Immunoprevention Of Cancer Research Articles

Differential effects of Fucus vesiculosus fucoidan on fibroblast and macrophage cell lines inflammatory activation

It is estimated that more than one-third of people aged over 16 reported living with inflammation-related chronic illness. Fucoidan, sulfated polysaccharide, has been proven to modulate immune response and inhibit inflammation in both in vitro and in vivo research. In the present study the effect of commercially available fucoidan from Fucus vesiculosus (with purity 97%) on immune response was investigated. Two cell lines, human fibroblasts (HDFa) and mouse macrophages (J774A.1) were used in the study. Cells were activated with pro-inflammatory stimulus (LPS/IFN-γ or PMA) and treated with fucoidan. Results of NO inhibition assay revealed that fucoidan has anti-inflammatory activity and significantly reduces the level of NO produced by the cells. A significant decrease in secretion of IL-6 from both cell lines was observed. Moreover, fucoidan inhibits IL-12 production by mouse macrophages. The obtained results indicate that fucoidan not only acts as anti-inflammatory compound, but also has immunomodulatory activity. Enhanced secretion of TNF-α and IL-8 from macrophages and fibroblasts, respectively, was also noted. The antioxidant activity of fucoidan has also been studied. Fucoidan demonstrates dose-dependent scavenging properties by DPPH assay. Fucoidan's simultaneous ability to reduce inflammation, activate macrophages, and remove free radicals may be used as a tool to fight chronic inflammation disorders. These all contribute to the effective immunoprevention of cancer or other diseases related to the impaired function of the immune cells.

Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer

Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.

Abstract IA015: Immunoprevention of triple negative breast cancer by TOP2A derived peptide vaccination

Abstract Top2A is a key enzyme involved in DNA replication and is a therapeutic target for several cancer types including breast cancer. Overexpression of Top2A has been observed in both human and mouse triple-negative breast cancer (TNBC). The present study evaluated both immunogenicity and antitumor efficacy of a newly formulated multi-peptide vaccine targeting multiple epitopes of the Top2A protein. Top2A-specific MHC II epitopes with optimal binding affinity were identified using a combined scoring system, which predicted their potential to elicit a Th1 immune response. The formulated vaccine contained top three Top2A peptides, which elicited the strongest immunologic response and showed 100% sequence homology between human and mouse. Anti-tumor efficacy of the Top2A vaccine was initially evaluated in a syngeneic TNBC mouse model, in which pre-graft preventive vaccination was associated with significantly decreased tumor growth as compared to the adjuvant controls. The Top2A peptide vaccine exhibited striking efficacy in a genetically engineered TNBC mouse model (C3(1)/Tag), reducing tumor burden by >90% when compared with adjuvant alone. Splenocytes collected from vaccinated animals showed a robust immunologic response to the immunizing peptides. There were no overt toxicities observed with the Top2A vaccination. To explore potential mechanisms underlying the anti-tumor response induced by Top2A vaccine treatment, scTCR-seq of tumors in both control and Top2A vaccine groups revealed new T cell clones as a consequence of Top2A vaccination. Furthermore, in vitro stimulation of these splenocytes by the vaccinated Top2A peptides resulted in the secretion of cytokines indicative of Th1 responses but with minimal secretion of Th2-related cytokines. Our data indicate that the newly developed multi-peptide Top2A vaccine is immunogenic and efficacious in the prevention of TNBC development and progression in vivo. Citation Format: Sang Beom Lee, Jing Pan, Donghai Xiong, Katie Palen, Bryon Johnson, Jeffrey E. Green, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Ming You. Immunoprevention of triple negative breast cancer by TOP2A derived peptide vaccination [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA015.

Advances in Nanotechnology for Cancer Immunoprevention and Immunotherapy: A Review.

One of the most effective cancer therapies, cancer immunotherapy has produced outstanding outcomes in the field of cancer treatment. However, the cost is excessive, which limits its applicability. A smart way to address this issue would be to apply the knowledge gained through immunotherapy to develop strategies for the immunoprevention of cancer. The use of cancer vaccines is one of the most popular methods of immunoprevention. This paper reviews the technologies and processes that support the advantages of cancer immunoprevention over traditional cancer immunotherapies. Nanoparticle drug delivery systems and nanoparticle-based nano-vaccines have been employed in the past for cancer immunotherapy. This paper outlines numerous immunoprevention strategies and how nanotechnology can be applied in immunoprevention. To comprehend the non-clinical and clinical evaluation of these cancer vaccines through clinical studies is essential for acceptance of the vaccines.

