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Ethanol

We propose to conduct a multifactorial genetic study of cancer risk-related behaviors and other complex human characteristics. The main areas of interest are tobacco smoking, excess alcohol consumption, psychological traits, and HIV/AIDS susceptibility and progression. The subjects will be adult male and female probands who display one or more of the phenotypes of interest together with their brothers, sisters and parents. Information on tobacco and alcohol use, psychological and personality traits, sexual behavior, HIV status and progression, and other characteristics with possible genetic components will be obtained through structured interviews and questionnaires. DNA will be prepared from blood samples and typed for a series of candidate genes chosen for function and for random polymorphic markers. By correlating the genotypic and phenotypic information, we hope to identify individual loci that interactively contribute to many different aspects of human health and disease.

Genetic Factors and Interrelationships for Cancer Risk-Related Behaviors and Complex Traits

National Cancer Institute (NCI)

Neoplasms

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Vaccines

Chi-An Chen, MD

Cervical cancer is the most frequent neoplasm and the third in mortality rate of the malignancies in women in the world. It results in about 200,000 women dying of cervical cancer each year worldwide. The available forms of treatment - surgery, radiation therapy, and chemotherapy - are all cytoreductive treatment modalities, so, in addition to killing cancerous cells, healthy cells are also destroyed in the process. Indeed, there is a need to decrease the incidence of cervical cancer and develop better forms for its treatment.

Human papillomaviruses (HPV) have been consistently implicated in causing cervical cancer especially those high-risk types (HPV 16, 18, 31, 45) which have been strongly associated with cervical cancer. HPV 16 was found in more than 50% of cervical cancer tissues. So, the host immune response plays an important role in determining the regression of a cervical abnormality or persistence and progression to a malignancy via targeting HPV.

The ideal cancer treatment should be able to eradicate systemic tumors at multiple sites in the body while having the specificity to discriminate between neoplastic and nonneoplastic cells. In this regard, antigen-specific cancer immunotherapy represents an attractive approach for cancer treatment. By cooperating with Dr. TC Wu at the Johns Hopkins Medical Institutes, the investigators have recently developed some E7-specific cancer vaccines of different strategies such as DNA, or replication-defective SINrep5 virus. They found that these E7-chimeric DNA vaccines are capable of preventing and treating the growth of murine model tumors expressing E7. These positive results from the preclinical murine models have encouraged the investigators to focus on the development of a cancer vaccine and immunotherapy and apply these vaccines to human subjects. However, it is very important to set up various E7-specific immunologic assays of human beings to evaluate the effects of a cancer vaccine or immunotherapy in future clinical trials. So the investigators would like to provide this proposal to address the development of HPV 16 E7-specific immunologic assays in human beings. There are two main goals in this study. First, the investigators would like to establish and compare the differences of HPV type 16 E7-specific immunologic responses between the normal population, people with HPV infection, patients with cervical intraepithelial neoplastic (CIN) lesions, and patients with cervical cancer. Second, they would like to correlate the disease severity of cervical cancer with the immunologic responses to HPV type 16 E7 antigen.

HPV and Cervical Cancers:

Human papillomaviruses (HPV) are small, nonenveloped DNA viruses which induce epithelial tumors of skin or mucosa. The majority of tumors are benign, show limited growth and usually regress spontaneously. However, a number of human papillomaviruses induce tumors that may eventually progress to carcinomas. The genital HPV types 16 and 18, and less frequently, types 31, 33, 35, 45, 51 and 56, have been implicated in the etiology of cervical and other anogenital cancers. Approximately 500,000 women worldwide develop cervical cancer yearly and it is the second leading cause of death from cancer in women. In developed countries, cancer of the cervix ranks behind cancers of the breast, lung, uterus, and ovaries and accounts for 7% of all female cancers. In the United States, there are about 4,800 deaths annually from cervical cancer. The evidence linking HPVs to anogenital cancer comes from epidemiologic and laboratory studies. More than 90% of cervical cancers and their precursors, so-called cervical intraepithelial neoplasia (CIN), contain human papillomavirus (HPV) DNA sequences. The HPV types found in cancer cells have transforming activity in in vitro studies and the viral transforming proteins, E6 and E7, are consistently expressed in cervical cancer cell lines and in HPV-associated cancers of patients. In HPV-associated malignant transformation, viral DNA may be integrated into the cellular DNA and integration often results in deletion of large sectors of the viral genome. Late genes (L1 and L2) and some early genes (E1 and E2) are usually lost, leaving E6 and E7 as the only open reading frames frequently found in carcinomas. Expression of E6 and E7 is likely to overcome the regulation of cell proliferation normally mediated by proteins like p53 and Rb, allowing uncontrolled growth and providing the potential for malignant transformation.

