by Bruce Shriver and Tom Swartz

The Cancer Stem Cell: Evidence for its Origin as an Injured Autoreactive T Cell

This article explores similarities between lymphocytes and cancer cells, and proposes a new model for the genesis of human cancer. It suggests that the development of cancer requires infection(s) during which antigenic determinants from pathogens mimicking self-antigens are co-presented to the immune system, leading to breaking T cell tolerance. The abstract of the article sets forth the rest of the reasoning of the article as follows. Some level of autoimmunity is normal and necessary for effective pathogen eradication. However, autoreactive T cells must be eliminated by apoptosis when the immune response is terminated. Apoptosis can be deficient in the event of a weakened immune system, the causes of which are multifactorial. Some autoreactive T cells suffer genomic damage in this process, but manage to survive. The resulting cancer stem cell still retains some functions of an inflammatory T cell, so it seeks out sites of inflammation inside the body. Due to its defective constitutive production of inflammatory cytokines and other growth factors, a stroma is built at the site of inflammation similar to the temporary stroma built during wound healing. The cancer cells grow inside this stroma, forming a tumor that provides their vascular supply and protects them from cellular immune response. As cancer stem cells have plasticity comparable to normal stem cells, interactions with surrounding normal tissues cause them to give rise to all the various types of cancers, resembling differentiated tissue types. Metastases form at an advanced stage of the disease, with the proliferation of sites of inflammation inside the body following a similar mechanism. Immunosuppressive cancer therapies inadvertently re-invigorate pathogenic microorganisms and parasitic infections common to cancer, leading to a vicious circle of infection, autoimmunity and malignancy that ultimately dooms cancer patients. Based on this new understanding, the article recommends a systemic approach to the development of cancer therapies that supports rather than antagonizes the immune system.

SYT-SSX1 and SYT-SSX2 Interfere with Repression of E-Cadherin by Snail and Slug: A Potential Mechanism for Aberrant Mesenchymal to Epithelial Transition in Human Synovial Sarcoma, by Tsuyoshi Saito, Makoto Nagai and Marc Ladanyi, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. From the abstract: “Synovial sarcoma is a primitive mesenchymal neoplasm characterized in almost all cases by a t(X;18) fusing the SYT transcriptional coactivator gene with either SSX1 or SSX2, with the resulting fusion gene encoding an aberrant transcriptional regulator. A subset of synovial sarcoma, predominantly cases with the SYT-SSX1 fusion, shows foci of morphologic epithelial differentiation in the form of nests of glandular epithelium. The striking spontaneous mesenchymal to epithelial differentiation in this cancer is reminiscent of a developmental switch, but the only clue to its mechanistic basis has been the observation that most cases of synovial sarcoma with glandular epithelial differentiation (GED) contain SYT-SSX1 instead of SYT-SSX2. We report here that SYT-SSX1 and SYT-SSX2 interact preferentially with Snail or Slug, respectively, and prevent these transcriptional repressors from binding to the proximal E-cadherin promoter as shown by coimmunoprecipitation and chromatin immunoprecipitation. Luciferase reporter assays reveal that SYT-SSX1 and SYT-SSX2 can respectively overcome the Snail- or Slug-mediated repression of E-cadherin transcription. This provides a mechanism by which E-cadherin expression, a prerequisite of epithelial differentiation, is aberrantly derepressed in synovial sarcoma and may also explain the association of GED with the SYT-SSX1 fusion because it interferes with Snail, the stronger repressor of the E-cadherin promoter. Thus, our data provide a mechanistic basis for the observed heterogeneity in the acquisition of epithelial characteristics in synovial sarcoma and highlight the potential role of differential interactions with Snail or Slug in modulating this phenotypic transition. (Cancer Res 2006; 66(14): 6919-27)

Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas, by Elai Davicioni, Friedrich Graf Finckenstein, Violette Shahbazian, Jonathan D. Buckley, Timothy J. Triche and Michael J. Anderson. From the abstract: Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior. (Cancer Res 2006; 66(14): 6936-46)

