Ignite Creation Date:
2024-05-05 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00155935
Status:
UNKNOWN
Last Update Posted:
2007-08-13
First Post:
2005-09-09
Brief Title:
The Development of Human Immunologic Assays Specific to Folate Receptor Antigen
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
The Development of Human Immunologic Assays Specific to Folate Receptor Antigen
Status:
UNKNOWN
Status Verified Date:
2004-01
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Ovarian cancer has the highest mortality rate of gynecologic malignancies and the overall 5-year survival rate of ovarian cancer is only 20-30 Additionally the incidence of ovarian cancer has increased in recent years in Taiwan Ovarian cancer is indeed a disease that should be respected however there was very little research work 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 cancer spreading beyond the ovaries have median survival rates that decrease to less than 10 for patients with bulky residual disease after surgery and treatment 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 such as chemoimmunotherapy or biochemoimmunotherapy The folate receptor FR is expressed in some normal epithelial cells and is elevated in certain carcinomas The FR has been reported to be selectively overexpressed in 90 of non-mucinous ovarian carcinomas The specific epitopes of the folate receptor in the HLA-A2 haplotype have been identified It appears that the folate receptor could be a target antigen for the immunotherapy of ovarian cancer
Therefore the investigators would like to propose the development of folate receptor-specific immunologic assays There are two aims in this project
1 to develop and utilize assays to measure cytotoxic T-lymphocytes CTLs to folate receptors and
2 to evaluate the folate receptor-specific immunologic responses between normal controls and ovarian cancer patients
Therefore the investigators would like to propose the development of folate receptor-specific immunologic assays There are two aims in this project
1 to develop and utilize assays to measure cytotoxic T-lymphocytes CTLs to folate receptors and
2 to evaluate the folate receptor-specific immunologic responses between normal controls and ovarian cancer patients
Detailed Description:
Incidence of Ovarian Cancer
Ovarian cancer is the first mortality rate of 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 was very little research work 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 cisplatinpaclitaxel significantly greater than 24 months for the cisplatincytoxan treatment arm In an interim analysis of an equivalency trial survival after carboplatinpaclitaxel was not worse than cisplatinpaclitaxel 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
Folate receptor
The folate receptor FR a 38 kDa membrane glycoprotein is represented by a homologous family of glycoproteins two of which FR-a and FR-b are attached to the cell surface by a glycosyl-phosphatidylinositol anchor the third isoform FR- and its truncated version FR-9 are constitutively secreted because of a lack of an efficient signal for glycosyl-phosphatidylinositol modification FR-a is expressed in some normal epithelial cells and is elevated in certain carcinomas whereas FR-b is a myeloid differentiation marker and is elevated in some nonepithelial malignancies FR-9 is expressed in hematopoietic tissues At present FR is a major focus as a tumor target for multiple experimental approaches in cancer therapy One novel approach uses bifunctional antibodies to target T cells to the FR on the surface of ovarian carcinoma cells Selective growth inhibition of the tumor cells was obtained by this approach The chimeric antibodies which bind to both FR and either CD3 or CD28 produced impressive results in a xenogeneic model and in patients with advanced ovarian cancer Similarly a chimeric molecule consisting of a single-chain Fv of anti-FR antibody and interleukin 2 was effective in inhibiting tumor growth in vivo Alternatively folic acid conjugates of single chain anti-T-cell receptor antibody could mobilize T-cell response against FR-rich tumors Taking advantage of the nondestructive nature of FR-mediated internalization of folate-coupled macromolecules cytotoxins such as momordin Pseudomonas exotoxin and maytansinoids were shown to produce selective killing of FR-rich cells Furthermore the toxicity of such conjugates was dependent upon receptor density on the cell surface Folate-conjugated radiopharmaceuticals also appear to offer a means of tumor imagingradiation therapy Folate-coated liposomes were shown to selectively target FR-rich tumor cells and selective killing of the malignant cells was obtained by encapsulating doxorubicin in the liposomes By a similar strategy it was possible to deliver antisense oligonucleotides against the epidermal growth factor receptor to FR-rich tumor cells Furthermore selective targeting of an adenoviral vector to FR-rich tumor cells has been achieved in the presence of an antibody to ablate the endogenous viral tropism Finally several studies have shown that FR when expressed at high levels could offer the preferred uptake route of novel classes of antifolate drugs that target glycineamide ribonucleotide formyltransferase and thymidylate synthase A soluble form of FR has been detected in the serum and ascites of patients with ovarian cancer The FR has been reported to be selectively overexpressed in 90 of non-mucinous ovarian carcinomas and in some other malignant tissues The receptor has only been detected in a few other normal cell types but not in normal ovarian surface epithelium It seems that FR could be a potential target antigen for the immunotherapy of ovarian cancer