HPV Oncogenic Proteins, E6 and E7, as Ideal Targets for the Development of Antigen-Specific Immunotherapies or Vaccines for HPV-Associated Cervical Malignancies:

E6 and E7 represent ideal targets for the development of antigen-specific immunotherapies or vaccines for HPV-associated malignancies. First, more than 90% of cervical cancers have been associated with HPVs, particularly type 16, and E6 and E7 are consistently expressed in most cervical cancers. Second, while most tumor specific antigens are derived from normal proteins or mutated proteins, E6 and E7 are completely foreign viral proteins, and potentially may harbor more antigenic peptides/epitopes than a mutant protein (i.e. p53) or a reactivated embryonic protein (i.e. MAGE-1). Third, since E6 and E7 are required for the induction and maintenance of malignant phenotypes of cancer cells, cells of cervical cancer cannot evade an immune response through antigen loss. Without functional E6 and E7, these cells would cease to be tumorigenic. Therefore, E6 and E7 proteins represent ideal targets for developing antigen-specific immunotherapies or vaccines for cervical cancer.

Various forms of vaccines, such as vector-based vaccines, tumor-based vaccines, DNA based vaccines and protein/peptide-based vaccines have been described in experimental systems targeting HPV-16 E6 and/or E7 proteins. For example, Meneguzzi et al. reported that inoculation of rats with vaccinia recombinants expressing HPV-16 E6 or E7 retarded or prevented tumor development in 25-47% of rats challenged with a tumorigenic rat cell line co-transfected with HPV-16 and activated ras. In addition, Chen et al. demonstrated that immunization of mice with syngeneic non-tumorigenic cells transfected with the HPV-16 E7 gene confers protection against transplanted HPV-16 E7 positive syngeneic tumor cells. Feltkamp et al. identified a CTL epitope in HPV-16 E7 using H-2Kb and H-2Db MHC class I-peptide-binding studies. Immunization with this peptide rendered mice resistant to a challenge with HPV-16 transformed tumor cells. Furthermore, chimeric papillomavirus-like particles (CVLPs) consist of HPV-16 L1-E7 (Nieland et al., personal communication) or HPV-16 L1/L2-E7 (Greenstone et al., personal communication) chimeric proteins have been used as therapeutic vaccines against HPV-16 E7 expressing tumors in murine models. More recently, a phase I/II clinical trial was performed in eight patients with late stage cervical cancer using a live recombinant vaccinia virus expressing the E6 and E7 proteins of HPV 16 and 18 (TA-HPV). In that study, no significant clinical side-effects or environmental contamination by live TA-HPV were observed.

Importance of Cell Mediated Immune Responses in Controlling both HPV Infections and HPV-Associated Neoplasms:

Several lines of evidence suggest that cell mediated immune responses are important in controlling both HPV infections and HPV-associated neoplasms. First, the prevalence of HPV-related diseases (infections and neoplasms) is increased in transplant recipients and human immunodeficiency virus (HIV) infected patients, both of whom are known to have impaired cell mediated immunity. Second, animal studies have demonstrated that immunized animals are protected from papillomavirus infection and from the development of neoplasia. Immunization also facilitates the regression of existing lesions. Third, infiltrating CD4+ (T helper cells) and CD8+ (cytotoxic/suppressor T cells) T cells have been observed in spontaneously regressing warts and fourth, warts in patients who are on immunosuppressive therapy often disappear when this treatment is discontinued.

