Novel “Jantibody Fusion Protein” Cancer Vaccine Holds Promise Against Ovarian Cancer

A novel approach to cancer immunotherapy – strategies designed to induce the immune system to attack cancer cells – may provide a new and cost-effective weapon against some of the most deadly tumors, including ovarian cancer and mesothelioma.

A novel approach to cancer immunotherapy – strategies designed to induce the immune system to attack cancer cells – may provide a new and cost-effective weapon against some of the most deadly tumors, including ovarian cancer and mesothelioma. Investigators from the Massachusetts General Hospital (MGH) Vaccine and Immunotherapy Center (VIC) report in the Journal of Hematology & Oncology that a protein engineered to combine a molecule targeting a tumor-cell-surface antigen with another protein that stimulates several immune functions prolonged survival in animal models of both tumors.

“Some approaches to creating cancer vaccines begin by extracting a patient’s own immune cells, priming them with tumor antigens and returning them to the patient, a process that is complex and expensive,” says Mark Poznansky, M.D., Ph.D., director of the MGH Vaccine and Immunotherapy Center and senior author of the report. “Our study describes a very practical, potentially broadly applicable and low-cost approach that could be used by oncologists everywhere, not just in facilities able to harvest and handle patient’s cells.”

The MGH team’s vaccine stimulates the patient’s own dendritic cells, a type of immune cell that monitors an organism’s internal environment for the presence of viruses or bacteria, ingests and digests pathogens encountered, and displays antigens from those pathogens on their surface to direct the activity of other immune cells. As noted above, existing cancer vaccines that use dendritic cells require extracting cells from a patient’s blood, treating them with an engineered protein or nucleic acid that combines tumor antigens with immune-stimulating molecules, and returning the activated dendritic cells to the patient.

Fusion protein activates immune cells against tumors The Jantibody fusion protein, combining an antibody fragment targeting an antigen found on tumor cells with an immune-response-inducing protein (MTBhsp70), activates dendritic cells against several tumor antigens and induces a number of T-cell-based immune responses. (Jianping Yuan, PhD, MGH Vaccine and Immunotherapy Center)

Fusion protein activates immune cells against tumors. The Jantibody fusion protein, combining an antibody fragment targeting an antigen found on tumor cells with an immune-response-inducing protein (MTBhsp70), activates dendritic cells against several tumor antigens and induces a number of T-cell-based immune responses. (Jianping Yuan, PhD, MGH Vaccine and Immunotherapy Center)

The approach developed by the MGH team starts with the engineered protein, which in this case fuses an antibody fragment targeting a protein called mesothelin – expressed on the surface of such tumors as mesothelioma, ovarian cancer and pancreatic cancer – to a protein from the tuberculosis bacteria that stimulates the activity of dendritic and other immune cells. In this system, the dendritic cells are activated and targeted against tumor cells while remaining inside the patient’s body.

In the experiments described in the paper, the MGH team confirmed that their mesothelin-targeting fusion protein binds to mesothelin on either ovarian cancer or mesothelioma cells, activates dendritic cells, and enhances the cells’ processing and presentation of several different tumor antigens, inducing a number of T-cell-based immune responses. In mouse models of both tumors, treatment with the fusion protein significantly slowed tumor growth and extended survival, probably through the activity of cytotoxic CD8 T cells.

“Many patients with advanced cancers don’t have enough functioning immune cells to be harvested to make a vaccine, but our protein can be made in unlimited amounts to work with the immune cells patients have remaining,” explains study co-author Jeffrey Gelfand, MD, senior scientist at the Vaccine and Immunotherapy Center. “We have created a potentially much less expensive approach to making a therapeutic cancer vaccine that, while targeting a single tumor antigen, generates an immune response against multiple antigens. Now if we can combine this with newly-described ways to remove the immune system’s “brakes” – regulatory functions that normally suppress persistent T-cell activity – the combination could dramatically enhance cancer immunotherapy.”

Poznansky adds that the tumors that might be treated with the mesothelin-targeting vaccine – ovarian cancer, pancreatic cancer and mesothelioma – all have poor survival rates. “Immunotherapy is generally nontoxic, so this vaccine has the potential of safely extending survival and reducing the effects of these tumors, possibly even cutting the risk of recurrence. We believe that this approach could ultimately be used to target any type of cancer and are currently investigating an improved targeting approach using personalized antigens.” The MGH team just received a two-year grant from the Department of Defense Congressionally Directed Medical Research Program to continue their research.

