The promise of vaccine-based anticancer therapies has been explored for a number of years. However, the research met with little success in its early phases, largely because of a poor understanding of the biology of the immune system and its role in combatting cancer.
The promise of vaccine-based anticancer therapies has been explored for a number of years. However, the research met with little success in its early phases, largely because of a poor understanding of the biology of the immune system and its role in combatting cancer. Recent years have seen an enormous expansion in our knowledge of immune mechanisms and their complex interactions, yielding insights that are now being exploited to develop therapeutic strategies. In fact, anticancer immunotherapy has now taken center stage in the war against cancer, with notable successes in the treatment of specific malignancies. Among the various immunotherapy approaches, vaccines that utilize tumor-specific antigens provide a unique opportunity to harness the body’s natural immune responses to target malignancies. However, for primary brain tumors such as gliomas, the promise of immunotherapy has yet to be realized. The comprehensive review by Desjardins and colleagues provides a concise overview of the rationale for the development of various vaccination strategies and of the promises and practical challenges of these approaches. In particular, the authors focus on vaccines based on tumor protein peptides, heat shock proteins (HSPs), and dendritic cells (DCs), outlining the clinical studies that have explored the use of these various vaccines in adults with gliomas.
Immune surveillance is thought to be one of the major mechanisms for the identification and elimination of cancer cells. The emergence of cancer is partly attributed to the failure of the immune system to eliminate aberrant cells that have acquired tumorigenic potential. The adaptation of the vaccination strategy from the prevention of infectious diseases to applications in cancer was based on the principle that the immune system can be induced to act against cancer cell neoantigens. However, most such proteins elicit weak immune responses, either because they are overexpressed normal proteins or because they are similar enough to their normal counterparts that they do not trigger the degree of immune activation needed to induce cytotoxic effects against cancer cells. To overcome this, most trials of anticancer vaccines have used costimulatory molecules to enhance the immune response and raise it to cytotoxic levels.
Cancer-related peptide vaccine strategies, exemplified in this review by rindopepimut, an epidermal growth factor receptor (EGFR) variant III (EGFRvIII)-targeted peptide vaccine, falls into the category of active immunotherapy, which means it attempts to induce the immune system to act against the tumor by presenting the mutant peptide to the stimulated immune cells. The in-frame deletion of exons 2–7 on EGFR generates a novel amino acid sequence and yields a truncated protein with an altered extracellular domain epitope that is identifiable by and accessible to the immune system; this novel tumor-specific epitope, conjugated to the keyhole limpet hemocyanin molecule, constitutes the vaccine. Successful activation of the immune system to target EGFRvIII-expressing glioma cells would be expected to eliminate this subpopulation of cells from the tumor. This indeed appears to have been the case in the ACTIVATE and ACT II trials, which showed that the majority of the tumors that recurred after vaccine therapy demonstrated elimination of EGFRvIII-expressing glioma cells. However, some studies of patient cohorts not treated with rindopepimut have reported a loss of EGFRvIII expression in recurrent glioblastoma (GBM) compared with tissue from primary resection, although the degree of loss was less than that reported in rindopepimut-treated patients.[7,8] Another issue is that, because of intratumoral heterogeneity, only a subset of cells in the tumor may express EGFRvIII, and such expression may be highly variable, as reported in a study using single-cell DNA analysis.[9,10] Such heterogeneity may result in the survival and regrowth of the non–EGFRvIII-expressing cells. Despite these concerns, trials of rindopepimut to date have shown promising results overall, which have led to an ongoing phase III trial (ACT IV; ClinicalTrials.gov identifier: NCT01480479). Favorable results have also been seen in a study of rindopepimut in combination with bevacizumab in patients with recurrent GBM (ReACT trial). The results of the phase III study are expected to definitively answer the question of whether active immune targeting of a single antigen that is tumor-specific can yield a durable improvement in survival in patients with newly diagnosed EGFRvIII-expressing GBM. Rindopepimut has also been tested against diffuse intrinsic pontine glioma, a uniformly fatal primary pediatric brain tumor that also exhibits EGFRvIII expression.
Targeting single antigens restricts the use of vaccine-mediated approaches to only the relatively small subset of patients with gliomas that express those antigens; the heterogeneity of expression of such antigens can also potentially limit the utility of single-antigen vaccines. The need for wider application of vaccine therapies prompted the adoption of broader strategies, including the simultaneous use of multiple tumor-derived antigens, which could have the potential to more broadly activate the immune system against the tumor. In this context, the ability of chaperones, such as HSPs, to process polypeptides-including tumor antigens-in various cellular compartments has been of particular interest. HSP gp96 is the primary resident chaperone of the endoplasmic reticulum and binds various client proteins that are involved in the antigen-presenting pathway. Its ability to process peptides and to interact with professional antigen-presenting cells (APCs) enables HSP gp96 to function as a natural adjuvant that primes innate and adaptive immunity, allowing the complex formed when it is conjugated to tumor peptides to be internalized into APCs and the tumor peptides to be presented by class I and II major histocompatibility complexes (MHCs). Thus, HSP gp96–tumor peptide complexes can generate potent tumor-specific immune responses. This strategy is currently being studied in gliomas in a phase II clinical trial, in which HSP gp96–loaded antigens are extracted from patient-derived glioma tissue for use as a personalized anti-glioma vaccine. Some studies have reported that HSP gp96–based vaccines can stimulate both cytotoxic T lymphocytes and immunosuppressive regulatory T cells, particularly at higher doses; the latter can potentially dampen the antitumor immune response. Thus, such immunotherapeutic approaches can prove to be a double-edged sword.
Cell-based immunotherapeutic strategies using DC vaccines for the treatment of gliomas have been particularly exciting. Of the three cell types (DCs, macrophages, and B lymphocytes) that can process antigens and present them to naive T cells by means of MHC class I and II molecules, DCs are the most efficient at activating T cells; this makes DCs attractive candidates for therapeutic antitumor strategies, as in the DCVax-L approach. DCs process antigens more slowly than the other cell types and are thus capable of preserving the peptides longer for sustained T-cell recognition, triggering a more efficacious antitumor effect. The generation of tumor lysates allows multiple tumor-specific antigens associated with MHCs to be used to prime autologous DCs; the vaccine is then administered together with specific adjuvants. However, the ex vivo modification of DCs is a time-consuming, expensive, and labor-intensive process that must be undertaken in specialized facilities. In addition, some antigens from the tumor may vary in their ability to induce an immune response, resulting in variable and inconsistent responses. To circumvent this variability, tumor-specific proteins not expressed in normal tissue have been identified, and peptides representing these proteins have then been used as antigens to enhance tumor-specific cytotoxicity. Another approach used an immunotherapeutic strategy to target glioma stem cells (GSCs), which have emerged as the putative source of tumor regeneration; in this approach, GSC-specific proteins are isolated and vaccines are then generated that can target these cells. An example of the latter strategy is ICT-107, a DC vaccine loaded with six synthetically generated GSC-associated peptides; ICT-107 has shown promising results in phase II trials in GBM patients with a specific human leukocyte antigen (HLA) subtype (HLA-A2–positive).
Approaches that utilize peptide vaccines such as rindopepimut allow for predictable and immediate availability of a commercially made product that can be readily accessed for treatment. In contrast, cell-based vaccines require extensive processing and the risk of failed vaccine production if a sufficient amount of good-quality tumor tissue is not available, which may preclude the generation of vaccine for some patients who would otherwise be candidates for this therapy. Additionally, similar to tumor heterogeneity and the problems it gives rise to, there is wide variation in immune responses among patients and additional variability induced by treatment-related immune changes; for all anticancer vaccines, these variations contribute to differences in efficacy independent of the variability of the tumor-specific antigen involved. These factors may determine which treated patients respond to immunotherapy and which do not. Hence, the next major step in immunotherapy will be to identify the nuances of the complex immune responses that are patient-specific and tumor-specific in order to optimize the utilization of vaccine-based and other emerging immunotherapeutic strategies against gliomas in a personalized manner. This hopefully will allow full realization of the potential of vaccine therapies in the treatment of gliomas.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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