Prospects and challenges of building a cancer vaccine targeting telomerase

Abstract

Despite their origin from self-tissue, tumor cells can be immunogenic and trigger immune responses that can profoundly influence tumor growth and development. Clinically, it may be possible to amplify or induce anti-tumor immune responses to achieve tumor rejection in patients. Increasing data over the last 8 years suggest that the human telomerase reverse transcriptase hTERT is immunogenic both in vitro and in vivo and may be a suitable target for novel cancer immunotherapy. Peptides derived from hTERT are naturally processed by tumors and presented on MHC molecules and trigger effector functions of specific T lymphocytes. Vaccination of cancer patients against hTERT epitopes induces anti-tumor T cells without clinical toxicity. If second-generation vaccines and other strategies are able to generate optimal cellular immunity against hTERT without toxicity in humans, the possibility of broad-spectrum immunotherapy or even immunoprevention therapy of cancer may be possible.

Harnessing the Immune System to Fight Cancer: The Promise of Genetic Cancer Vaccines

“…A list of well-known TAAs subdivided in four main categories is provided in Table 1. Among the most studied and validated TAAs, vaccinations against CEA (Marshall et al, 2003), HER-2/neu (Shumway et al, 2009), TERT (Vonderheide, 2008), EpCAM (Chaudry et al, 2007), survivin (Andersen and Thor, 2002), prostate-specific antigens (Doehn et al, 2008) provided good immunologic results. In light of the increasing interest and potential for cancer immunotherapy, the National Cancer Institute recently conducted an interesting pilot project to prioritize cancer antigens and to develop a priorityranked list of cancer vaccine target antigens based on predefined and pre-weighted objective criteria (Cheever et al, 2009).…”

“…Widely occurring, overexpressed TAAs have been detected in different types of tumours as well as in many normal tissues, and their overexpression in tumour cells can reach the threshold for T cell recognition, breaking the immunological tolerance and triggering an anticancer response. Among the most interesting TAAs of this group are the antiapoptotic proteins (survivin) (Schmidt et al, 2003), hTERT (Vonderheide et al, 2008), and tumour suppressor proteins (e.g., p53) (Umano et al, 2001). Unique tumour antigens.…”

The anti-apoptotic members of the Bcl-2 family are attractive tumor-associated antigens

“…A large number of such target structures have been characterized over the past more than 10 years [5]. Due to the phenomenon of "immune escape", in which antigen-negative cancer cells avoid immune recognition, strategies have been developed that conceptually focus on specifically targeting proteins that are important for the function, survival and growth of cancer cells [6]. Likewise, the tumor microenvironment, and conventional disease management has been taken into consideration.…”

Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes

“…Individual clones were obtained from the bulk population, after several cycles of restimulation, by limiting dilution. Human TERT CTLs were obtained from splenocytes (5 ϫ 10 6 ) of vaccinated HHD mice grown in presence of 0.1M of either hTERT [865][866][867][868][869][870][871][872][873] (RLVDDFLLV) or hTERT [30][31][32][33][34][35][36][37][38] (RLGPQGWRV) peptide. Human HER2/neu CTLs were obtained from HHD-vaccinated splenocytes stimulated with 1M HER-2 369-377 (TYVPANASL) peptide.…”

“…26 The 3 hTERT immunogenic regions that were found corresponded to epitopes already described (supplemental Figure 3A-C). 25,27,28 T cells specific for the 2 epitopes hTERT 865-872 and hTERT [30][31][32][33][34][35][36][37][38] , showing the strongest reactivity ex vivo (supplemental Figure 3D), were further enriched from splenocytes through repeated peptide stimulations. Specific recognition of 293 cells stably transfected with HLA-A2 molecule (293-A2) and loaded with the relevant peptides was readily demonstrated ex vivo (supplemental Figure 3C).…”