Poznansky is an associate professor of Medicine, and Gelfand is a clinical professor of Medicine at Harvard Medical School. Jianping Yuan, Ph.D., of the MGH Vaccine and Immunotherapy Center (VIC) is the lead author of the Journal of Hematology and Oncology report. Additional co-authors include Pierre LeBlanc, Ph.D., Satoshi Kashiwagi M.D., Ph.D., Timothy Brauns, and Svetlana Korochkina, Ph.D., MGH VIC; and Nathalie Scholler, M.D., Ph.D., University of Pennsylvania School of Medicine.

The authors dedicate their report to Janet Gelfand, the wife of Jeffrey Gelfand, who died of ovarian cancer in 2006 and inspired their investigation. In her honor they named their tumor-targeting fusion protein “Jantibody.” Support for the study includes grants from the Edmund Lynch Jr. Cancer Fund, Arthur Luxenberg Esq., Perry Weitz Esq., the VIC Mesothelioma Research and Resource Program, and the Friends of VIC Fund.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Sources:

  • Novel cancer vaccine holds promise against ovarian cancer, mesothelioma — Antigen-targeting fusion protein should be less expensive, more accessible than current approaches, Massachusetts General Hospital, Press Release, March 5, 2014.
  • Yuan J et al., A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesotheliomaJ Hematol Oncol. 2014 Feb 24;7(1):15. doi: 10.1186/1756-8722-7-15. (Abstract – PMID: 24565018; Full Text – PMCID: PMC3943805)

Mesothelin Antibodies Occur In Some Women With An Epidemiologic Risk For Ovarian Cancer.

Researchers at Rush University Medical Center discover mesothelin antibodies in the bloodstream of infertile women, who possess a higher risk of ovarian cancer.

Using a new approach to developing biomarkers for the very early detection of ovarian cancer, researchers at Rush University Medical Center have identified a molecule in the bloodstream of infertile women, who possess a higher risk of ovarian cancer. This finding may be relevant in the future for screening women at high risk for the disease — or even those with early-stage ovarian cancer.

The molecule — an antibody that the human body manufactures — is an autoimmune response to mesothelin. Mesothelin a well-characterized ovarian cancer antigen and protein which is found in abundance on the surface of ovarian cancer cells, but present only in limited amounts in normal human tissue.

The study is published in the August 16 online version issue of Cancer Epidemiology, Biomarkers & Prevention, published by the American Association for Cancer Research (AACR).

Judith Luborsky, Ph.D., Lead Study Author; Professor, Pharmacology, Obstetrics & Gynecology and Preventive Medicine, Rush Medical College

“The finding is extremely important because at present medical tests are unable to detect ovarian cancer in its early stages, which is why death rates from this disease are so high,” said Judith Luborsky, Ph.D., professor of pharmacology, obstetrics and gynecology and preventive medicine at Rush and the lead author of the study.

“Our approach to discovering cancer biomarkers was unique in this study. Instead of investigating molecules specific to ovarian cancer alone, we asked what molecules women with a risk of ovarian cancer and those with ovarian cancer had in common,” Luborsky said.

The study may have enabled the researchers to explain, in part, the link between infertility and ovarian cancer that has been established in numerous epidemiological surveys.

“More important, with the discovery of the mesothelin antibody, we now have what appears to be a biomarker that can potentially be used in screening tests to help us conquer ovarian cancer,” Luborsky said.

According to the American Cancer Society’s most recent estimates, it is anticipated that 21,900 new cases of ovarian cancer will be diagnosed in the U.S. in 2011, and approximately 15,460 deaths will occur in connection with the disease. Ovarian cancer is the ninth most common cancer in women (not counting skin cancer) and ranks as the fifth highest cause of cancer death in women. It is the most lethal gynecologic cancer. The poor prognosis for women with ovarian cancer is due to the lack of both clinical symptoms when the cancer first develops and the absence of laboratory tests specific to the disease.