Epitopes of folate receptor for human haplotype
The incidence of HLA-A2 haplotype is over 50 in the Western countries The incidence of HLA-A2 haplotype is around 30 in Taiwan The specific epitopes of the folate receptor in the HLA-A2 haplotype have been identified They are E39 FR 191-199 EIWTHSTKV and E75 FR 245-253 LLSLALMLL respectively It seems that folate receptors could be a target antigen for the immunotherapy of ovarian cancer
Our research team has focused on the development of a 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 folate receptor-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 folate receptor-specific immunologic assays in human beings There are several aims in this project
1 to develop and utilize assays to measure CTLs to folate receptors and
2 to evaluate the folate receptor-specific immunologic responses between normal controls and ovarian cancer patients
Ovarian cancer is the first mortality rate of 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 was very little research work 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 cisplatinpaclitaxel significantly greater than 24 months for the cisplatincytoxan treatment arm In an interim analysis of an equivalency trial survival after carboplatinpaclitaxel was not worse than cisplatinpaclitaxel 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
Folate receptor
The folate receptor FR a 38 kDa membrane glycoprotein is represented by a homologous family of glycoproteins two of which FR-a and FR-b are attached to the cell surface by a glycosyl-phosphatidylinositol anchor the third isoform FR- and its truncated version FR-9 are constitutively secreted because of a lack of an efficient signal for glycosyl-phosphatidylinositol modification FR-a is expressed in some normal epithelial cells and is elevated in certain carcinomas whereas FR-b is a myeloid differentiation marker and is elevated in some nonepithelial malignancies FR-9 is expressed in hematopoietic tissues At present FR is a major focus as a tumor target for multiple experimental approaches in cancer therapy One novel approach uses bifunctional antibodies to target T cells to the FR on the surface of ovarian carcinoma cells Selective growth inhibition of the tumor cells was obtained by this approach The chimeric antibodies which bind to both FR and either CD3 or CD28 produced impressive results in a xenogeneic model and in patients with advanced ovarian cancer Similarly a chimeric molecule consisting of a single-chain Fv of anti-FR antibody and interleukin 2 was effective in inhibiting tumor growth in vivo Alternatively folic acid conjugates of single chain anti-T-cell receptor antibody could mobilize T-cell response against FR-rich tumors Taking advantage of the nondestructive nature of FR-mediated internalization of folate-coupled macromolecules cytotoxins such as momordin Pseudomonas exotoxin and maytansinoids were shown to produce selective killing of FR-rich cells Furthermore the toxicity of such conjugates was dependent upon receptor density on the cell surface Folate-conjugated radiopharmaceuticals also appear to offer a means of tumor imagingradiation therapy Folate-coated liposomes were shown to selectively target FR-rich tumor cells and selective killing of the malignant cells was obtained by encapsulating doxorubicin in the liposomes By a similar strategy it was possible to deliver antisense oligonucleotides against the epidermal growth factor receptor to FR-rich tumor cells Furthermore selective targeting of an adenoviral vector to FR-rich tumor cells has been achieved in the presence of an antibody to ablate the endogenous viral tropism Finally several studies have shown that FR when expressed at high levels could offer the preferred uptake route of novel classes of antifolate drugs that target glycineamide ribonucleotide formyltransferase and thymidylate synthase A soluble form of FR has been detected in the serum and ascites of patients with ovarian cancer The FR has been reported to be selectively overexpressed in 90 of non-mucinous ovarian carcinomas and in some other malignant tissues The receptor has only been detected in a few other normal cell types but not in normal ovarian surface epithelium It seems that FR could be a potential target antigen for the immunotherapy of ovarian cancer
Epitopes of folate receptor for human haplotype
The incidence of HLA-A2 haplotype is over 50 in the Western countries The incidence of HLA-A2 haplotype is around 30 in Taiwan The specific epitopes of the folate receptor in the HLA-A2 haplotype have been identified They are E39 FR 191-199 EIWTHSTKV and E75 FR 245-253 LLSLALMLL respectively It seems that folate receptors could be a target antigen for the immunotherapy of ovarian cancer
Our research team has focused on the development of a 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 folate receptor-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 folate receptor-specific immunologic assays in human beings There are several aims in this project
1 to develop and utilize assays to measure CTLs to folate receptors and
2 to evaluate the folate receptor-specific immunologic responses between normal controls and ovarian cancer patients
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None