Vaccines for immunoprevention of cancer.

The immunoprevention of cancer and cancer recurrence is an important area of concern for the scientific community and society as a whole. Researchers have been working for decades to develop vaccines with the potential to alleviate these health care and economic burdens. So far, vaccines have made more progress in preventing cancer than in eliminating already established cancer. In particular, vaccines targeting oncogenic viruses, such as the human papillomavirus and the hepatitis B virus, are exceptional examples of successful prevention of virus-associated cancers, such as cervical cancer and hepatocellular carcinoma. Cancer-preventive vaccines targeting nonviral antigens, such as tumor-associated antigens and neoantigens, are also being extensively tested. Here, we review the currently approved preventive cancer vaccines; discuss the challenges in this field by covering ongoing preclinical and clinical human trials in various cancers; and address various issues related to maximizing cancer vaccine benefit.

Abstract 4563: Immunoprevention of triple negative breast cancer by a multi-antigen, multi-peptide vaccine

Abstract Triple negative breast cancer (TNBC) is the most aggressive sub-type of breast cancer, comprising approximately 20% of all breast cancers, and has a poor prognosis due to its aggressive behavior and lack of effective targeted therapies. In the present study, we employed transcriptome and protein analyses to select genes that are uniquely overexpressed in human triple-negative breast cancer. Overexpression of selected genes, Cyclin A2, CDK1, Cyclin E2, PRC1, Kif15, TPX2, Ki67, Top2A, were confirmed on human breast cancer tissue microarrays and in TNBC derived cell lines from C3(1)/TAg mice. Antigen-specific MHC class II epitopes with promiscuous high-binding affinity were identified using the “combined scoring system”, based on their potential to elicit a selective Th1 immunity. Furthermore, all peptides were selected to have over 85% amino acid sequence homology between human and mice for potential clinical translation. Strong immunogenic peptides from five antigens were selected by immunogenicity testing in tumor naïve mice based on high IFN-γ and low IL-10 ELISpot response data. The selected peptides, Cyclin A2 (#335), CDK1 (#113), Cyclin E2 (#93, 298, 334), KIF15 (#129), and Top2A (#236, 410, 606), were combined to form a multi-antigen, multi-peptide vaccine (MAMPV). The tumor preventive efficacy of the MAMPV was evaluated in syngraft study using a TNBC model: C3(1)/TAg-REAR mice and a TNBC cell line derived from C3(1)/TAg (M6). MAMPV-vaccinated animals demonstrated a significant reduction in tumor volume, and significantly higher tumor infiltration of CD4+ T cells compared to the control animals. Pathological examination of major organs did not reveal any toxicity associated with the vaccine. Similar tumor preventive efficacy was demonstrated in genetically engineered mouse model (GEMM) using C3(1)/TAg mice. Taken together, our data indicate that formulation of the multi-antigen multi-peptide vaccine is highly immunogenic and has the potential to be safe and efficacious in the immunoprevention of TNBC. Citation Format: Yian Wang. Immunoprevention of triple negative breast cancer by a multi-antigen, multi-peptide vaccine [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4563.

Abstract 647: Immunoprevention of triple negative breast cancer by a TOP2A multi-peptide vaccine