In the study at Rush, researchers tested for mesothelin antibodies in the bloodstream of 109 women who were infertile; 28 women diagnosed with ovarian cancer, 24 women with benign ovarian tumors or cysts, and 152 healthy women. Causes of infertility included endometriosis, ovulatory dysfunction, and premature ovarian failure. Some causes of infertility were unexplained.

Significant levels of mesothelin antibodies were found in women with premature ovarian failure, ovulatory dysfunction and unexplained infertility, as well as in women with ovarian cancer. The same results were not found in women with endometriosis, good health, or benign disease. Endometriosis is generally associated with the clear cell and endometrioid subtypes of epithelial ovarian cancer, as compared to other forms of the disease associated with infertility, which may explain why mesothelin antibodies were not found in the endometriosis cases.

It is important to emphasize that the explanation as to why the presence of mesothelin antibodies in the bloodstream should be linked with ovarian cancer is not clear.

“It has been hypothesized that an autoimmune response precedes or somehow contributes to the development and progression of malignant tumors,” Luborsky said. “We think that antibodies may arise in response to very early abnormal changes in ovarian tissue that may or may not progress to malignancy, depending on additional triggering events. Or, alternatively, antibodies may bind to normal cells in the ovary, causing dysfunction and leading to infertility — and, in a subpopulation of women, to the development of ovarian cancer.”

Other researchers involved in the study were Yi Yu, MS, and Seby Edassery, MS, both from Rush, as well as a group led by Ingegerd Hellstrom, M.D., Ph.D., and Karl Eric Hellstrom, M.D., Ph.D., which included Yuan Yee Yip, BS, Jade Jaffar, BS, and Pu Liu, Ph.D. from Harborview Medical Center at the University of Washington.

The study was supported by funding from the National Institutes of Health and Fujirebio Diagnostics, Inc.

About Rush

Rush is a not-for-profit academic medical center comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health.

Rush’s mission is to provide the best possible care for its patients. Educating tomorrow’s health care professional, researching new and more advanced treatment options, transforming its facilities and investing in new technologies—all are undertaken with the drive to improve patient care now, and for the future.

Sources:

  • Luborsky JL, et al. Autoantibodies to Mesothelin in Infertility. Cancer Epidemiol Biomarkers Prev. 2011 Aug 16. PubMed PMID: 21846819 [Epub ahead of print]
  • Researchers at Rush University Medical Center Discover Antibody That May Help Detect Ovarian Cancer in its Earliest Stages, News Release, Rush University Medical Center, August 16, 2010.

Elevated Proteins May Warn of Ovarian Cancer, But Sufficient Lead Time & Predictive Value Still Lacking

Fred Hutchinson Cancer Center researchers discovered that concentrations of the serum biomarkers CA125, human epididymis protein 4 (HE4), and mesothelin began to rise 3 years before clinical diagnosis of ovarian cancer, according to a new study published online December 30 in the Journal of the National Cancer Institute. However, the biomarkers became substantially elevated only in the last year prior to diagnosis. … In an accompanying editorial to the study results reported by Anderson et. al., Patricia Hartge, ScD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, applauds the researchers for taking the field one step closer to successful screening study designs by showing that the levels of certain biomarkers do not increase early enough to be used for screening.

Fred Hutchinson Cancer Center researchers discovered that concentrations of the serum biomarkers CA125, human epididymis protein 4 (HE4), and mesothelin began to rise 3 years before clinical diagnosis of ovarian cancer, according to a new study published online December 30 in the Journal of the National Cancer Institute (JNCI). [1] However, the biomarkers became substantially elevated only in the last year prior to diagnosis.

Garnet L. Anderson, Ph.D., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

CA125, HE4, mesothelin, B7-H4, decoy receptor 3, and spondin-2 have been identified as potential ovarian cancer serum biomarkers, but their behavior in the prediagnostic period, with the exception of CA125, has not been evaluated.  In the JNCI study, Garnet L. Anderson, Ph.D., of the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, and colleagues analyzed prediagnostic serum samples and patient data from the Carotene and Retinol Efficacy Trial (CARET), a randomized, double-blind, placebo-controlled chemoprevention trial testing the effects of beta-carotene and retinol on lung cancer incidence among individuals at high risk for lung cancer. Prediagnostic serum samples (taken up to 18 years prior to diagnosis) were obtained for 34 CARET patients with ovarian cancer and 70 matched control CARET subjects. Changes in the levels of these biomarkers prior to ovarian cancer diagnosis were analyzed.

