Continuing advances in immunology and molecular biology during the past several decades have provided optimism that immunomodulatory strategies may be clinically useful in patients with cancer. Key advances have included: (1) recognition of the critical role of the antigen-presenting cell and greatly improved understanding of antigen processing and presentation, including the molecular interactions between HLA molecules and antigenic epitopes on the antigen-processing cell and the receptors on T cells, and (2) the roles of costimulatory molecules such as B7.1, ICAM-1, and LFA-3 in the induction and maintenance of an immune response. In addition, new techniques have allowed us to identify immunogenic antigenic determinants, alter their binding affinities, and evaluate the overall success of the intervention through both in vivo and in vitro assays. Carcinoembryonic antigen (CEA) is overexpressed in a large number of gastrointestinal, lung, and breast cancers. Clinical trials have established treatment protocols using viral vectors to immunize patients to CEA without producing deleterious autoimmune phenomena. By combining various vectors to include MUC-1 and/or CEA plus costimulatory molecules in a prime-and-boost regimen, we are beginning to see signs that this intervention can not only produce changes in immune function but also potentially improve clinical outcomes. Phase III studies to test these hypotheses are under way.
T cells require at least two signals for activation. The first is delivered when the antigen binds to the T-cell receptor. The second is a costimulatory signal delivered by receptorligand interactions between the T cell and the antigen-presenting cell (eg, CD28 and B7.1). Binding of CD28 to B7.1 upregulates the production of multiple cytokines by CD8+ and CD4+ cells, including IL-2 and interferon-gamma. Von Mehren et al demonstrated that a fowlpox- CEA B7.1 vaccine was well tolerated and induced CEA-specific T-cell responses in patients with advanced re- current adenocarcinomas. Thus, it was logical to explore the potential of vaccination with multiple costimulatory molecules. Hodge et al reported that murine cells infected with a recombinant virus expressing genes for three costimulatory molecules (eg, B7.1 [CD80], ICAM-1 [CD54], A-3 [D58] referred to as the TRIad of COstimulatory Molecules [TRICOM]), activated T cells to a far greater extent than cells infected with either one or two of the costimulatory molecules. This was the first experimental evidence that vectors could be used to transfect cells with three costimulatory molecules; in addition, the TRICOM strategy activated both CD8+ and CD4+ cells. Direct intralesional injection of TRICOM into metastatic melanoma has been shown to alter the tumor's microenvironment with a resultant local tumor regression. Subsequently, the gene for CEA has been incorporated along with the TRICOM molecules to provide a single vector that can transfect cells with genetic elements supplying both signals necessary for T-cell activation, thereby amplifying T-cell responses.[ 63-65] With this approach, therapeutic vaccines could alter the phenotype of an infected cell by converting any cell into an antigenpresenting cell expressing both costimulatory molecules and antigen- MHC complexes on its surface. This approach appears to be augmented when the prime-and-boost administration strategy is employed, and is facilitated by coadministration of GMCSF and/or IL-2. Studies by Marshall et al have demonstrated that rV-CEA and fowlpox- CEA (rF-CEA) are well tolerated and have clinical activity with a correlation between CEA-specific immune reactivity and survival.[67,68] The investigators recently published the results of a phase I study of a primeand- boost strategy with rV-CEA/ fowlpox-CEA plus TRICOM in 58 patients with advanced CEA-expressing cancers. Patients were accrued to eight cohorts that involved vaccinations with the following: fowlpox- CEA-TRICOM; primary vaccination with rV-CEA-TRICOM plus fowlpox- CEA-TRICOM booster vaccinations; and rV-CEA-TRICOM and then fowlpox-CEA-TRICOM plus GM-CSF with vaccines, or with divided doses of vaccine with GM-CSF (Table 1). The therapeutic cancer vaccines were administered for six doses at 28-day intervals and then once every 3 months. If, in the judgment of the investigator, patients progressed on the 3-month schedule, they were allowed to revert to 28-day treatment intervals. The vaccines were well tolerated. One patient (2%) had a histologically documented, complete response. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having stable disease for 6 months or longer. Eleven patients (19%) had decreasing or stable serum CEA. The ELISpot assay was used to assess interferon-gamma released by peripheral blood mononuclear cells in response to CEA peptide exposure. The majority of the patients demonstrated enhanced CEAspecific T-cell responses. Interestingly, several patients had preexisting CEA-specific T-cell responses prior to vaccination-presumably reflecting an endogenous, but suboptimal, response to their tumor. The investigators concluded that not only is the vaccine well tolerated and able to generate significant CEA-specific immune responses, but the vaccines also appeared to clinically benefit some patients. Addition of MUC-1
Alterations in mucin are common in colonic tumors. Mucins are high-molecular-weight, carbohydrate- rich proteins. cDNA sequences of genes coding for mucin protein have identified a number of mucin genes. They have been designated based upon their chronologic order of identification as MUC-1 through MUC- 17. However, the nomenclature is somewhat convoluted since additional studies have demonstrated mucins originally attributed to one gene that are actually products of two separate genes and two named mucins that may actually be the product of two closely related genes or a single gene. In addition to CEA, mucin-associated antigens (particularly the MUC-1 gene product) are overexpressed on the surface of many human malignancies including adenocarcinomas of the gastrointestinal system, prostate, and breast, and hematologic malignancies including non-Hodgkin's lymphoma and multiple myeloma. Experimentally, MHC-restricted T cells have been shown to recognize epitopes in the MUC-1 protein. Thus, employment of MUC-1 epitopes in vaccine therapy in a fashion similar to that described for CEA offers the potential of additional hope to future patients with a variety of cancers. Autoimmunity Use of autoantigens raises the possibility that vaccination with therapeutic vaccines expressing the CEA or MUC-1 antigens might precipitate the development of autoimmune side effects such as enteritis or colitis. However, studies of mice transgenic for human CEA have demonstrated that significant antitumor activity can be produced by vaccination strategies without upregulation of autoreactive T cells. In a murine intestinal tumor model, Greiner et al were able to use a CEA-based vaccine to dramatically reduce the number of malignant tumors. Histopathologic study of normal intestinal tissues from the animals demonstrated preservation of the normal architecture and CEA expression. Since CEA is normally expressed on the luminal surface of the colonic epithelium, it may be able to escape immune detection. Thus, CEA may be an optimal target for therapeutic antitumor vaccines. Poxvirus-Based Vaccine Safety Issues Between 1991 and 2003, recombinant poxvirus vaccines have been administered to over 700 patients participating in 29 clinical trials. Targets of the recombinant virus vaccines have included CEA, MUC-1, prostate-specific antigen (PSA), gp100, MART-1, and tyrosinase. The vaccines have been administered through intradermal, intralesional, subcutaneous, intramuscular, intravenous, and intrathecal routes. Administration has been generally well tolerated. The most common adverse events are flu-like symptoms. Phase I Studies in Pancreatic Cancer Schuetz et al recently reported the preliminary results of two phase I studies of vaccines targeting CEA and MUC-1 in 22 patients with stage III or IV pancreatic cancer. While the first study tested an earlier generation of the vaccines (N = 12), the second study tested a prime-and-boost strategy with rV-CEA-MUC-1-TRICOM genes plus fowlpox-CEA-MUC-1-TRICOM genes (N = 10). All patients had received prior therapy and 20 (91%) had metastatic disease. Patients received a "prime" dose of vaccinia on day 0, followed by the "boost" doses of fowlpox on days 14, 28, and 42. GMCSF (100 μg) was administered to all patients following each vaccination for 4 days. All patients who were stable and able to participate received vaccinations on a monthly basis. Safety parameters included vital signs, physical examination, laboratory tests, and adverse events. All subjects were followed for survival. The most common vaccine-related adverse event was injection-site reaction (grade 1); flu-like symptoms were also common. A single patient reported grade 3 fever. Among the 10 patients enrolled in the second study, the median survival was 6.3 months, compared to historical controls of approximately 3 months; 1-year survival was 30%. The investigators concluded that the vaccination strategy was well tolerated, and, although the study was small and uncontrolled, the results suggested that therapeutic vaccination had improved median overall survival. Realizing the Promise: Current and Future Studies Recent research suggests that other interventions can alter the phenotype of tumor cells, thereby lessening their immune tolerance. Chakraborty et al, for example, have demonstrated that when sublethal doses of radiation are combined with vaccination using a prime-and-boost strategy, dramatic and significant cure rates can occur in mice transgenic for human CEA with a murine carcinoma transfected with CEA. Within 72 hours of irradiation, multiple human cancer cell lines show alterations in expression of Fas and other cell-surface antigens that make them more susceptible to cytotoxic T cells. Other strategies that may also contribute to immunotherapy and improve clinical outcomes include use of adjuvants such as CpG oligonucleotides, cytokine combinations to improve harvest of antigenpresenting cells or stimulate in vivo immunity, and additional studies of the phenotypic and genotypic properties of tumor-infiltrating T cells. Potential Limitations Despite the advances described above, a number of issues remain and present potential obstacles to implementing vaccine strategies in patients with cancer. Disease burden is a significant issue. At some point, the tumor mass may become so large that it over whelms the immune system; alternatively, the antigen burden of the tumor might render the patient anergic to the tumor antigens. While tumor bulk can be reduced prior to immunotherapy in patients with localized disease, the issue of management of metastatic disease in candidates for immunotherapy remains unresolved. Although vaccinations clearly modulate the function of lymphocytes, it is important to evaluate various therapeutic interventions to maximize the results of the immune intervention. For example, different routes of administration should be evaluated. The complex nature of the immune system consists of a series of regulatory and counterregulatory processes finely balanced to discriminate self from not-self and eliminate the latter. Therefore, additional work is needed to modulate the activities of inhibitory T cells and cytokines during vaccine therapy. Lastly, malignant cells have demonstrated remarkable evolutionary capacities. Selection of one or more clones by tumoricidal interventions allows resistant clones to emerge and become dominant. Therefore, additional studies should assess means to counteract immune evasion. While these limitations might seem daunting, our progress from the time of Dr. Coley offers encouragement.
Dr. Marshall is a consultant and researcher for Therion Biologics Corporation.
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