Expression of the FUS-CHOP Fusion Protein in Primary Mesenchymal Progenitor Cells Gives Rise to a Model of Myxoid Liposarcoma, by Nicolò Riggi, Luisa Cironi, Paolo Provero, Mario-Luca Suvà, Jean-Christophe Stehle, Karine Baumer, Louis Guillou and Ivan Stamenkovic. From the abstract: A subset of sarcomas is associated with specific chromosomal translocations that give rise to fusion genes believed to participate in transformation and oncogenesis. Identification of the primary cell environment that provides permissiveness for the oncogenic potential of these fusion genes is essential to understand sarcoma pathogenesis. We have recently shown that expression of the EWS-FLI-1 fusion protein in primary mesenchymal progenitor cells (MPCs) suffices to develop Ewing's sarcoma-like tumors in mice. Because most sarcomas bearing unique chromosomal translocations are believed to originate from common progenitor cells, and because MPCs populate most organs, we expressed the sarcoma-associated fusion proteins FUS/TLS-CHOP, EWS-ATF1, and SYT-SSX1 in MPCs and tested the tumorigenic potential of these cells in vivo. Whereas expression of EWS-ATF1 and SYT-SSX1 failed to transform MPCs, FUS-CHOP–expressing cells formed tumors resembling human myxoid liposarcoma. Transcription profile analysis of these tumors revealed induction of transcripts known to be associated with myxoid liposarcoma and novel candidate genes, including PDGFA, whose expression was confirmed in human tumor samples. MPCFUS-CHOP and the previously described MPCEWS-FLI-1 tumors displayed distinct transcription profiles, consistent with the different target gene repertoires of their respective fusion proteins. Unexpectedly, a set of genes implicated in cell survival and adhesion displayed similar behavior in the two tumors, suggesting events that may be common to primary MPC transformation. Taken together, our observations suggest that expression of FUS-CHOP may be the initiating event in myxoid liposarcoma pathogenesis, and that MPCs may constitute one cell type from which these tumors originate. (Cancer Res 2006; 66(14): 7016-23)

Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma, by F. Grosso, P. Dileo, R. Sanfilippo, S. Stacchiotti, R. Bertulli, C. Piovesan, J. Jimeno, M. D’Incalci, A. Gescher and P.G. Casali. From the abstract: Trabectedin is a marine-derived cytoxic alkaloid which has shown promising antitumour activity in a variety of human malignancies including sarcoma. Fifty-four patients with advanced sarcoma (age 43 yrs, range 18–70), all pretreated with prior chemotherapy, were enrolled on a named individual basis for treatment with trabectedin. Diagnosis was adult soft tissue sarcoma (STS) in 46 patients, Ewing’s family tumour (EFT) in 4, and osteosarcoma (OS) in 4. The initial 23 patients (total number of courses administered: 68) did not receive premedication prior to trabectedin, while the other 31 patients (total number of courses administered: 134) received premedication with dexamethasone 4 mg po bid 24 hours before therapy. Incidence of toxicity (grade 3–4), expressed as percentage of courses, was as follows: in patients without dexamethasone, elevation of transaminases 34%, neutropenia 24% and thrombocytopenia 25%; in patients with prior dexamethasone, elevation of transaminases 2%, neutropenia 2% and no thrombocytopenia. The median received dose intensity of trabectedin was superimposable in the two groups (404 μg and 400 μg per week, respectively), as well as progression-free survival (19% at 6 months). Among STS patients, 9% had objective responses. In this unselected patient series, premedication with dexamethasone strongly reduced drug-induced hepatotoxicity and myelosuppression. European Journal of Cancer Volume 42, Issue 10 , July 2006, Pages 1484-1490.