Anderson et. al. discovered that concentrations of CA125, HE4, and mesothelin (but not B7-H4, decoy receptor 3, and spondin-2) began to increase slightly in cancer patients relative to control subjects approximately 3 years before diagnosis, but became substantially elevated within one year prior to diagnosis. Thus, the diagnostic value of these biomarkers is limited because accuracy only increased shortly before diagnosis. “Although these markers are not accurate enough to prompt early intervention in existing screening protocols, the multivariable regression analyses identified modest but statistically significant increases in risk associated with CA125, HE4, and mesothelin, which are consistent with many of the established epidemiological risk factors for ovarian cancer,” say the authors of the study.

“I still think biomarkers may play a role in a cost-effective screening program, although none of these seem accurate enough either alone or together to justify their use in average-risk women,” Anderson told Medscape Oncology. “I do not know of any other currently identified biomarkers that hold more promise than these, but there has been a massive effort over the last few years to identify candidates and not all have been thoroughly vetted,” said Dr. Anderson.

One problem, cites Dr. Anderson, may lie in the approach used in identifying potential ovarian cancer biomarkers. “Most of the discovery work done so far has been conducted in women with advanced-stage disease and compared them to healthy women,” she explained. “If discovery work were done in samples like the ones we used here, representing specimens collected months to years prior to the advanced stage diagnosis, we might have a better chance of finding earlier signals of aggressive disease.”

Another opportunity for improving screening and early diagnosis lies in imaging, she adds. “Currently the most common and only affordable imaging option that could be considered for routine screening is transvaginal ultrasound, but it performs poorly in terms of accurately determining those women [who] have ovarian cancer from those who do not,” said Dr. Anderson. “A substantial improvement in this area would be very exciting.”

Study Limitations Cited By JNCI Editors

The JNCI editors state three limitations that they believe are associated with the study by Anderson et. al. First, the study sample size was small.  Second, all women who participated in CARET had a history of heavy smoking, and therefore, the JNCI editors believe that the blood serum testing results obtained by Anderson et. al. may not apply to other non-smoking groups. Third, the blood collected from women participating in CARET was collected at different times, but only a few samples were collected during the last 2–3 years before ovarian cancer diagnosis.

Designing Ovarian Cancer Early Detection Programs — Accompanying JNCI Editorial

Patricia Hartge, Sc.D. Deputy Director, Epidemiology and Biostatistics Program, Division of Cancer Epidemiology & Genetic, National Cancer Institute

In an accompanying editorial to the study results reported by Anderson et. al., Patricia Hartge, ScD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, applauds the researchers for taking the field one step closer to successful screening study designs by showing that the levels of certain biomarkers do not increase early enough to be used for screening. [2]

Dr. Hartge notes that despite the discovery that CA125 and other serum markers increase before the clinical onset of ovarian cancer, it has been exceedingly difficult to devise a successful ovarian cancer early screening program for asymptomatic women. Nevertheless, Hartge believes that Anderson et al. take a valuable step toward the design of such a successful screening program by demonstrating why screening regimens that are based on markers, or panels of markers, can fail. Specifically, the researchers discovered that blood levels of CA125, HE4, mesothelin, and three other promising markers did not increase early enough in the course of the disease to allow detection in early stages. Dr. Hartge emphasizes that the markers typically rose within one year of the disease symptoms that led to an accurate diagnosis, and therefore, many of the ovarian cancer patients were diagnosed with advanced stage disease.

Hartge further states “[t]hat the results of Anderson et al. are not the last word in serum markers or in combinations of markers.” “Serum markers likely will form a key element in any screening regimen, with the lead time and other parameters of each marker or combination of markers being taken into account. The careful evaluation technique applied in the current study fits into a staged approach necessary for testing performance of early markers of disease.” Hartge adds that “[o]nly the time-consuming, expensive, and demanding randomized clinical trial can reveal whether an early detection program that includes the biomarkers can save lives.”

