“Adoptive T-Cell” Immunotherapy Shows Activity Against Advanced Ovarian Cancer in Phase I Study

In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using the patient’s own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in advanced ovarian cancer patients.

Most ovarian cancer patients are diagnosed with late stage disease that is unresponsive to existing therapies. In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using the patients’ own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in these type of patients. Four of the six patients treated in the phase I trial responded to the therapy, the investigators report this month in OncoImmunology.

“What we proved in this study is that this is a safe treatment strategy,” says co-first author Lana Kandalaft, PharmD, MTR, Ph.D., research assistant professor of Obstetrics and Gynecology and director of clinical development in the Ovarian Cancer Research Center. “It is a walk in the park for patients, especially compared to standard chemotherapies and surgical treatments for ovarian cancer – literally, some patients left the clinic and went for a walk in a nearby park after their treatment.”

The findings follow research by the study’s senior author, George Coukos, M.D., Ph.D., director of the Ovarian Cancer Research Center at Penn, who showed in 2003 that women whose ovarian tumors were infiltrated by healthy immune cells, called T cells, tended to live longer than women whose tumors were devoid of T cells. That observation and other subsequent ones suggest the patient’s immune system is trying to fight off the disease but can’t quite muster the strength to beat it. Therefore, investigators have been trying to find ways using patients’ own tumor cells to boost the immune system’s power.

Adoptive T-Cell Therapy Approach

DendriticCellVaccine

In the first segment of the study, the University of Pennsylvania researchers prepared an individualized dendritic cell vaccine for each ovarian cancer patient. (Photo Credit: Penn Medicine)

In the current study, Coukos, Kandalaft, co-first author Daniel J. Powell Jr., PhD, research assistant professor of Pathology and Laboratory Medicine, and colleagues treated six women with advanced ovarian cancer in a two-staged immunotherapy protocol in which they utilized a dendritic cell vaccine created from tissue in the patients’ own tumor, which was stored at time of surgery. All of these women’s cancers had progressed on standard of care chemotherapy.

In the first segment of the study, the team prepared an individualized dendritic cell vaccine for each patient. They harvested dendritic cells from each patient using apheresis, the same process volunteers go through when they donate platelets or other blood products such as those collected for stem cell transplants. Kandalaft and colleagues then exposed each patient’s dendritic cells to tumor extract produced from the woman’s ovarian cancer tumor, which teaches the dendritic cells who the enemy is. After this priming, the investigators vaccinated each patient with her own dendritic cells and gave them a combination chemotherapy regimen consisting of bevacizumab (Avastin) and  metronomic cyclophosphamide. Because dendritic cells are like the generals of the immune system, they then induce other immune cells to take up the fight.

Of the six advanced ovarian cancer patients who received the dendritic cell vaccine, four patients developed an anti-tumor immune response, indicating that the approach was working. One of those patients had no measurable disease at study entry because all of it had been successfully removed during surgery. She remains in remission today, 42 months following vaccine treatment. The remaining three who had an immune response to the vaccine still had residual disease and went on to the second segment of treatment.

AdoptiveTcells

In the second segment of the study, T cells were harvested from the ovarian cancer patients, grown in the laboratory, thereby expanding their numbers exponentially, and then were reintroduced into each patient after she underwent a lymphodepleting chemotherapy regimen. (Photo Credit: Penn Medicine)

In the second segment of the study, the team harvested T cells from each of the three women mentioned above. Using a technique developed at Penn, the researchers grew the cells in the laboratory, expanding their numbers exponentially, and then reintroduced them into each patient after she underwent a lymphodepleting chemotherapy regimen. Because the T cells had already been trained by the dendritic cell vaccine to attack the tumor cells, the adoptive T cell transfer amplifies the anti-tumor immune response.

Two of the women showed a restored immune response after the T cell transfer. One of the women continued to have stable disease, whereas the other had a complete response to the therapy.