High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours, by A. McTiernan, D. Driver, M. P. Michelagnoli, A. M. Kilby and J. S. Whelan. Background: The outcome for patients with recurrent or progressive Ewing's sarcoma family of tumours (ESFT) is poor. High dose therapy (HDT) has been used for a number of years in an attempt to improve survival; however, evidence for the efficacy of this treatment remains limited. Patients and methods: Between 1992 and 2004, 33 patients with recurrent or progressive ESFT were treated with HDT with bone marrow (n = 2), peripheral blood stem cell (n = 30), or bone marrow and peripheral blood stem cell support (n = 1), at a single institution. HDT was with busulphan and melphalan in 22 patients; melphalan and etoposide in seven patients, three with total body irradiation (TBI); melphalan in three patients (2 with TBI), and busulphan and cyclophosphamide in one patient. Results: The 2 and 5 year event free survival was 42.5% (95% CI, 26–59%) and 38.2% (95% CI, 21–55%) respectively. There was one treatment related death from colitis, and grade 4 infection was observed in two patients. Conclusions: Long-term survival can be attained in patients with recurrent or refractory ESFT treated with HDT. However, this treatment is associated with severe toxicity. A need remains for prospective randomised clinical trials of HDT in this group of patients. Annals of Oncology 2006 17(8):1301-1305.

Molecular Diagnosis of Sarcomas: Chromosomal Translocations in Sarcomas

Article by Alexander Lazar, MD, PhD; Lynne V. Abruzzo, MD, PhD; Raphael E. Pollock, MD, PhD; Sangkyou Lee, PhD; Bogdan Czerniak, MD, PhD, Archives of Pathology and Laboratory Medicine: Vol. 130, No. 8, pp. 1199–1207. Accepted April 17, 2006. Sarcomas are rare, numerous in type, and often difficult to definitively classify. Work in the last 2 decades has revealed that a significant subset of sarcomas are associated with specific chromosomal translocations producing chimeric (fusion) genes that play a role in the sarcomas' biology and are helpful in their differential diagnosis. The objective of this work is "To briefly review the sarcomas associated with specific translocations presenting Ewing sarcoma and synovial sarcoma as archetypes and to further explain how cytogenetic and molecular biologic approaches are being used in the diagnosis of sarcomas." From the conclusions, "In addition to, and complementing, the traditional diagnostic methods of examination of hematoxylin-eosin stained slides, immunohistochemistry, and sound clinical-pathologic correlation, additional cytogenetic and molecular biologic methods are being increasingly utilized and relied on in sarcoma pathology. These methods include chromosomal karyotyping, fluorescence in-situ hybridization, spectral karyotyping, and polymerase chain reaction– based methods for demonstrating specific chromosomal translocations and fusion genes. Understanding the basis of these methods and their application is critical to better provide accurate and validated specific diagnoses of sarcomas."

Cancer Experts Spot Protein Which Triggers the Spread of Cancer

Experts at Edinburgh University have identified the way a specific cell protein triggers the spread of cancer. A biochemical imbalance causes the protein, MDM2, to activate the destruction of the key cancer-preventing protein p53. The scientists said that new drugs could be designed to help prevent MDM2 acting as a cancer-promoting agent. Lead investigator Dr. Kathryn Ball said the study, which is funded by Cancer Research UK, had also identified a possible template for new drugs. "We have identified protein fragments which can bind to MDM2, inhibiting its activity," she said. "These fragments could be a good template for drugs designed to hinder the role of MDM2 in the p53 destruction pathway." Prof John Toy, medical director at Cancer Research UK, welcomed the findings. He said: "p53 is a crucial protein that acts as a guardian of the normal cell. Its failure to do its job properly is associated with many types of cancer. If p53 is being destroyed by another protein in a cancer cell, then it offers an excellent target when designing new anti-cancer drugs. This research suggests MDM2 is just such a target." The study is published in the July 21 edition of Molecular Cell. Click on abstract to view the same. The full text of the research paper is available by subscription.

Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age for Soft Tissue Sarcomas and Malignant Bone Tumors: 1975-2000

This monograph from the National Cancer Institute (NCI) is the first to collect detailed information about cancer incidence and outcomes in adolescents and young adults. It was developed to gather population-based incidence, mortality, and survival data specific to cancers that occur in the adolescent and young adult population, along with epidemiological data and risk factors for the development of age-specific cancers. The monograph is intended to help educate medical providers and the public about cancer incidence and survival in this age group, and provide the impetus for further research to improve the survival and the quality of life of these young people. This publication was prepared by the NCI's Surveillance Epidemiology and End Results (SEER) Program and the Children’s Oncology Group (COG), with special assistance from the Adolescent and Young Adult (AYA) and Epidemiology Committees, volunteer editors and authors from the NCI, NCI-sponsored adult cancer cooperative groups (Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, National Surgical Adjuvant Breast and Bowel Program, American College of Surgeons Oncology Group), and NCI-Designated Comprehensive Cancer Centers. The monograph has separate chapters dealing with Soft Tissue Sarcomas and Malignant Bone Tumors. The compete report can be downloaded free of charge using the above link.

Cardiotoxicity of the Cancer Therapeutic Agent Imatinib Mesylate

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. In this paper, the investigators report on ten individuals who developed severe congestive heart failure while on imatinib and they show that imatinib-treated mice develop left ventricular contractile dysfunction.

Progressive Heart Damage Seen Two Decades After Adriamycin

The cardiotoxicity of Adriamycin (doxorubicin) apparently does not fade away, even after two decades or more Dutch researchers have found. The researchers conducted a longitudinal assessment of the cardiac function in anthracycline-treated survivors. In the current 2004 study, the patients were treated with Adriamycin for osteogenic sarcoma or malignant fibrous histiocytoma between 1977 and 1990 and were followed for 15 to 27.5 years. Combination chemotherapy included moderate-to-high doses of Adriamycin (225-550 mg/m²; cumulative dose 360 mg/m ²). The researchers found systolic dysfunction in more than a quarter of the patients and diastolic dysfunction in nearly half. Moreover, cardiac dysfunction was progressive as measured at nine, 14, and 22 years. Specifically, in a 2004 follow-up, 27% of the patients had systolic dysfunction and 45% had diastolic dysfunction. This compared with the 1997 follow-up when 9% had systolic dysfunction and 18% had diastolic dysfunction. Heart-rate variability in 19 available patients showed further deterioration compared with earlier results, the researchers reported. Although in the earlier analyses of these patients, systolic dysfunction had not progressively decreased in the nine-year and 14-year follow-ups, the number of patients with abnormal systolic function increased significantly in the extended follow-up. In addition, all six of the patients with decreased systolic function at the current assessment (2004) had an elevated wall motion score index. Four had diffuse wall motion abnormalities, and two had regional abnormalities, suggesting ischemic heart disease (confirmed in one by PET scan), the investigators said. Although some studies have found that younger patients are more at risk for of heart damage, age was not a factor in this study, the researchers said. There were 31 long-term survivors in the original group treated between 1977 and 1999, with an age range of 10 to 38 years. All had cardiac assessments at nine years (1992), 14 years (1997), and at 22 years in the current assessment. Patients were assessed by blood tests, blood pressure measurement, Doppler echocardiography, ECG, and 24-hour Holter monitoring, among other studies. No relation was found between cardiac abnormalities and the cumulative dose of Adriamycin, probably because all patients had moderate-to-high doses of the drug, the researchers said. Among limitations of this study, the investigators note are its small size and the fact that although the patients reported no cardiac symptoms, this was not confirmed by exercise tests. Finally, the investigators mentioned that the results of the current study may not be completely comparable with those of the earlier assessments. In the current study they used the wall motion score index (WMSI) and tissue velocity imaging (TVI) to determine cardiac function, superior techniques not available in their previous studies. In conclusion, researcher Dr. Inge Brouwer said, "our results suggest that after treatment with anthracyclines, there is an ongoing deterioration of cardiac function and no extinction is anticipated. Therefore, anthracycline-treated survivors are considered for life-long cardiac surveillance." "We need to keep checking these patients," she said, "and be ready to start medication to stabilize their heart function in order to prevent further cardiac deterioration." In addition to treating risk factors, such as high cholesterol and blood pressure, patients should be encouraged to make helpful lifestyle changes, she added. The abstract of the original research paper is reported online in the Annals of Oncology. The full text is available by subscription only.