In support of her position, Dr. Hartge observes that current randomized trials are testing the value of different screening programs that are built on combinations of CA125, ultrasound, and risk factor data (e.g., family history and age). After four rounds of screening 34,261 postmenopausal women for ovarian cancer with both CA125 and ultrasound, University of Alabama at Birmingham School of Medicine investigators of the large U.S. screening trial observed that the predictive value of a positive screen was quite low — approximately 1%. Of the 60 screen-detected cancers, 72% had already advanced to at least stage III. [3] In addition, of every 20 women who underwent surgery after a positive screen, only one women was diagnosed with cancer. Furthermore, in a recent UK trial with a slightly different design, positive predictive values from the first round of screening were higher; 35% in the 50,078 women whose risk was assessed with CA125 and risk factor data, followed by ultrasound only if indicated, and 3% in the 50,639 women screened first with ultrasound. [4] The effects on mortality in both trials remain to be determined.

Confronting The “Daunting Arithmetic” Required To Detect Early Stage Ovarian Cancer

Based upon the foregoing, Dr. Hartge highlights the “daunting arithmetic” required to detect early stage ovarian cancer. In the U.S., Surveillance, Epidemiology and End Results (SEER) data indicates that incidence amounts to 13 cases of ovarian cancer per 100,000 woman per year, referred to by Dr. Hartge as the “proverbial needles in the haystack.” [5] So as not to present a problem without a potential solution, Hartge provides a roadmap to additional factors that may help future researchers develop early screening methods to identify those rare cases of ovarian cancer in the general population.  Notably, SEER data also indicates that incidence of ovarian cancer steadily increases with age from 21 cases per 100,000 women per year within the 50-54 age range to 57 cases per 100,000 women per year within the 80-84 age range. [6] Furthermore, family history, low parity, and more ovulations over a woman’s lifetime predict additional risk, with the strongest but least common predictor being a mutation in the BRCA1 or BRCA2 gene. Thus, the general approach suggested by Hartge focuses on women with higher baseline risks, for whom the predictive value of a positive serum test tends to increase. Dr. Hartge believes that the performance of an overall screening program will improve by targeting higher-risk subgroups of women for screening by combining personal history, genetic abnormality status, and levels of serum markers in one prediction model. With ongoing advances in understanding the origin and causes of ovarian cancer, Hartge states that the risk models that are useful for screening programs should also improve.

Further technology advancements may also improve future ovarian cancer early detection screening models, says Hartege. For example, a screening program that is based on a panel of biomarkers can be improved by developing new medical imaging technology that is more specific than current ultrasound technology.  If better imaging existed, fewer women would undergo surgery following a suspicious biomarker finding.  Similarly, development of less invasive surgery could further reduce harmful side effects.  Although Hartge observes that a highly accurate biomarker(s) or an overall screening program does not yet exist, she also explains that the current study by Anderson et. al., with its sobering implications, brings future researchers closer to understanding the crucial elements in designing an effective early detection program for ovarian cancer.

References:

1/Anderson GL , McIntosh M, Wu L, et. al. Assessing Lead Time of Selected Ovarian Cancer Biomarkers: A Nested Case–Control Study. Journal of the National Cancer Institute Advance Access published on January 6, 2010, DOI 10.1093/jnci/djp438. J. Natl. Cancer Inst. 102: 26-38.

2/Hartge P. Designing Early Detection Programs for Ovarian Cancer. Journal of the National Cancer Institute Advance Access published on January 6, 2010, DOI 10.1093/jnci/djp450. J. Natl. Cancer Inst. 102: 3-4.

3/Partridge E, Kreimer AR, Greenlee RT, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol (2009) 113(4):775–782. [PMCID: PMC2728067; PMID: 19305319].

4/Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol (2009) 10(4):327–340. [PMID: 19282241]

5/ Horner MJ, Ries LAG, Krapcho M, et al, eds. SEER Cancer Stat Fact Sheets (2009) Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed December 2, 2009.

6/Horner MJ, Ries LAG, Krapcho M, et. al., eds. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006, based on November 2008 SEER data submission, posted to the SEER web site, 2009 [See Table 21.6: Incidence & Mortality Rates By Age].