Abstract Triple negative breast cancer (TNBC) comprises approximately 20% of all breast cancers, and it has a poor prognosis due to aggressive growth characteristics and lack of effective targeted therapies. Emerging data suggest vaccination as a promising approach to prevent TNBC as well as other cancer types, but appropriate vaccine targets need to be identified. In the present study, we employed in silico analyses to select genes that are uniquely expressed in TNBC. Topoisomerase 2 alpha (Top2A) was found to be highly expressed in human TNBC. Top2A is a key enzyme in DNA replication and has been identified as a target of anti-cancer therapy. Overexpression of Top2A was confirmed in human breast cancer tissue microarrays and in mouse TNBCs derived from C3(1)/TAg mice. Top2A-specific MHC class II epitopes with optimal binding affinity were identified using the “combined scoring system”, based on their potential to elicit a Th1 immune response. Furthermore, all peptides were selected to have 100% amino acid sequence homology between humans and mice for potential clinical translation. Four Top2A peptides with strong immunogenic responses were selected by immunization of tumor naïve mice followed by IFN-γ-based ELISPOT assays. These peptides were combined to form a multi-peptide Top2A vaccine. The anti-tumor efficacy of the Top2A vaccine was tested in a preventive setting using a syngeneic TNBC model in C3(1)/TAg-REAR mice. Vaccinated animals demonstrated a significant reduction in tumor growth when compared to the adjuvant control with tumor size decreasing from 278.1 mm3 in adjuvant control to 150.4 mm3 in vaccinated group (p < 0.05). Taken together, our data clearly demonstrate that the Top2A multi-peptide vaccine is highly immunogenic and provides immunopreventive efficacy against TNBC in mice. Citation Format: Sang Beom Lee, Jing Pan, Yueqiang Jiang, Katie Palen, Bryon Johnson, Romaine Ingrid Fernando, Shizuko Sei, Ronald Lubet, Ming You, Yian Wang. Immunoprevention of triple negative breast cancer by a TOP2A multi-peptide vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 647.

Immunoprevention of Pancreatic Cancer.

Pancreatic cancer (PC) is considered an incurable disease due to late diagnosis, rapid spread and negligible response treatment methods, with a 5-year survival rate of only 7%. Hence, there is an urgency in developing novel strategies for PC prevention. This review is focused on discussing the challenges in understanding complex immune functions in tumor microenvironment and host-induced immune responses against tumors, selection of antigens for development of preventive vaccines, lessons from immunoprevention clinical trials and challenges in developing future vaccines. 65 original articles were referenced from various sources, based on immunoprevention or criteria pertaining to tumor antigens and immune responses in PC. All these articles were analyzed for the method details and results obtained, and the existing challenges were derived for successful development of clinical immunoprevention strategies. The analysis of these articles and our experience with preclinical efficacy evaluations of various preventive approaches against PC helped in identifying specific tumor antigens as targets which can overcome tumor cell immune suppression. This review discussed the status of primary, secondary and tertiary preventive vaccines and reasons for failure of therapeutic vaccines. The key parameters for effective vaccination were identified, including stage of the disease for vaccination efficacy, use of appropriate animal models for development of preventive vaccines. Potential of chemopreventive agents as adjuvants in immunoprevention was discussed. This review identified new challenges for development of immunopreventive vaccines. This review analyzed various aspects of vaccine development for immunoprevention of PC and emphasized the challenges for development of immunoprevention strategies.

Abstract IA05: Immunoprevention of oral cancers

Abstract Oral pre-malignant lesions (OPLs) are usually clinically characterized as leukoplakia or erythhroplakia, and confer an increased risk of oral cancer. Despite decades of clinical investigations with candidate chemopreventive agents such as 13-cis-retinoic acid, beta-carotene, fenretinide, green-tea extract, celecoxib, erlotinib, among others, a standard-of-care chemoprevention strategy for oral cancers has not yet been developed. Importantly, OPLs and oral cavity cancers are not related to HPV, thus HPV vaccines are not expected to be effective in this setting. One of the greatest challenges in managing patients with OPLs is determining risk for malignant transformation and need for intervention. To that end, retrospective and prospective studies have been completed by our group and others and demonstrate that LOH profiles (primarily at 13p14 and/or 9p21) in OPLs are associated with higher incidence of oral cancers. LOH is now considered the most robust prognostic marker of cancer risk in this setting, and these data now set the stage for development of clinical trials focused on molecularly-defined high risk groups of OPLs. Immune checkpoint blockade with antibodies directed at programmed cell death protein 1 (PD-1) has recently been successfully developed for the management of advanced head and neck squamous cell carcinomas, validating the importance of immune modulation in the progression of these invasive tumors. Given the favorable toxicity profile, there is interest in studying these agents for prevention of oral cancers in patients with high risk OPLs. In this presentation, we will review the data that support a role for immune surveillance and immune editing in the development of oral cancers, and describe the rationale and clinical trial design of the Immunoprevention of Oral Cancer (IPOC) study, the first randomized trial to evaluate the PD-1 inhibitor pembrolizumab for oral cancer prevention in patients with molecularly-defined high-risk OPLs. Citation Format: William N. William, Jr. Immunoprevention of oral cancers [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA05.

Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer.

We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are “retired” from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a “retired” self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC)—the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as well as immunotherapy against TNBC.

Abstract P4-11-04: Targeted vaccination against human a-lactalbumin may provide immunotherapy and immunoprevention of triple negative breast cancer

Abstract We have previously shown that a-lactalbumin vaccination mediates protection against the development of murine breast cancer in the absence of any detectable inflammatory changes in all normal non-lactating tissues examined. Based on these results, we have proposed that α-lactalbumin vaccination of healthy, cancer-free, adult women may provide safe and effective immunoprevention of breast cancer. Several issues have been raised over the past several years questioning the feasibility of applying this autoimmune strategy for breast cancer immunoprevention in the normal, healthy, cancer-free adult female population. These concerns have focused on whether adult women would be immunologically responsive to human α-lactalbumin, whether a history of lactation would create an insurmountable tolerance that would preclude generating effective immunity against α-lactalbumin, whether α-lactalbumin is immunologically available in human breast tumors, and whether expression of α-lactalbumin in normal non-breast tissues would predispose to systemic autoimmune complications. Here we provide an accumulation of several new findings that directly address these issues: 1) In vitro priming of peripheral blood mononuclear cells (PBMC) from normal healthy adult women results in frequencies of α-lactalbumin-specific interferon-gamma (IFNγ) producing T cells that are consistent with those mediating protection against breast tumor formation in mice; 2) Frequencies of IFNγ-producing T cells and the level of protection from the development of breast tumors are virtually identical whether vaccination occurs in parous mice with a history of lactation and breastfeeding or whether vaccination occurs in non-parous mice with no history of lactation; 3) ONCOMINE data base searches repeatedly show highly significant overexpression of α-lactalbumin in triple negative breast cancer (TNBC). This expression was confirmed experimentally using several methods including RT-PCR, Western blot analysis, and longitudinal visualization of α-lactalbumin gene expression during in vivo growth of human TNBC in immunodeficient mice. This in vivo visualization of α-lactalbumin gene expression was facilitated by measuring bioluminescence from growing human HCC1937 TNBC cells stably transfected with a lentivirus designed to regulate firefly luciferase expression under control of the human α-lactalbumin promoter; and 4) Evidence from the Human Protein Atlas indicates negative immunohistochemical staining for α-lactalbumin in 78 normal human tissues examined, thereby confirming the widely held view that α-lactalbumin expression in normal human tissues is confined exclusively to the lactating breast. Collectively, these findings indicate that normal, healthy, adult women are capable of mounting an immune response to human α-lactalbumin, that a history of lactation and breastfeeding has no impact on the induced immunity and the protection it provides against the development of breast cancer, and that α-lactalbumin vaccination may be most effective in providing therapy and immmunoprevention of TNBC, the most aggressive form of breast cancer and the most common variant occurring in women with BRCA1 mutations (supported by NIH R01 CA140350). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-11-04.

Tumor Growth is Stimulated by Muscarinic Receptor Agonism: Role of Autoantibodies in Breast Cancer Patients

