The identification of key signaltransduction pathways and, inparticular, specific proteins thatare involved in the regulation of cancercell growth has provided unprecedentedopportunities for researchersinterested in targeted cancer treatment.The identification of molecular target-specific therapy offers the potentialof maximal therapeutic benefitwhile minimizing toxicity to normalcells. The accomplishment that led tothe sequencing and analysis of theentire human genome in 2001 has providedresearchers with the basic criticaltools to begin to identify anddifferentiate cancer from normal tissueat the genetic level.[1,2] Whilethe implications of this landmarkachievement are still being realized,it has become evident that the identificationof critical genes and proteinsinvolved in cell division and growthare just the beginning. The complexrelationships between multiple signaltransduction pathways, the surroundingtumor microenvironment, andpathways involved in immune-systemregulation have gained new appreciation.The ability to manipulate thesemultiple interactive systems with targetedtherapies represents a new treatmentparadigm in oncology.
The identification of key signal transduction pathways and, in particular, specific proteins that are involved in the regulation of cancer cell growth has provided unprecedented opportunities for researchers interested in targeted cancer treatment. The identification of molecular target- specific therapy offers the potential of maximal therapeutic benefit while minimizing toxicity to normal cells. The accomplishment that led to the sequencing and analysis of the entire human genome in 2001 has provided researchers with the basic critical tools to begin to identify and differentiate cancer from normal tissue at the genetic level.[1,2] While the implications of this landmark achievement are still being realized, it has become evident that the identification of critical genes and proteins involved in cell division and growth are just the beginning. The complex relationships between multiple signal transduction pathways, the surrounding tumor microenvironment, and pathways involved in immune-system regulation have gained new appreciation. The ability to manipulate these multiple interactive systems with targeted therapies represents a new treatment paradigm in oncology. Dr. Marshall has provided a thoughtful and comprehensive review regarding the rationale for the use of carcinoembryonic antigen (CEA) and MUC-1-targeted vaccine approaches for gastrointestinal cancer. He describes the history of the early development of CEA and MUC-1 antigen-specific vaccines and nicely highlights a number of challenges important for potent immunization, including the use of specific immune adjuvants and antigen delivery systems. This is a very important and timely review. Significant Hurdles
Based on the recent cloning and characterization of new immune checkpoints, it is important to also emphasize the significant hurdles that must be overcome if immune-based therapies are to play an important role in the treatment of advanced cancer. The implementation of optimal cancer immunotherapies will likely require several elements. First, cancerspecific proteins that are immunerelevant targets of the immune response must be identified. Such antigens would likely include proteins that are involved in cancer growth or progression pathways and that are unique to the cancer. Second, these tumor-specific proteins must be delivered to the immune system in a way that will elicit a robust tumor protein-specific immune response. The best carriers to deliver the appropriate immunogenic tumor proteins are likely those that deliver antigens to the critical antigen- presenting cells, the dendritic cells. The pox family of viral vectors fall into this category. Third, immuneinhibitory molecules-usually expressed or released by regulatory immune cells or by cells in the local tumor environment-that can dampen activated T-cell activity need to be identified, characterized, and ultimately modulated, so that the end effect is an enhancement of the immune response. Immune-Relevant Proteins
While antigens such as CEA and MUC-1 might very well be important overexpressed tumor-associated proteins, it is not clear if these proteins are the most immune-relevant. These antigens were identified over 10 years ago using various methods to analyze gene expression in cancer cells. Vaccines and antibodies designed to target these antigens have been tested in early-phase clinical trials.[2-11] As these antigens are known to have weak inherent immune potential, various immune-modulating agents were coadministered, including granulocyte macrophage colony-stimulating factor (GM-CSF, Leukine), and interleukin- 2 (IL-2, Proleukin). So far, a few studies have demonstrated postvaccination immune responses to the relevant peptides or whole proteins. Significant clinical responses have not yet been observed. This might be due to the lack of pooling of the right antigens, the existence of host mechanisms of immune tolerance, the inability of the relevant immune cells to effectively localize to sites of disease, or a combination of these factors. Recent advances in gene-expression analysis have allowed for the identification of new cancer targets, including candidate tumor antigens that might serve as T-cell and antibody targets. These advances now make it possible to exploit the immune system in the fight against a number of cancers. Several methods have been used to identify tumor-specific antigens. An "indirect" antigen discovery method-Serial Analysis of Gene Expression (SAGE)-is particularly promising.[12,13] SAGE uses differential gene display technology to identify genes that are more strongly expressed by tumor cells relative to the normal cells of origin. The most relevant of these candidate proteins can be further refined based on other important features including identifying proteins that are nonmutated, proteins thought to be of biologic importance to tumor growth and disease progression, and those that are not expressed or minimally expressed in normal tissue. Immunized lymphocytes can then be used to further define which of these overexpressed cancer proteins are most relevant to the host's immune responses. This method has been used to identify several novel candidate pancreatic tumor antigens. A similar method for identifying B-cell targets that employs immunized sera to screen phage display libraries has also identified candidate tumor antigens. Novel Approaches
Dr. Marshall highlights the rationale for using a novel combinatorial vaccinia and avian pox vaccine vector approach as both efficient carriers of relevant tumor antigens and as an effective prime-and-boost mechanism. This approach has shown promise in preclinical models as one form of dendritic cell-targeted vaccine. However, the most effective antigen delivery systems capable of inducing potent antitumor responses in patients remain unknown. Thus, other approaches, including the use of dendritic cells as vaccines and other foreign viral or bacterial attenuated vectors that target dendritic cells, still need to be further evaluated.[16-19] Other important elements in regulating T-cell recognition of tumors are the inhibitory pathways, termed "immunologic checkpoints." Immunologic checkpoints serve two purposes: One is to help generate and maintain tolerance to self antigens; the other is to restrain the amplitude of normal T-cell responses so that they do not "overshoot" in their natural response to foreign pathogens. The prototypical systemic immunologic checkpoint is mediated by the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) counter-regulatory receptor that is expressed by T cells when they become activated.[ 20,21] However, additional systemic checkpoints and checkpoints within the tumor microenvironment are actively being studied. These checkpoints, as well as regulatory T cells that may be present, will require modulation using targeted agents given in sequence with vaccination for cancer immunotherapy to realize its full potential. Conclusions
In summary, ultimately the success of immune-based therapies against cancer will depend on the development of multiple strategies that can be applied in synergy with immunotherapy. Although a substantial amount of work remains, the possibility of designing an effective cancer vaccine approach will hopefully become a reality.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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2. Lander ES, Linton LM, Birren B, et al: Initial sequencing and analysis of the human genome. Nature 409:869-921, 2001.
3. Xiong HQ, Rosenberg A, LoBuglio A, et al: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: A multicenter phase II trial. J Clin Oncol 22:2610-2616, 2004.
4. Kindler HL, Friberg G, Stadler WM, et al: Bevacizumab plus gemcitabine in patients with advanced pancreatic cancer: Updated results of a multi-center phase II trial (abstract 4009). Proc Am Soc Clin Oncol 23:314, 2004.
5. Morse M, Clay T, Hobeika A et al: Phase I study of immunization with dendritic cells modified with recombinant fowlpox encoding carcinoembryonic antigen (CEA) and the triad of costimulatory molecules CD54,CD58 and CD80 (rF-CEA(6D)-TRICOM) in patients with advanced malignancies (abstract 2508). Proc Am Soc Clin Oncol 23:165, 2004.