Sources:

Novel Targeted Gene Therapies Use Diphtheria Toxin To Fight Ovarian Cancer; One Clinical Trial Underway

Two separate research teams reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer. … A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells. Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

Targeted Gene Therapy In the Fight Against Ovarian Cancer

The peritoneal cavity is a common site of ovarian cancer and accompanying ascites caused by the disease. Ascites is an abnormal buildup of fluid in the peritoneal cavity that causes swelling.  Malignant tumor cells may be found in the ascites fluid in connection with late stage ovarian cancer.  Massive ascites and the related abdominal distention can cause anorexia, nausea, vomiting and respiratory difficulties, and negatively impact the patient’s quality of life. Ovarian cancer patients frequently experience disease involvement of the pelvic and retroperitoneal lymph nodes as well. The standard primary treatment of patients with advanced stage ovarian cancer is cytoreductive surgery followed by platinum drug and taxane drug doublet chemotherapy. Despite this aggressive approach, there is a high rate of disease recurrence. Although discovery of several other active nonplatinum cytotoxic agents has improved outcome, long-term survival rates are low. Success of traditional chemotherapy has been limited by drug resistance and lack of specificity with respect to disease formation and progression. Thus, novel “targeted” ovarian cancer therapies that achieve improved long-term disease control with lower toxicity are desperately needed.

A so-called “targeted therapy” utilizes drugs or other medically manufactured substances (e.g., small molecule drugs or monoclonal antibodies) to block the growth and spread of cancer by interfering with specific molecules involved in cancer tumor growth and progression.  By identifying and selectively focusing upon molecular and cellular changes or unique genetic characteristics that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy, and less harmful to normal cells.

It is possible for a targeted therapy to incorporate a gene therapy. Gene therapy is an experimental treatment that involves the introduction of genetic material (DNA or RNA) into a human cell to fight a disease such as cancer.  When both therapeutic approaches are combined by researchers, a “targeted gene therapy” is the result.  A targeted gene therapy is an attractive approach to controlling or killing human cancer cells only if the therapy can selectively identify and exploit the genetic and epigenetic alterations in cancer cells, without harming normal cells that do not possess such alternations.

Two separate research groups reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer.  The toxin is produced by a deadly bacterium (Corynebacterium diphtheriae).  A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells.  Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

MIT-Lankenau Institute Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The MSLN & HE4 Ovarian Cancer Genes.

anderson

Daniel Anderson, Ph.D., Research Associate, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

The first study, which appears in the August 1 issue of the journal Cancer Research, was conducted by a team of researchers from the Massachusetts Institute of Technology (MIT) and the Lankenau Institute of Medical Research (Lankenau Institute). In this study, the researchers used a nanoparticle as a delivery vehicle (or vector) for DNA that encodes a diphtheria toxin suicide protein (DT-A).  The novel nanoparticles are made with positively charged, biodegradable polymers known as poly(beta-amino esters). When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can deliver functional DNA when injected into or near the targeted tissue.

The nanoparticle carrying the DT-A is designed to target overexpression of two genes (mesothelin (MSLN) and HE4 (or WFDC2)) that are highly active in ovarian tumor cells, but not in normal cells. Once inside an ovarian cancer tumor cell, the DT-A disrupts the tumor cell’s ability to manufacture critical life sustaining proteins, thereby causing cell death.  Accordingly, the choice of the DT-A fragment of a diptheria toxin gene ensures high ovarian cancer cell killing activity.  It also avoids unintended toxicity to normal cells because the DT-A released from destroyed ovarian cancer cells is not able to enter normal neighboring tissue cells in the absence of the DT-B fragment which was excluded from the original nanoparticle delivery system or vector.

As part of this study, researchers administered DT-A nanoparticles directly into the peritoneal cavity – which encases abdominal organs such as the stomach, liver, spleen, ovaries and uterus – of mice xenografted with primary and metastatic ovarian tumors.  Ovarian cancer is known to initially spread throughout the peritoneal cavity, and current therapeutic approaches in humans include direct injection into the peritoneal space, thereby targeting the therapy to the ovaries and nearby tissues where tumors may have spread.

“… [The researchers] discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. …”

langerrobert

Robert S. Langer is the David H. Koch Institute for Integrative Cancer Research Professor (there are 14 Institute Professors at MIT; being an Institute Professor is the highest honor that can be awarded to a faculty member). Dr. Langer has written approximately 1,050 articles. He also has approximately 750 issued and pending patents worldwide. Dr. Langer’s patents have been licensed or sublicensed to over 220 pharmaceutical, chemical, biotechnology and medical device companies. He is the most cited engineer in history.

Sawicki

Janet Sawicki, Ph.D., Professor, Lankenau Institute of Medical Research. Dr. Sawicki also serves as an Associate Professor at the Kimmel Cancer Center of Thomas Jefferson University. Her ovarian cancer research is funded by the National Institutes of Health, the U.S. Department of Defense, the Sandy Rollman Foundation, the Teal Ribbon Ovarian Cancer Foundation, and the Kaleidoscope of Hope Foundation.

Daniel Anderson, Ph.D., research associate in the David H. Koch Institute for Integrative Cancer Research at MIT and a senior author of the paper, and others from MIT, including Institute Professor Robert Langer, along with researchers from the Lankenau Institute, led by Professor Janet Sawicki, discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. Furthermore, the novel therapy did not have the toxic side effects of chemotherapy because the diptheria toxin gene is engineered to function in ovarian cells but is inactive in normal cell types.

Based upon these finding, the MIT and Lankenau Institute researchers concluded that IP administration of DT-A nanoparticles, combined with designed targeting of those nanoparticles against ovarian tumor cell gene (MSLN & HE4) expression, holds promise as an effective therapy for advanced-stage ovarian cancer. According to Anderson, human clinical trials could start, after some additional preclinical studies, in about 1 to 2 years.  Currently ovarian cancer patients undergo surgery followed by chemotherapy. In many cases, the cancer returns after treatment.  Disease recurrence is problematic because there are no curative therapies for advanced-stage tumors.

For several years, the MIT-Lankenau Institute team worked to develop the DT-A nanoparticles as an alternative to viruses, which are associated with safety risks. In addition to ovarian cancer, these nanoparticles have demonstrated treatment potential for a variety of diseases, including prostate cancer and viral infection. “I’m so pleased that our research on drug delivery and novel materials can potentially contribute to the treatment of ovarian cancer,” Langer said. In future studies, the team plans to examine the effectiveness of nanoparticle-delivered diphtheria toxin genes in other types of cancer, including brain, lung and liver cancers.

Other MIT authors of the paper are recent MIT Ph.D. recipients Gregory Zugates and Jordan Green (now a professor at John’s Hopkins University), and technician Naushad Hossain. The research was funded by the Department of Defense and the National Institutes of Health.

Israeli Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The H19 Ovarian Cancer Gene.

The second study was conducted by Israeli researchers and was published August 6 online ahead of print in the Journal of Translational Medicine.

In the provisional study report, the researchers note that based upon earlier studies from their team and others, the H19 gene has emerged as a candidate for cancer gene therapy. The H19 gene is expressed at substantial levels in ovarian cancer tumor cells, but is nearly undetectable in surrounding normal tissue cells.  Although the Israeli research team acknowledges that the exact function of H19 is the subject of past debate, it notes that recent data suggests a role for H19 in promoting cancer progression, angiogenesis and metastasis.

As a first step, Israeli researchers tested H19 gene expression in ovarian cancer cells obtained from the ascites fluid of 24 patients, and established that H19 expression levels were detected in 90% of the tested patients. Of those patients with positive H19 expression, 76% showed a moderate or high level of expression, while 24% showed a low level of expression.

Next, the researchers created a DT-A nanoparticle similar to the one created by the MIT/Lankenau research team as described above, except the Israeli nanoparticle was designed to target H19 overexpression within ovarian cancer cells.  The therapeutic effect of the DT-A/H19 nanoparticles was first tested in vitro against various ovarian cancer cell lines and cells obtained from patient ascites fluid.  The researchers determined that the DT-A/H19 nanoparticle therapy caused ovarian cancer cell death.  The therapeutic effect of the DT-A nanoparticles was tested in vivo by injecting the DT-A nanoparticles into mice xenografted with ovarian cancer tumors. The researchers estimate that the DT-A nanoparticle therapy reduced ovarian cancer tumor growth in the treated mice by 40%.

Based upon these finding, the researchers note that although the study report issued is provisonal, it is their working hypothesis that intraperitoneal administration of DT-A/H19 nanoparticles holds the potential to (1) reach ascites tumor cells, (2) deliver its intracellular toxin without targeting normal tissue cells, and (3) reduce tumor burden & fluid accumulation; and therefore, improve the patient’s quality of life, and hopefully, prolong her survival.

