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)

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 mesothelioma. J Hematol Oncol. 2014 Feb 24;7(1):15. doi: 10.1186/1756-8722-7-15. (Abstract – PMID: 24565018; Full Text – PMCID: PMC3943805)

“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

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.

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.

Ampligen® To Be Tested In Phase I/II Study In Tandem With UPenn Ovarian Cancer Vaccine

Hemispherx Biopharma’s Ampligen® is being tested in combination with an experimental ovarian cancer vaccine developed by the Penn Ovarian Cancer Research Center.

Hemispherx Biopharma, Inc. (“Hemispherx”) announced yesterday that it entered into a Material Transfer and Research Agreement with the University of Pennsylvania School of Medicine to provide Ampligen® [rintatolimod; poly(I)•poly(C12,U)], an experimental therapeutic, for testing as a vaccine adjuvant in a human ovarian cancer clinical study.

George Coukos, M.D., Ph.D., Celso Ramon Garcia Associate Professor of Reproductive Biology; Associate Chief, Division of Gynecologic Oncology & Director, Ovarian Cancer Research Center; Abramson Cancer Center, University of Pennsylvania

The principal investigator is Dr. George Coukos, who is the Celso Ramon Garcia Associate Professor of Reproductive Biology, Associate Chief of the Division of Gynecologic Oncology, and Director, Ovarian Cancer Research Center, at the University of Pennsylvania School of Medicine Abramson Cancer Center. He is a recognized global leader in ovarian cancer treatment and research. His research focus over the last several years has been on understanding the immune system’s response to ovarian cancer, and on developing therapies which enhance that response.

This study is a Phase 1/2 randomized clinical trial for subjects with recurring ovarian, fallopian tube or primary peritoneal cancer to determine the feasibility, safety, and immunogenicity of a vaccine comprised of autologous oxidized tumor cell lysate (OC-L) administered by intradermal /subcutaneous injection in combination with intravenous Ampligen®. The OC-L vaccine is an experimental cancer immunotherapy under development by the University of Pennsylvania. This study represents the first use of Ampligen® as a cancer vaccine adjuvant in a well-controlled clinical study.

Dr. William A. Carter, CEO and Chief Scientific Officer at Hemispherx stated “…we are excited to have the opportunity to work with Dr. Coukos and his colleagues to combine Ampligen®, our selective Toll-like receptor 3 agonist which has potent immune modulating activity, with their creative OC-L autologous cancer vaccine. We are particularly pleased that the first patient has already been enrolled in the study and has received their initial dose of study drug.”

Hemispherx views the potential use of Ampligen® as a component of cancer immunotherapy as an important development opportunity. The company’s near term focus in cancer is to initiate a series of collaborations with renowned cancer research experts at premier institutions to help define the best mode of integrating Ampligen® into immunotherapy strategies to potentially advance the treatment of cancer.

Source:

• Hemispherx Biopharma’s Ampligen® Tested in Combination with Experimental Vaccine from Leading Cancer Research Institute, Hemispherx Biopharma, Inc., Press Release, June 21, 2011.

• A Phase I/II Randomized Clinical Trial of Autologous Oxidized Tumor Cell Lysate Vaccine For Recurrent Ovarian, Fallopian Tube or Primary Peritoneal Cancer, Clinical Trial Summary, NCT01312389, http://www.ClinicalTrials.gov.

About Ampligen®

Nucleic acid compounds represent a potential new class of pharmaceutical products that are designed to act at the molecular level for treatment of human diseases. The Hemispherx Biopharma drug technology utilizes specifically-configured RNA (Ribonucleic acid). The Hemispherx double-stranded RNA drug product, trademarked Ampligen®, an experimental, unapproved drug, which is administered intravenously, is in human clinical development for various therapeutically oriented studies, including treatment for chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME), HIV, renal cell carcinoma and malignant melanoma.

Based on the results of pre-clinical studies and clinical trials, Hemispherx believes that Ampligen®, an experimental agent, may have broad-spectrum anti-viral and anti-cancer properties. Approximately 500 patients have received Ampligen® in clinical trials authorized by the Food and Drug Administration (“FDA”) at over twenty clinical trial sites across the U.S., representing the administration of more than 40,000 doses of this drug, and Ampligen® is available only through clinical trials for limited indications.

Clinical trials already conducted by Hemispherx U.S. include treatments of CFS/ME, other infectious diseases such as Hepatitis B, HIV, and clinical trials for cancer including patients with renal cell carcinoma and malignant melanoma. Certain of these studies to date have not been well-controlled and accordingly additional tests will be necessary for support of regulatory approvals.

Hemispherx believes that Ampligen® has been generally well tolerated with a low incidence of clinical toxicity, particularly given the severely debilitating or life threatening diseases that have been treated. A mild flushing reaction has been observed in approximately 15% of patients treated in our various studies. This reaction is occasionally accompanied by erythema, a tightness of the chest, tachycardia, anxiety, shortness of breath, subjective reports of “feeling hot,” sweating and nausea. The reaction is usually infusion-rate related and can generally be controlled by slowing the infusion rate. Other adverse side effects include liver enzyme level elevations, diarrhea, itching, urticaria (swelling of the skin), bronchospasm, hypotension, photophobia, rash, bradycardia, transient visual disturbances, arrhythmias, decreased platelets and white blood cell counts, anemia, dizziness, confusion, elevation of kidney function tests, occasional temporary hair loss and various flu-like symptoms, including fever, chills fatigue, muscular aches, joint pains, headaches, nausea and vomiting. These flu-like side effects typically subside within several months.

About Hemispherx Biopharma

Hemispherx Biopharma, Inc. is an advanced specialty pharmaceutical company engaged in the manufacture and clinical development of new drug entities for treatment of seriously debilitating disorders. Hemispherx’s flagship products include Alferon N Injection® (FDA approved for a category of sexually transmitted diseases) and the experimental therapeutics Ampligen® and Alferon® LDO. Ampligen® is an experimental RNA nucleic acid being developed for globally important debilitating diseases and disorders of the immune system. Hemispherx’s platform technology includes components for potential treatment of various severely debilitating and life threatening diseases. Hemispherx has patents comprising its core intellectual property estate and a fully commercialized product (Alferon N Injection®). Hemispherx wholly owns and exclusively operates a GMP-certified manufacturing facility in the United States for commercial products. For more information please visit www.hemispherx.net.

Libby’s H*O*P*E*(tm) Adds New Cancer Video Archive Courtesy of Vodpod.com

Yesterday, Libby’s H*O*P*E* added a new cancer video archive to the weblog courtesy of Vodpod.com.  Currently, the archive contains approximately 90 videos that address many general cancer and ovarian cancer issues, as well as the personal voices of those affected by cancer. The new video archive is located on the homepage right sidebar.  All you have to do is “click and play.”

Yesterday, Libby’s H*O*P*E* added a new cancer video archive to the weblog courtesy of Vodpod.com.  Currently, the archive contains approximately 90 videos that address many general cancer and ovarian cancer issues, as well as the personal voices of those affected by cancer. The new video archive is located on the homepage right sidebar.  All you have to do is “click and play.”  The video arrangement is set to “random order” so that new videos appear on the homepage sidebar each time you visit Libby’s H*O*P*E*.

If you are aware of a general cancer/ovarian cancer video that is educational, heartfelt, inspirational, humorous, poignant, or is simply dedicated to the one you love, please provide us with the URL address of the video.  The URL video address can be sent to us by email (click on the “contact” button located at the top of the homepage), or by comment (post a comment under this post).  Upon receipt of the video URL address, we will add the referenced video to the new archive.  We appreciate your participation in adding to our video archive and hope you find the archive helpful.

IL-7 Boosts Immune Response in Cancer Patients

” … [Recombinant human interleukin-7] rhIL-7 appears to be an effective T cell growth factor with “immune rejuvenating” properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note. In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.”

“Data from a preliminary study suggest that recombinant human interleukin (r-hIL)-7 can enhance and broaden immune responses in patients with impaired immunity due to lymphocyte depletion.

The results of the phase 1 trial, published online June 23 in The Journal of Experimental Medicine, showed that when given to cancer patients, rhIL-7 induced a dramatic polyclonal prolonged expansion of CD4+ and CD8+ T cells, which in turn caused a significant broadening of circulating T cell receptor repertoire diversity. These effects were mediated primarily through an increase in peripheral T cell cycling and augmented cell survival.

Lymphopenia induced by cytotoxic chemotherapy, or pathologies such as HIV infection, can significantly weaken immune function; as a physiologic immuno-enhancer, IL-7 can enhance the restoration of T cells. CD4+ T cell recovery in adults who have experienced severe depletion requires the reemergence of a pool of naive T cells, which generally takes 18 to 24 months and might only occur in people younger than 40 to 45 years. Thus, the authors note, a strategy that can accelerate or promote the recovery of a widely diverse T cell repertoire in older people might be useful for a large number of clinical applications.

‘We know that IL-7 can enhance tumor vaccines in animals, so that would be a clear avenue of research,’ said lead author Claude Sportès, MD, senior staff clinician at the National Cancer Institute‘s Center for Cancer Research, Experimental Transplantation and Immunology Branch, in Bethesda, Maryland. ‘But it wouldn’t only have to be tumor vaccines. Hopefully we will have a trial underway in the not-too-distant future looking at how it can enhance anti-viral and other immunizations, particularly in the elderly.’

Treatment with IL-7 therapy exerted a marked effect on T cell immune reconstitution during preliminary trials with animal models. It also appeared to augment effector and memory responses to vaccination in mice; in preclinical models, IL-7 therapy was able to augment anti-tumor responses that might improve survival when combined with anti-tumor vaccines.