In developed countries, cancer has replaced infectious diseases as a major cause of death. Currently, efforts in the immunoprevention of cancer are beginning to resemble those presented by the prevention of infectious diseases by immunization a century ago. Breast cancer is the most frequent type of tumor in women and is the second leading cause of death by this illness, among them. Moreover, cancer incidence will grow during next years. Some findings in autoimmunity related to breast cancer in animal models have been important to clarify mechanisms that potentiate tumor growth. Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in the neoplastic microenvironment where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Generally, antigens involved in autoimmune response in breast cancer are modified self-proteins or over-expressed normal proteins that induce autoantibodies (autoAbs) formation, which exhibit tumor promoting actions. Very frequently muscarinic acetylcholine receptors (mAChR) are up-regulated in different types of tumors appearing in different animal species. mAChR have the ability to act as autoantigens for tumor bearers. This article will review recent results concerning to the ability of mAChR expressed in transformed breast cells to trigger autoAbs formation either in experimental models or in breast cancer patients. We will also discuss the action of these antibodies as agonists of mAChR. Keywords: Autoantibodies, autoantigens, cells proliferation, inositol monophosphate, MCF-7 T1N0Mx breast tumors, muscarinic receptors, nitric oxide synthase, phospholipase Cβ2, protein kinase C, tumor progression

Identification of Tumor-associated Autoantigens for the Diagnosis of Colorectal Cancer in Serum Using High Density Protein Microarrays

There is a mounting evidence of the existence of autoantibodies associated to cancer progression. Antibodies are the target of choice for serum screening because of their stability and suitability for sensitive immunoassays. By using commercial protein microarrays containing 8000 human proteins, we examined 20 sera from colorectal cancer (CRC) patients and healthy subjects to identify autoantibody patterns and associated antigens. Forty-three proteins were differentially recognized by tumoral and reference sera (p value <0.04) in the protein microarrays. Five immunoreactive antigens, PIM1, MAPKAPK3, STK4, SRC, and FGFR4, showed the highest prevalence in cancer samples, whereas ACVR2B was more abundant in normal sera. Three of them, PIM1, MAPKAPK3, and ACVR2B, were used for further validation. A significant increase in the expression level of these antigens on CRC cell lines and colonic mucosa was confirmed by immunoblotting and immunohistochemistry on tissue microarrays. A diagnostic ELISA based on the combination of MAPKAPK3 and ACVR2B proteins yielded specificity and sensitivity values of 73.9 and 83.3% (area under the curve, 0.85), respectively, for CRC discrimination after using an independent sample set containing 94 sera representative of different stages of progression and control subjects. In summary, these studies confirmed the presence of specific autoantibodies for CRC and revealed new individual markers of disease (PIM1, MAPKAPK3, and ACVR2B) with the potential to diagnose CRC with higher specificity and sensitivity than previously reported serum biomarkers.

Antibodies Against Muscarinic Receptors in Breast Cancer: Agonizing Tumor Growth

In developed countries, cancer has replaced infectious diseases as a major cause of death. Currently, efforts in the immunoprevention of cancer are beginning to resemble that presented by the prevention of infectious diseases by immunization a century ago. Breast cancer is the most frequent type of tumor in women and is the first cause of death by this illness, among them. Moreover, cancer incidence will grow during next years. Some findings in autoimmunity related to breast cancer in animal models have been important to clarify mechanisms that potentiate tumor growth. Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in neoplastic microenvironment where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Generally, antigens involved in autoimmune response in breast cancer are modified self-proteins or over-expressed normal proteins that induce autoantibodies (autoAbs) formation which exhibit tumor promoting actions. This article will review recent results concerning to the ability of muscarinic acetylcholine receptors (mAChR) expressed in transformed cells, to trigger auto- Abs formation either in experimental models or in breast cancer patients. We will also discuss the action of these antibodies as agonists in mAChR functions.

Immunoprevention of cancer through targeting of precancerous stem cells

Recently we have identified a new type of cancer cells called precancerous stem cells (pCSCs) and proposed that cancer may arise from a lengthy developing process of tumor initiating cells (TICs) → pCSCs → cancer stem cells (CSCs) → cancer cells, which is in parallel to histological changes of hyperplasia (TICs) → precancer (pCSCs) → carcinoma (CSCs/cancer cells). Since the progression of pCSCs to cancer was suppressed in immunocompetent mice (IC) mice, we hypothesized that pCSCs can be used as a tumor vaccine. Here we report that the mice injected with pCSCs developed anti‐tumor immunity, because they were resistant to the challenge of tumor cell lines with different origin. The anti‐tumor immunity could be transferred into severe immunodeficient disease (SCID) mice, which appeared to be mediated by pCSC protein‐specific T cells. This finding suggests that cancer can be prevented by immunoprevention through targeting of pCSCs or precancerous lesions. The novel concept was further supported by immunoprevention with KaovaccineTM, a biological response modifier (BRM), from the spontaneous development of lung cancer in the SP‐C/p53‐273H mice transgenic with mutated human p53 (p53‐273H) under the transcriptional control of the lung‐specific human surfactant protein C (SP‐C) promoter. Taken together, our studies indicate that immunoprevention of cancer is feasible through targeting of pCSCs.