Cellular Immune Responses to HPV:

The understanding of T-cell mediated immunity to HPV infections was facilitated by identification of MHC class I and class II epitopes of HPV proteins. Several groups have attempted to map murine and human T helper (Th) cell epitopes on HPV proteins. Several groups have also tried to map murine as well as human cytotoxic T-lymphocyte (CTL) epitopes on HPV proteins. Kast et al. have identified several high affinity binding peptides of HPV-16 E6 and E7 proteins for human HLA-A alleles. Furthermore, HPV-specific CTLs recognizing HPV E6 and E7 proteins have been demonstrated in peripheral blood of cervical cancer patients, in healthy donors and in patients with CIN lesions \[Nakagawa, 1997 #562\]. Furthermore, infiltration of cervical cancer tissue with HPV-specific CTLs has been recently described.

Cell-mediated immune responses in HPV-infected lesions can be demonstrated by in vivo skin tests, in vitro CTL assays and in vitro lymphoproliferative responses. For instance, Hopfl et al. have used bacterially-expressed HPV-16 proteins for skin tests in patients with CIN lesions and have found specific skin responses to the virion protein L1 and not the E4 protein. In patients with CIN lesions, HPV-specific CTLs have been identified in PBMC and in cervical tissues. The in vitro lymphoproliferative responses in patients with CIN lesions have been actively investigated. For example, de Gruijl et al. reported that T cell proliferative responses against HPV-16 E7 oncogenic protein were most prominent in CIN patients with a persistent HPV infection. However, Kadish et al. reported that lymphoproliferative responses to specific HPV-16 E6 and E7 peptides appeared to be associated with the clearance of HPV infection and the regression of CIN lesions.

Importance of Helper T Cell Functions in Generating Effective Antitumor Responses:

Increasing evidence has suggested that inadequate antitumor responses can result from a failure of the helper arm of the immune response. The events leading to the activation of CTL are tightly regulated in order to protect against the development of inappropriate immune responses to self antigens or exaggerated responses to foreign antigens. This regulation is mediated by lymphokines produced by CD4+ T helper cells. CD4+ T helper cells are critical to the generation of potent antitumor immune responses. CD4+ T cells have been shown to be instrumental in generating immune responses against several solid malignancies in murine \[Fearon, 1990 #833; Golumbek, 1991 #834\] and in human populations \[Topalian, 1994 #396; Topalian, 1994 #397\]. Several mouse tumors that are transfected with syngeneic MHC class II genes become very effective vaccines against subsequent challenge with wild type class II negative tumors \[Ostrand-Rosenberg, 1990 #177; James, 1991 #272; Chen, 1993 #213\] In addition, as crucial memory cells in the T cell arm of the immune system, CD4+ cells may be able to provide long term immunity against specific antigens \[Tew, 1990 #624; Sprent, 1994 #625\].

Role of Cytokines in Cell-Mediated Immunity:

Cell mediated immunity is regulated by cytokines which are secreted by T helper cells. In general, T helper cells can be classified as Th1 and/or Th2 cells based on the different types of cytokines they secrete. Th1 cells secrete interleukin (IL) 2 and interferon gamma (IFN-gamma). Th2 cells produce IL-4, IL-5, IL-10 and IL-13. The Th1 lymphocytes are the most important effector cells in inflammatory reactions associated with vigorous delay-type hypersensitivity but low antibody production, as occurs in contact dermatitis and in viral or intracellular bacterial infections (for review, see \[Mosmann, 1989 #168; Romagnani, 1992 #130\]). The functional phenotype of most Th2 cells may account for both the persistent production of certain antibody isotypes, particularly IgG1 and IgE, and the eosinophilia observed in human helminthic infections and allergic disorders. Lymphocyte mediated protection from viral infections as well as control of tumors is thought to be mediated by Th1 cytokine responses and impaired by Th2 cytokine responses. The IL-2 and IFN-gamma producing Th1 response is likely to be the major component that contributes to the development of cell mediated immunity against HPV infections and HPV-associated neoplasms.

Chimeric E7-specific vaccines can control the HPV16 E7-expressing tumor model. By cooperating with Prof. TC Wu at the Johns Hopkins Medical Institutes, we have successfully developed several chimeric DNA, RNA, and virus-vector vaccines to prevent and treat HPV16 E7-expressing tumors in animal models. We found that these E7-chimeric DNA vaccines are capable of preventing and treating the growth of murine model tumors expressing E7. These positive results from the preclinical murine models have encouraged us to focus on the development of a cancer vaccine and immunotherapy and apply these vaccines to human subjects.

However, it is very important to set up various E7-specific immunologic assays of human beings to evaluate the effect of a cancer vaccine or immunotherapy in future clinical trials. So we would like to provide this proposal to address the development of HPV 16 E7-specific immunologic assays in human beings. There are several aims in this project:

1. to develop and utilize assays to measure CTLs to HPV 16 E7 proteins, and
2. to develop and utilize assays to measure T helper (Th) responses to HPV 16 E7 antigens.

Comparison of the Human Papillomavirus (HPV) Type 16 E7-Specific Immune Response Between a Normal Population and Patients With Cervical Lesions

National Taiwan University Hospital

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Dermatitis, Atopic

Dermatitis

Eczema

Mastocytosis

Mastocytosis, Systemic

Blister

Skin Diseases

Skin Diseases, Genetic

Genetic Diseases, Inborn

Skin Diseases, Eczematous

Hypersensitivity

Hypersensitivity, Immediate

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Mast Cell Activation Disorders

Systemic Mastocytosis

Cytokine Production Patterns in Patients with Systemic Mastocytosis Compared with Atopic Dermatitis and Healthy Individuals

Summary: This study will examine how mast cells (cells involved in allergic reactions) migrate and multiply in the skin of patients with mastocytosis, a condition characterized by too many mast cells in the body. The mast cells tend to multiply in the skin, causing dark, itchy skin spots known as urticaria pigmentosa. This study will determine if the skin of patients with mastocytosis produces chemicals called cytokines that cause mast cells to migrate to the skin and multiply. The findings will be compared with those from normal volunteers and patients with atopic dermatitis, a skin disease characterized by recurrent itchy rash usually seen in people with a family history of allergies.

Healthy volunteers, patients with mastocytosis and patients with atopic dermatitis 18 years of age and older may be eligible for this study. Participants will have the following tests and procedures:

* Suction blisters - Two to eight small blisters will be raised on the forearm using gentle suction. The fluid in the blisters will be collected with a syringe to study the chemicals produced by the skin. The tops of the blisters may be removed for research.
* Template study - Patients with high cytokine content in the blister fluid may have a template study. For this procedure, a plastic block (template) with holes matching the blister sites is placed over the blistered area. The wells of the template are filled with salt water and the fluid is removed with a syringe at 3, 8 and/or 24 hours. Patients are hospitalized for 24 hours for this study.
* Skin biopsy - A skin biopsy will be done to correlate cytokine levels with the number of mast cells in the skin. An area of skin is numbed with an anesthetic and a small circular area about the size of a pencil eraser is removed, using a sharp cookie cutter-type instrument.
* Blood draw - About 4 tablespoons of blood will be drawn to compare the chemicals in the blood with those in the blister fluid. The blood will also be analyzed for a complete blood count, clotting factors and substances that may be elevated in people with allergies.

Systemic mastocytosis is a disease characterized by an abnormal accumulation of mast cells in skin, bone marrow and viscera. Precise mechanisms of events leading to the migration and proliferation of mast cells in skin is not known. We propose to investigate the in vivo cytokine and chemokine production patterns of human skin in patients with mastocytosis and compare these findings to those of patients with atopic dermatitis and to healthy volunteers, using the suction blister technique. The cytokines/chemokines of interest in this study are stem cell factor (SCF), interleukin (IL)-3, IL-4, IL-6, IL-9, IL-10, TNF-alpha, TGF-beta, MCP-1 and RANTES, all of which have been shown to take part in the proliferation, differentiation or chemotaxis of mast cells. Our hypothesis is that human skin is producing mediators which allow the mast cells to migrate and proliferate in skin, resulting in the clinical picture of urticaria pigmentosa. Suction blisters will be generated in patients, and the cytokine/chemokine contents of the blister fluids will be analyzed by immunoassay. If the chemokine content of the blister fluid is found to be high, chemotaxis of mast cell precursors to the skin may also be examined in vivo by placing a template filled with sterile saline over the blister sites. Punch biopsies will be performed to correlate cytokine levels with mast cell numbers. This study will aid in understanding the pathogenesis of cutaneous mast cell disease and may provide insights into the regulation of mast cell growth and differentiation in tissue-specific microenvironments. It is hoped that these studies will contribute to the design of novel treatment strategies against mast cell associated skin diseases.