The researchers say it is too early to say whether this type of therapy will be effective in a large number of ovarian cancer patients, but the early results are promising. First, and foremost, she notes, the two-step approach appears safe and well tolerated by the patients. Additionally, the team saw a correlation in both treatment steps between immune responses and clinical benefit, suggesting that it is, in fact, the immune response that is holding the disease in check.

With these encouraging results in hand, the team has opened a larger trial (UPCC-19809 & UPCC-26810; clinical trial protocols listed below) in which they have already enrolled about 25 women and aim for up to 30 more. The new protocol uses an improved vaccine platform and an optimized adoptive T cell transfer protocol. The prinicipal investigator of this study is Janos Tanyi, MD, PhD.

“Large clinical trials have shown that intensifying chemotherapy doesn’t improve outcomes for women with advanced ovarian cancer,” Coukos says. “So we need to explore other avenues. We think the combinatorial approach of both immune and chemotherapy is the way to go.”

Other co-authors from Penn include Cheryl L. Chiang, Janos Tanyi, Sarah Kim, Kathy Montone, Rosemarie Mick, Bruce L. Levine, Drew A. Torigian, and Carl H. June. Co-author Marnix Bosch is from Northwest Biotherapeutics in Bethesda, Maryland.

This study was supported by National Cancer Institute Ovarian SPORE grant P01-CA83638, National Institution of Health R01FD003520-02, and the Ovarian Cancer Immunotherapy Initiative. 

___________________________

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

____________________________

Sources:

Kandalaft L, Powell D, Chiang C, et. al. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. OncoImmunology 2013; 2:e22664; http://dx.doi.org.

Two-Step Immunotherapy Attacks Advanced Ovarian Cancer, Penn Medicine Researchers Report, Penn Medicine, Press Release, January 31, 2013.

Closed Clinical Trial Protocols (two study segments discussed above):

Study Segment One: A Phase I Clinical Trial of Autologous Dendritic Cell Vaccine Loaded With Autologous Tumor Cell Lysate for Recurrent Ovarian or Primary Peritoneal Cancer; ClinicalTrials.gov Identifier: NCT00683241; UPCC ID: 11807.

Study Segment Two: A Phase-I/II Randomized Trial of Maintenance Vaccination Combined With Metronomic Cyclophosphamide w/wo Adoptive Transfer of CD3/CD28-CoStimulated T-Cells for Recurrent Ovarian or Primary Peritoneal Cancer Previously Vaccinated DCVax-L; ClinicalTrials.gov Identifier: NCT00603460; UPCC ID: 10808

Open Clinical Trial Protocols (enrolling new patients, as of this writing):

A Pilot Clinical Trial of Dendritic Cell Vaccine Loaded With Autologous Tumor for Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancer;  ClinicalTrials.gov ID: NCT01132014;  UPCC ID: 19809. [currently recruiting patients]

A Phase-1 Trial of Adoptive Transfer of Vaccine-Primed CD3/CD28-Costimulated Autologous T-Cells Combined With Vaccine Boost and Bevacizumab for Recurrent Ovarian Fallopian Tube or Primary Peritoneal Cancer Previously Vaccinated With Autologous Tumor Vaccine; ClinicalTrials.gov ID: NCT01312376;  UPCC ID: 26810. [currently recruiting patients]

Related Libby’s H*O*P*E* Articles:

Gene Transfer Therapy Destroys Tumors in Chronic Lymphocytic Leukemia Patients; Holds Promise For Ovarian Cancer, by Paul Cacciatore, August 11, 2011.

Penn’s Genetically Modified T Cells Create Antitumor Effect In Mice With Folate Positive Ovarian Cancer; Clinical Trial Pending, by Paul Cacciatore, August 17, 2011.