Consensus Recommendations for the Use of ^Sup 18^F-FDG PET as an Indicator of Therapeutic Response in Patients in National Cancer Institute Trials

^sup 18^F-FDG is a marker of metabolic activity in a variety of tissues and tumors (2). Most malignant tissues have increased ^sup 18^F-FDG uptake associated with an increased rate of glycolysis mid of glucose transport. Many therapeutic clinical trials have proposed using a measure of metabolic change to assess therapeutic response rather than relying on conventional anatomic measurements of changes in tumor size on CT or MRI. PET assessment of changes in ^sup 18^F-FDG uptake by tumors is gaining acceptance as such a measure. However, despite the increasing use of ^sup 18^F-FDG PET as a biomarker for predicting therapeutic response, there are no widely accepted standardized protocols for using ^sup 18^F-FDG PET as a tool for assessing response to therapy, nor are there validated criteria for judging response using ^sup 18^F-FDG PET. To provide such guidance and to help standardize the acquisition and interpretation of ^sup 18^F-FDG PET images in clinical trials sponsored by the National Cancer Institute (NCI), the Cancer Imaging Program of the NCI convened a workshop on January 10- 11, 2005, in Washington, DC, at which the current status of ^sup 18^F-FDG PET technology and clinical experience-both in diagnosis and in monitoring therapeutic response-was reviewed. The participants focused on patient preparation, image acquisition, image reconstruction, quantitative and semiquantitative image analysis, quality assurance, reproducibility, and other parameters important in ^sup 18^F-FDG PET studies before and after a therapeutic intervention. Their discussions were based on the existing medical literature and on their own expertise. The authors of this document present the outcome of those deliberations. They intend that it serve as the recommended set of procedures for the acquisition and analysis of ^sup 18^F-FDG PET scans of patients participating in NCI-sponsored diagnostic and therapeutic clinical trials. They hope that these guidelines will help bring about a future in which ^sup 18^F-FDG PET can provide an early metabolic assessment of therapeutic response. The specifics of the guidelines are beyond the scope of this summary. The full text of the document is available by subscription in the Journal of Nuclear Medicine by clicking here.

Chronic Musculoskeletal Pain in Children: Initial Evaluation

Musculoskeletal pain during childhood is common. In population surveys, 16 percent of school-age children reported limb pain. Musculoskeletal pain can be difficult for children to characterize and can cause children and parents great anxiety. Although the cause of acute musculoskeletal pain in children usually is obvious, the cause of chronic musculoskeletal pain or pain that has associated systemic symptoms can be more difficult to determine. The term "growing pains" may be applied mistakenly to children who have a serious rheumatic or malignant disease. Children who have unusual symptoms or abnormal findings on physical examination should be evaluated carefully. A logical and consistent approach to diagnosis is necessary to treat the pain and its cause effectively and to avoid the long-term complications of untreated disease. The above article published in American Family Physician (a peer reviewed journal of the American Academy of Family Physicians) outlines a primary care approach to evaluating and diagnosing the child with musculoskeletal pain. While the article focuses on the possibility of diagnosing rheumatic illness, the article points out that physicians must be alert to the possibility of malignancy as the cause of musculoskeletal pain in children. The article notes that malignant musculoskeletal tumors account for 5 to 10 percent of malignant neoplasms of childhood; the most common of these lesions being osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. The article states that cancer should be considered in a child who has pain out of proportion to clinical findings, or suggestive laboratory or radiologic test results. Pain is the most common presenting symptom of malignancy, with swelling and reactive arthritis over the involved bone occurring a few weeks or months after onset of pain. Children with fevers, weight loss, and abnormalities on laboratory evaluation may already have metastases. The article states that tumors may be indicated on plain radiographs by abnormalities such as periosteal elevation, cortical destruction with a "moth-eaten" appearance, and an apparent soft tissue mass. In addition, a bone scan may localize involved areas, and computed tomography or MRI may further delineate the lesion. Given the consequences of delayed diagnosis, pain indeed should always alert the physician to the possibility of malignancy.

Cytogen’s QUADRAMET Product for Metastatic Bone Pain

Cytogen Corporation has announced the publication of an article which reviews and discusses the company's QUADRAMET(R) product for the treatment of pain arising from metastatic bone disease. Each year, more than 100,000 patients in the U.S. develop bone metastases from spread of their primary cancer. Bone is the third most common site of metastatic disease after liver and lung, and spread to bone is associated with considerable morbidity. This includes bone pain and fracture, spinal cord compression, and hypercalcemia. The incidence of bone metastasis is expected to increase over the next decade as patient survival improves due to advances in anticancer therapy. This will make the treatment of this problem more important in the overall management of the surviving cancer patient. QUADRAMET is an oncology product administered for pain relief in patients with metastatic bone lesions which show up on radionuclide bone scan. It pairs the targeting ability of a small molecule, bone-seeking phosphonate (EDTMP) with the therapeutic potential of radiation (samarium Sm-153). Skeletal invasion by cancers often creates an imbalance between the normal process of bone destruction and formation. QUADRAMET selectively targets such sites of imbalance, thereby delivering radioactivity to areas of the skeleton that have been invaded by metastatic tumor. QUADRAMET has demonstrated a range of characteristics that may be advantageous for the treatment of pain arising from metastatic bone disease, including early onset of pain relief (patients may experience pain relief within the first week with maximal relief generally occurring at three to four weeks after injection), length of pain relief, lasting a median of four months in responding patients, and predictable and reversible bone marrow toxicity or myelosuppression that tends to return to pretreatment levels after eight weeks. QUADRAMET is administered as a single intravenous injection, usually on an outpatient basis, and exhibits selective uptake in areas of bone formation with little or no detectable accumulation in soft tissue. The publication, "Samarium for osteoblastic bone metastases and osteosarcoma" by Pete Anderson, M.D., Ph.D., a Pediatric Oncologist at The University of Texas MD Anderson Cancer Center, appears in the August 2006 issue of the peer-reviewed journal Expert Opinion on Pharmacotherapy (Expert Opin. Pharmacother. (2006) 7(11):1475-1486). The abstract is available by clicking on the above link. In the Expert Opinion section of the article, Dr Anderson writes: "QUADRAMET is all too infrequently utilized as a means of palliation and based on emerging clinical data is likely a useful adjunct to improve response and durability of lesion control in combination with other therapeutic approaches. Better education of both patient families and physicians regarding the safety and efficacy of the targeted radiation provided by QUADRAMET to areas 'hot' on routine bone scans should increase awareness and future utilization of this well-tolerated, targeted, bone-specific therapy for metastatic bone disease."

Cancer Vaccines: Preclinical Studies and Novel Strategies

The development of cancer vaccines, aimed to enhance the immune response against a tumor, is a promising area of research. A better understanding of both the molecular mechanisms that govern the generation of an effective immune response and the biology of a tumor has contributed to substantial progress in the field. In this review article areas of intense investigation in cancer immunotherapy are discussed including: (1) the discovery and characterization of novel tumor antigens to be used as targets for vaccination; (2) the investigation of different vaccine-delivery modalities such as cellular-based vaccines, protein- and peptide-based vaccines, and vector-based vaccines; (3) the characterization of biological adjuvants to further improve the immunogenicity of a vaccine; and (4) the investigation of multimodal therapies where vaccines are being combined with other oncological treatments such as radiation and chemotherapy. A compilation of data from preclinical studies conducted in vitro as well as in animal models is presented. The results from these studies would certainly support the development of new vaccination strategies toward cancer vaccines with enhanced clinical efficacy.