Cytokine Production Patterns in Patients With Systemic Mastocytosis Compared With Atopic Dermatitis and Healthy Individuals

Determination of Cytokine Production Patterns in the Skin of Patients With Systemic Mastocytosis and Atopic Dermatitis Using the Suction Blister Technique

National Institute of Allergy and Infectious Diseases (NIAID)

Patients have mast cell hyperplasia compatible with a diagnosis of systemic mastocytosis (applicable to systemic mastocytosis patients only) or other allergic, hematologic, orimmunologic condition.

Melody C Carter, M.D.

This study will investigate mast cell precursors that circulate in the blood. In a group of diseases collectively known as mastocytosis, mast cells accumulate in abnormal amounts in the skin, lymphoid tissues, bone marrow, liver and spleen. Some forms of mastocytosis have a generally good prognosis; for others, the prognosis is poorer. There is no known cure for any form of the disease. A better understanding of mast cells and how they respond to certain substances may provide insights that will lead to effective treatments for mastocytosis.

Patients with systemic mastocytosis and normal healthy volunteers between the ages of 20 and 60 may be eligible for this 8-day study. Participants will undergo the following procedures:

* Day 1 Medical history, physical examination, and blood tests to assess general health status
* Days 2 through 6 Daily injections under the skin of G-CSF a hormone that stimulates white blood cell production
* Day 7 Leukapheresis a procedure for collecting large numbers of white blood cells. In leukapheresis, blood is drawn through a needle placed in an arm and channeled into a cell separator machine. The white cells are collected and the rest of the blood is returned to the body through a needle in the other arm. The procedure takes up to 3 hours.
* Days 7 and 8 Blood draw (about 1 teaspoon) to monitor white blood cell counts.

The purpose of this protocol is to obtain large numbers of CD34+ cells from the peripheral blood of healthy volunteers and patients with systemic mastocytosis or other related allergic, hematological, and immunological conditions by leukapheresis for culture and characterization of mast cell progenitor cells and their response to various cytokines and anti-mitotic agents. Healthy volunteers and patients will be adults of both sexes from 18 to 70 years of age. Granulocyte colony stimulating factor (G-CSF) will be administered to healthy volunteers at dose of 10 mcg/kg/day as a subcutaneous dose daily for 5 days not to exceed 960mcg. Patients will receive Plerixafor at a dose of 0.24 mg/kg as a single subcutaneous dose not to exceed 24mg the night before leukapheresis as a mobilizing agent for CD34+ cells. In identified patients where leukapheresis yield is considered adequate without stimulation by the principal investigator, leukapheresis may proceed without stimulation. Healthy volunteers will undergo a single leukapheresis at day 7, and patients will undergo a single leukapheresis at day 3 or 4. This is not a therapeutic protocol and does not involve reinfusion of any manipulated cells, viruses or DNA constructs back into human subjects.

Study of Mast Cell Precursors

The Characterization of CD34+ Derived Mast Cell Precursors

Use of G-CSF administration healthy volunteers to mobilize and enhance CD34+ hematopoietic progenitor cell numbers into the peripheral blood in order to culture and characterize human mast cells, study and characterize CD34+ -derived human mast cells.

Collection of CD34+ cells with or without use of Plerixafor administration in patients with systemic mastocytosis and other related allergic, hematological and immunological conditions to mobilize and enhance CD34+ cells into the peripheral blood to culture and learn how mast cells contribute to these disease states.