Penn’s Genetically Modified T Cells Create Antitumor Effect In Mice With Folate Positive Ovarian Cancer; Clinical Trial Pending

In a recent issue of Cancer Research, researchers from the University of Pennsylvania showed for the first time that engineered human T cells can eradicate deadly human ovarian cancer in immune-deficient mice. A clinical trial involving the modified T cells is expected to be announced within the next few months.

In a recent issue of Cancer Research, Daniel J. Powell, Jr., Ph.D., a research assistant professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, showed for the first time that engineered human T cells can eradicate deadly human ovarian cancer in immune-deficient mice. Ovarian cancer is the most lethal reproductive cancer for women, with one-fifth of women diagnosed with advanced disease surviving five years. Nearly all ovarian cancers (90%) are characterized by their expression of a distinct cell-surface protein called alpha-folate receptor, which can be targeted by engineered T cells.

Daniel J. Powell, Jr., Ph.D., Research Assistant Professor of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania.

The alpha-folate receptor is expressed on the surface of ovarian cancer cells and has a high affinity for folic acid, a vitamin which helps “feed” the cancer cells, and represents an “Achilles’ Heel” for cancer researchers to target.

Until now, human T cells engineered to express an antibody fragment specific for the alpha-folate receptor protein have shown anti-tumor activity against epithelial cancers in the lab, but not in the clinic due to their inability to persist and attack tumors in the human body. The modified T cells used in this study express an engineered fusion protein – called a “chimeric antigen receptor” (CAR) — that combines the specificity of an antibody with the T cell signaling portions from two different proteins that stimulate the immune system to recognize ovarian cancer cells. These added signaling protein pieces give the engineered T cells the extra survival signals they need to do their job.

In a past clinical study, first generation engineered T cells did not shrink tumors in women with ovarian cancer because the T cells did not persist in the patients. The new second generation technology developed in the current study overcomes the limitations of the first generation approach. Specifically, the second generation T cells shrank tumors in mice, but the T cells engineered using first generation technology did not. The second generation T cells also caused tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer.

“We anticipate the opening of a genetically modified T cell clinical trial in the next few months for women with recurrent ovarian cancer,” said Powell. “Targeting the alpha-folate receptor is an opportunity for widespread clinical application.”

Two Birds, One Stone T Cells

The double-barreled T cells are engineered to multiply, survive, recognize, and kill ovarian tumors. The modified T cells were expanded for two weeks in the lab, and then tested for reactivity by exposing them to human ovarian cancer cells to see if they destroyed the cancer cells. Researchers also tested for effectiveness by measuring cytokine production by the T cells, a sign of inflammation produced by the engineered T cells when killing cancer cells.

The new second generation engineered T cells were successful in many ways. First, they were resistant to cancer-induced cell death; that is, fewer new T cells died when exposed to cancer cells, compared to the older technology. Second, the new T cells also multiplied better and survived; therefore their numbers increased over time in in vitro experiments and in the mouse model.

A clinical trial using these T cells is pending with George Coukos, M.D., Director of the Ovarian Cancer Research Center at Penn and the principal trial investigator. Penn is the only study site identified to date. Investigators aim to recruit up to 21 patients with advanced recurrent ovarian cancer whose tumors express the alpha-folate receptor.

“This technology represents a promising advancement for the treatment of women with ovarian cancer,” said Powell. “But we will continue to work around the clock to improve this approach using other costimulatory portions and antibody-like proteins to make this the most powerful and safe approach for the treatment of the greatest number of women with this horrible disease.”

About Penn Medicine

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit the community.

About Perelman School of Medicine, University of Pennsylvania

Penn’s Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.

About University of Pennsylvania Health System

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Sources:

Song DG, et al.  In Vivo Persistence,Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB). Cancer Res. 2011 Jul 1;71(13):4617-27. Epub 2011 May 5. PubMed PMID: 21546571.

Penn Study Finds More Effective Approach Against “Achilles’ Heel” of Ovarian Cancer, News Brief, Penn Medicine, Perelman School of Medicine, University of Pennsylvania Health System, August 5, 2011.

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: