Enhancing Cellular Cancer Vaccines

Abstract

Various strategies have been used to generate cellular cancer vaccines with the expectation that they will become an effective part of the overall management of cancer patients. However, with few notable exceptions, immunization has not resulted in significant long-term therapeutic benefits. Tumor growth has continued and patient survival has been at best only modestly prolonged. One possible explanation is that as only a small proportion of the constituents of malignant cells are 'tumor specific' and the vast majority are the products of nonantigenic, normal 'housekeeping' genes, the immune response in patients immunized with cellular cancer vaccines is not sufficient to result in tumor rejection. Here, we review and characterize various types of cellular cancer vaccines. In addition, in a mouse breast cancer model system, we describe a unique strategy designed to enrich cellular vaccines for cells that induce tumor immunity. Numerous advantages and disadvantages of cancer immunotherapy with cellular vaccines are also presented. Keywordscancer vaccine; dendritic cell; dNA vaccine; enriched vaccine; fibroblast; leukapheresis; tumor dNA Numerous attempts have been made to prepare effective cancer vaccines that can be used to treat cancer patients in the expectation that the anti-tumor immune response will result in tumor regression [1][2][3][4][5][6][7][8][9]. The underlying rationale is that the antigenic phenotype of cells in the tumor differs from that of normal, nonmalignant cells in the patient. The immunity to unique antigens expressed by the malignant cells, which is induced by the vaccine, would, in theory, result in the selective killing of the patient's malignant cells only. However, relatively few antigenic determinants expressed by cancer cells are 'tumor specific. With few exceptions, the vast majority of determinants expressed by the patient's tumor are presented by normal, nonmalignant cells as well. MUC1 is a notable example. MUC1 is a heavily glycosylated glycoprotein associated with both normal and malignant cells. Its expression by cancer cells, specified by a mutant/dysregulated gene, is aberrant in the sense that the glycosylation pattern of the molecule is altered [10][11][12]. The altered glycosylation pattern renders the molecule antigenic. Other examples of dysregulated genes that specify tumor antigens include Her2/neu in breast cancer and KRAS in colon cancer [13][14][15][16][17]. In these instances, the density of the molecules expressed by the malignant cells is greater than that of normal cells. By contrast, cancer caused by oncogenic viruses express determinants specific to the virus. Cervical cancer caused by the human papillomavirus is a notable example. The malignant, virally infected cells express antigenic determinants specific to the papillomavirus. The products of the virally associated E6 and E7 genes are tumor specific [18][19][20]. The Epstein-Barr virus nuclear

Whole-cell vaccine coated with recombinant calreticulin enhances activation of dendritic cells and induces tumour-specific immune responses

“…However, the whole-cell vaccines have not resulted in significant longterm therapeutic benefits (22,23). One possible explanation is that only a small proportion of the molecules expressed on the cell surface are specific for cancer cells, whereas the vast majority of cell surface components are derived from housekeeping genes, carbohydrates, lipids and other molecules that are ubiquitously expressed by normal cells (24). As a result, the immune response induced by whole-tumour cell vaccine is insufficient to eliminate the cancer cells in vivo.…”

Cell‐Based Biohybrid Drug Delivery Systems: The Best of the Synthetic and Natural Worlds

“…Another limitation is their inability to cure an established tumor. Studies have shown that in order for an anti‐tumor vaccine to be effective, it must be administered at an early stage of tumor formation, which is often not feasible in a clinical setting because most tumors are detected only at a later stage. Another concern with these cancer cell membrane biohybrid vaccine systems is the risk of development of autoimmunity, because normal cells also express some of the same antigens as tumors.…”

“…Another concern with these cancer cell membrane biohybrid vaccine systems is the risk of development of autoimmunity, because normal cells also express some of the same antigens as tumors. Preclinical studies with cancer vaccines, however, suggest that autoimmunity is a rare and treatable side effect …”

Emerging nanotechnologies for cancer immunotherapy

“…18,87 While vaccines based on autologous cells are costly and technically challenging, peptide-based cancer vaccination suffers from inefficient uptake, processing and presentation of the delivered epitopes by activated professional APCs. 23,51,[87][88][89][90] Moreover, such vaccination strategies have led to the generation of low avidity tumorspecific T cell responses. Whole protein vaccination with powerful and often poorly tolerated adjuvants, immunostimulatory cytokines such as IL-2 or GM-CSF and/or TLR agonists have failed to induce clinically significant antitumor responses.…”