs. This virus stimulated an antigen-specific cytotoxic T cell response against TERT in mice that was correlated with a clear anti-tumour effect. However, in our subsequent study, we found that the therapeutic anti-tumour efficacy of the vaccine was unsatisfactory. Here, we have dramatically improved the efficacy of this approach by creating a "universal" and effective vaccine, which consists of mannan-modified TERT and VEGFR-2 recombinant adenovirus. The vaccine was tested for its ability to induce anti-tumour immunity in a mouse tumour model. We found that it elicited two kinds of anti-tumour response: an immune cell-mediated attack of tumour cells and suppression of intratumoural angiogenesis. The reduced requirement for ex vivo manipulation and the remarkable synergy achieved by targeting both tumour cells and tumour vasculature suggest that this approach is may be suitable for translation to future clinical studies.