  • DT-A/H19 Nanoparticle Therapy Administered To An Israeli Patient On A Compassionate Use Trial Basis

In the provisional study report, the researchers state that the targeted gene therapy was administered to an Israeli patient with advanced, recurrent ovarian cancer, who qualified for compassionate use treatment under Israeli regulatory rules.  Specifically, the patient’s intraperitoneal ovarian cancer metastases and ascites were treated with the DT-A/H19 nanoparticle therapy after the failure of conventional chemotherapy. The results of the single patient compassionate use trial suggest that the drug caused no serious adverse events at any drug dosage level.  Moreover, the patient experienced (1) a 50% decrease in serum cancer marker protein CA-125, (2) a significant decrease in the number of cancerous cells in the ascites, and (3) a clinical improvement as reported by her doctors.  It is reported that the patient’s quality of life increased during the course of treatment and her condition continues to be stable, with no new cancerous growths.

  • Phase I/II Clinical Trial To Test DT-A/H19 Nanoparticle Therapy (BC-819) In the U.S. & Israel

The DT-A/H19 nanoparticle therapy is being developed commercially by BioCancell Therapeutics, Inc (BioCancell) Recently, BioCancell announced the opening of a clinical trial to test the DT-A/H19 nanoparticle therapy (also referred to as BC-819) in patients with advanced stage ovarian cancer.  The clinical trial is entitled, Phase 1/2a, Dose-Escalation, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Intraperitoneal Administration of DTA-H19 in Subjects With Advanced Stage Ovarian Cancer, and the trial investigators are recruiting patients in the U.S. and Israel as indicated below.

University of Pennsylvania Medical Center [Abramson Cancer Center] (Recruiting)
Philadelphia, Pennsylvania, United States, 19104-6142
Contact: Lana E. Kandalaft, Pharm.D, PhD – 215-537-4782 (lknd@mail.med.upenn.edu)
Principal Investigator: George Coukos, M.D., Ph.D.

Massey Cancer Center (Not yet recruiting)
Richmond, Virginia, United States, 23298-0037
Contact: Jane W. Baggett, RN 804-628-2360 (jbaggett@mcvh-vcu.edu)
Principal Investigator: Cecelia H. Boardman, M.D.

The Edith Wolfson Medical Center (Recruiting)
Holon, Israel
Contact: Pnina Nir (972)-52-8445143 (pninanir@wolfson.health.gov.il)
Principal Investigator: Tally Levy, M.D.

Hadassah University Hospital (Recruiting)
Jerusalem, Israel
Contact: Zoya Bezalel (972)-2-6776725 (zoyab@hadassah.org.il)
Principal Investigator: David Edelman, MD

Meir Hospital (Recruiting)
Kfar Saba, Israel
Contact: Tal Naderi 09-7472213 (Ta.INadiri@clalit.org.il)
Principal Investigator: Ami Fishman, MD

In the provisional study report, the Israeli researchers discuss the importance of collecting data regarding the correlation between the level of ovarian cancer cell H19 expression and the efficacy of the treatment as part of the clinical trial discussed above.  Based upon accrued future clinical trial data, the researchers believe that they will be able to identify in advance patients that will respond to this novel therapy, as well as non-responders who are resistant to all known therapies, thereby avoiding treatment failure and unnecessary suffering and cost.

References:

Mesothelin – A Potential New Target For Ovarian Cancer ImmunoTherapy

Researchers have generated altered immune cells that are able to shrink, and in some cases eradicate, large tumors in mice. The immune cells target mesothelin, a protein that is highly expressed, or translated in large amounts from the mesothelin gene, on the surface of several types of cancer cells. The approach, developed by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and at the University of Pennsylvania School of Medicine, shows promise in the development of immunotherapies for certain tumors. The study appeared online the week of Feb. 9, 2009, in the Proceedings of the National Academy of Sciences. In a more recent study, appearing online May 5, 2009, in Molecular Cancer Therapeutics, NCI researchers developed a human antibody against mesothelin that shows potential, in laboratory experiments, for cancer treatment and diagnosis.

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