Immunoprevention of cancer: time to reconsider timing of vaccination against cancer

Expert Rev. Anticancer Ther. 6(12), 1689–1691 (2006) The immune system has the ability to remember an encounter with an antigen for decades or even a lifetime. Exploration of this property and the induction of a longterm, pathogen-specific immune response led to the phenomenal success of vaccination programs against infectious diseases that still represent some of the most impressive triumphs of modern medicine and immunology. The immune system also plays a crucial role in the control of tumor development, as now convincingly documented by studies carried out on immunodeficient mice. Thus there is a hope that similar to the success of vaccination against infections, immune responses could also be harnessed to protect against cancer. This enthusiasm has been further fueled by recent advances in our understanding of the mechanisms controling activation of the immune system, together with the progress in laboratory techniques that allows manipulation of components of the immune system in vitro and the generation of increasingly sophisticated vaccines. Some of the important findings relevant to the development of tumor immunotherapeutic strategies include:

Immunomodulating Activity of Arabinogalactan and FucoidanIn Vitro

Many polysaccharides obtained from natural sources are considered to be biological response modifiers and have been shown to enhance various immune responses. Here, we investigated the immunomodulating effects of arabinogalactan (AG) and fucoidan (FU) in vitro. Mouse spleen lymphocytes became cytotoxic to tumor cells after culture with AG and FU at concentrations of 10-100 microg/mL. Also, AG and FU were mitogenic in spleen lymphocytes and peripheral macrophages. Macrophages treated with AG and FU (10-100 microg/mL) exhibited induced tumoricidal activity and increased phagocytosis, lysosomal enzyme activity, and production of nitrite, H2O2, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6. However, AG and FU had little effect on the level of IL-1beta. Thus, the tumoricidal effect of AG- and FU-activated macrophages appeared to be mainly mediated by production of free radicals (NO and H2O2) and cytokines (TNF-alpha and IL-6). These data suggest that AG and FU are activators of lymphocytes and macrophages. This property may contribute to their effectiveness in the immunoprevention of cancer.

Immunotherapy and immunoprevention of cancer: where do we stand?

Although evolution has shaped the immune system to control microbial in-vasions, this does not necessarily mean that the immune system can not be triggered to eliminate tumour cells. The exploitation of the terrific potential of the immune system to recognise cell alterations and to selectively destroy large populations of neoplastic cells is a possibility made even more attractive by the advances in our understanding of the immune mechanisms and our ability to manipulate them. This review summarises the state of the different immunotherapy strategies available or in development today, and examines the future developments that hold out the promise of an effective control of cancer growth.

Immunoprevention and immunotherapy of cancer in ageing.

Over the last few years there has been a growing interest in geriatric oncology, mainly because of the evidence that advanced age is the greatest risk factor for the development of cancer and that, since the elderly population is rapidly expanding, so too will the number of cancer patients. This forecast necessitates the development of new and more specific strategies for the prevention and cure of cancer in the elderly and as a result an ever-increasing need for oncologists, geriatricians and researchers to work closely together. The increased incidence of cancer in elderly people has been related to the age-associated changes occurring in the immune system, the so-called immunosenescence. This phenomenon is best characterised by a remodelling of the immune system, which appears early on and progresses throughout a person's life and mainly involves a decrease in cellular functions. This review aims to provide a rationale for the development of specific immunotherapeutic and immunopreventive regimens for the elderly. We also include a discussion on the influence that immunosenescence has on the growth of tumours and the effectiveness of immunogene therapy and cancer vaccination following a brief analysis of the age-related alterations of the cell populations involved in antitumour immunity.

Is immunoprevention of cancer a feasible possibility?

Is immunoprevention of cancer a feasible possibility?