Gland and Hormone Related Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Ovarian Cancer

Ovarian Epithelial Cancer

Immunomodulating Agents

Ovarian cancer is the first in mortality rate of the gynecologic malignancies and the overall 5-year survival rate of ovarian cancer is only 20-30%. Besides, the incidence of ovarian cancer increased in recent years in Taiwan. Ovarian cancer is indeed a disease that should be respected, however, there has only been a little research done focusing on it in Taiwan. Patients with ovarian cancer who have stage I disease (localized to ovaries) after optimal surgical staging do not need any adjuvant therapy. In contrast, patients with disease spreading beyond the ovaries have median survival rates that decrease to \< 10% for patients with bulky residual disease after surgery and treated with platinum-based combination chemotherapy. In developing effective therapy for ovarian cancer, there should be a distinction between preventative and therapeutic approaches. Immunoprevention will be developed for women who are at an increased risk for the development of ovarian cancer. In contrast, immunotherapy would be used as an adjuvant to surgery or in combination with chemotherapy or other biologics as chemoimmunotherapy or biochemoimmunotherapy. Mesothelin is expressed in some normal epithelial cells and is elevated in certain carcinomas. Mesothelin has been reported to be selectively overexpressed in most of the non-mucinous ovarian carcinomas. In addition, the specific epitopes of mesothelin in the HLA-A2 and A24 haplotype have been identified. It seems that mesothelin has the potential to be a target antigen for the immunotherapy of ovarian cancer.

So the investigators would like to provide this proposal to address the development of mesothelin -specific immunologic assays. There are two aims in this project:

1. to develop and utilize assays to measure cytotoxic T lymphocytes (CTLs) to mesothelin, and
2. to evaluate the mesothelin-specific immunologic responses between normal control and ovarian cancer patients.

Incidence of Ovarian Cancer:

Ovarian cancer is the first in mortality rate of the gynecologic malignancies with an overall 5-year survival rate of only 20-30%. It became a more and more important disease in recent years and the incidence of ovarian cancer also increased in recent years in Taiwan. The lack of symptoms, difficulties in early diagnosis, insufficient accurate tumor markers, and lack of information about ovarian tumor biology contribute to the poor prognosis in ovarian cancer patients. The prognostic parameters for ovarian carcinomas are tumor stage, histologic subtype, degree of malignancy, and residual tumor after surgical treatment. However, these factors present an incomplete picture of the tumor biology of ovarian cancer and are frequently interrelated. Thus, the identification of new biologic factors predictive of individual disease course and prognosis would be extremely useful. From the above-mentioned data, ovarian cancer is indeed a disease that should be respected, however, there has only been a little research done focusing on it in Taiwan.

Treatment of Ovarian Cancer:

Epithelial Ovarian Cancer (EOC) and extraovarian Müllerian carcinoma are similar pathologic entities that share a preference for peritoneal cavity involvement. The spread pattern of these tumors presents a challenge and unique opportunities for immunotherapy. Patients with EOC who have stage I disease (localized to ovaries) after optimal surgical staging, have a 5-year survival rate of 90%, with no significant change at 10 years. In contrast, patients with spreading beyond the ovaries have median survival rates that decrease to \< 10% for patients with bulky residual disease after surgery and treatment with platinum-based combination chemotherapy. A randomized trial of first-line chemotherapy in patients with EOC with residual masses larger than 1 cm after initial surgery, showed a median survival period of 38 months for cisplatin/paclitaxel, significantly greater than 24 months for the cisplatin/cytoxan treatment arm. In an interim analysis of an equivalency trial, survival after carboplatin/paclitaxel was not worse than cisplatin/paclitaxel. Even though early diagnosis is an important goal of ongoing clinical research efforts, it is unclear whether advanced EOC starts as a multicentric process involving the ovaries and the peritoneal surface. It is now established that hereditary factors contribute to the development of EOC. Germline BRCA1 and BRCA2 mutations account for approximately 10% of all EOC. In a woman with a BRCA 1 or 2 mutation, lifetime risk for ovarian cancer ranges from 16%-44%. With the commercial availability of genetic testing for BRCA1 and BRCA2, more women are being identified as being at high risk for ovarian cancer. There are no clear guidelines on cancer prevention for these individuals. Although prophylactic oophorectomy is a reasonable option for women who have completed childbearing, these women are still at risk for developing peritoneal cancer. Clearly, other options for prevention are needed.

Immunotherapy for Ovarian Cancer:

In developing effective immune-based strategies for EOC, there should be a distinction between preventative and therapeutic approaches. It is anticipated that immunoprevention (immunoprophylaxis) will be developed for women who are at an increased risk for the development of EOC. In contrast, immunotherapy would be used as an adjuvant to surgery or in combination with chemotherapy or other biologics as chemoimmunotherapy or biochemoimmunotherapy. Patients with undetectable disease after being restaged after chemotherapy could be considered for immunotherapy with the presumption that a majority does in fact have micrometastases. Development of effective immune-based concepts for prevention or treatment of EOC will require an understanding of tumor-immunology principles, mechanisms of action of the expanding array of immune modulating molecules, identification and characterization of tumor antigens, and determination of the microenvironment factors that could impact on the different immune-effector mechanisms. The clinical researcher has been provided with many immune directed agents, but progress on their integration into standard therapies has been somewhat slow.

Mesothelin:

Mesothelin is a 40-kDa glycosylphosphatidylinositol-linked glycoprotein. It is synthesized as a precursor of molecular mass 69 kDa, which then is proteolytically processed into an N terminal secreted form of molecular mass 30 kDa and a membrane-bound form of 40 kDa. In normal tissues, the expression of mesothelin has subsequently been shown to be largely restricted to mesothelial cells, although immunoreactivity has also been reported in epithelial cells of the trachea, tonsil, fallopian tube, and kidney. Hough et al. observed that mesothelin was over-expressed in ovarian carcinoma. It seems that mesothelin may be utilized as a tumor marker or target antigen for ovarian carcinoma.

Epitopes of Mesothelin for Human Haplotype:

The incidence of HLA-A2 haplotype is over 50% in the Western countries. The incidence of HLA-A2 and A24 haplotype is around 30% and 15% in Taiwan, respectively. The specific epitopes of the mesothelin in the HLA-A2 and A24 haplotype have been identified. There are Mesothelin aa20-28 (peptide SLLFLLFSL) and aa530-538 (peptide VLPLTVAEV) for the HLA-A2 haplotype. And Mesothelin aa435-443 (peptide FYPGYLCSL) and aa475-483 (peptide LYPKARLAF) are the epitopes of HLA-A24 haplotype.

Our research team has focused on the development of cancer vaccine and immunotherapy for several years. Our laboratory facilities have also been set up to evaluate the human immunologic assays for human papilloma virus type 16 E7 antigen by the grant supported from National Taiwan University Hospital. It is very important to set up various mesothelin-specific immunologic assays of human beings to evaluate the effect of cancer vaccine or immunotherapy for ovarian cancer in future clinical trials. So we would like to provide this proposal to address the development of mesothelin-specific immunologic assays in human beings. There are several aims in this project:

1. to develop and utilize assays to measure CTLs to mesothelin, and
2. to evaluate the mesothelin-specific immunologic responses between normal controls and ovarian cancer patients.

The Assessment of Mesothelin Antigen Specific Immunologic Assays in Ovarian Cancer Patients

Study title	NCT ID	Conditions	Eligibility	Organization
Genetic Factors and Interrelationships for Cancer Risk-Related Behaviors and Complex Traits	NCT00001500	Acquired Immuno... Alcoholism HIV Infection Neoplasm Smoking	-	National Institutes of Health Clinical Center (CC)
Comparison of the Human Papillomavirus (HPV) Type 16 E7-Specific Immune Response Between a Normal Population and Patients With Cervical Lesions	NCT00154583	Cervical Cancer	18 Years - 80 Years	National Taiwan University Hospital
Cytokine Production Patterns in Patients With Systemic Mastocytosis Compared With Atopic Dermatitis and Healthy Individuals	NCT00001760	Atopic Dermatit... Healthy Mastocytosis	-	National Institutes of Health Clinical Center (CC)
Study of Mast Cell Precursors	NCT00001756	Mastocytosis Healthy Volunte...	18 Years - 70 Years	National Institutes of Health Clinical Center (CC)
The Assessment of Mesothelin Antigen Specific Immunologic Assays in Ovarian Cancer Patients	NCT00173394	Ovarian Cancer	18 Years - 80 Years	National Taiwan University Hospital

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