‘In older individuals, therapy with IL-7 could lead to a rejuvenation of the phenotype,’ explained Dr. Sportès in an interview. ‘This in turn can lead to better vaccine responses in general and, in oncology, better tumor vaccine responses.’

The implications for rhIL-7 are potentially vast, and there are many promising therapeutic avenues. ‘But as often happens in medicine,’ he cautioned, ‘things can be very promising at this stage and then fizzle out.’

First Human Trial

In this phase 1 dose-escalation study, the first initiated in a human population, Dr. Sportès and colleagues evaluated the effects of IL-7 therapy on human lymphocytes in 16 patients, between the ages of 20 to 71 years, with nonhematologic, nonlymphoid refractory cancer. The doses, extrapolated from previous mouse and primate studies, were 3, 10, 30, and 60 μg/kg, and were administered by subcutaneous injection every other day for 14 days, for a total of 8 doses.

They found that after a very transient decrease, the numbers of circulating lymphocytes and CD4+ and CD8+ T cells increased in a dose-dependent manner. At the highest dose levels, increases approached 300% for CD4+ and exceeded 400% for CD8+ T cells. Overall, the treatment induced widespread T cell cycling and was able to expand the T cell pool in human patients while preserving T cell function.

Treatment with rhIL-7 also seems to have advantages over rhIL-2, explained Dr. Sportès. The expanded T cells retained significant functional capacity, and the CD4+ T cell expansion was not accompanied by a disproportionate increase in T regulatory cells, a phenomenon that has been observed after rhIL-2 therapy. Previous data have shown that in vivo IL-2 administration in humans has minimal effects on CD8+ T cell numbers, whereas rhIL-7 effects on CD8+ T cell expansion are at least comparable to the effects on CD4+ T cells.

The researchers noted that rhIL-7 increases T cell receptor repertoire diversity, and that although it appears to selectively expand CD4+ recent thymic emigrants, naive cells, and central-memory populations, it did not have the same effect on effector T cells.

The details of the clinical trial will be the focus of a separate paper, said Dr. Sportès. ‘But it was well tolerated and we went to full-dose escalation.’

“Immune Rejuvenating” Properties

rhIL-7 appears to be an effective T cell growth factor with “immune rejuvenating” properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note.

In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.”

[Quoted Source: IL-7 Therapy Boosts Immune Response in Cancer Patients, by Roxanne Nelson, Medscape Medical News, Medscape Today, July 4, 2008 (summarizing the findings of Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets; Sportes, C. et. al., J Exp Med. 2008 Jun 23. Epub ahead of print]

2008 American Society of Clinical Oncology (ASCO) Annual Meeting Abstracts Available On-Line

The 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) will be held on May 30th through June 3rd, 2008 in Chicago, Illinois. Under a new policy, ASCO publicly released clinical trial brief abstracts two weeks before the start of its 2008 Annual Meeting on May 30th, where full results will be presented before thousands of cancer doctors. The new ASCO policy was intended to avoid stock trading on non-public information that was believed to have occurred under a prior policy in which ASCO mailed out abstracts under embargo weeks before its annual meeting.

I have provided hyperlinks below to a variety of cancer topics that may be of interest to ovarian cancer survivors. Please note that with the exception of the first “ovarian cancer” category listed below, the remaining categories will contain abstracts that address various types of cancer. H*O*P*E*™ will provide one or more posts that address ovarian cancer abstract highlights after the completion of the 2008 ASCO Annual Meeting on June 3rd.

Gynecologic Cancer:

Ovarian Cancer

Developmental Therapeutics: Cytotoxic Chemotherapy:

Cytotoxic Chemotherapy
Drug Resistance
Pharmacology / Pharmacokinetics
Phase I Studies

Developmental Therapeutics: Immunotherapy:

Antibodies
Cell-Based Therapy
Cytokines
Other: developmental therapeutics: immunotherapy
Vaccines

Developmental Therapeutics: Molecular Therapeutics:

Antiangiogenic or Antimetastatic Agents
Cell Cycle Inhibitors
Chemoprevention
Epigenetic Strategies
Functional Imaging
Gene Therapy/Antisense Strategies
Other Novel Agents
Pharmacodynamics
Pharmacogenomics
Pro-Apoptotic Agents
Receptor-Targeted Antibodies/Ligands
Tyrosine Kinase Inhibitors
Vascular Targeting

Tumor Biology and Human Genetics:

Cancer Genetics
Epidemiology / Molecular Epidemiology
Immunobiology
Molecular Diagnostics and Staging
Molecular Targets
Other: Tumor Biology and Human Genetics
Prognostic Factors
Radiation Biology
Tumor and Cell Biology

Cancer Prevention:

Cancer Prevention

Patient Care:

Cancer in Older Patients
Cancer-Related Complications
End-of-Life Care
Other: patient care
Palliative Care
Quality-of-Life Management
Supportive Care

Health Services Research:

Health Services Research
Outcomes Research
Practice Management/Professional Issues

Small Phase I Study Reports 2 to 4 Year Ovarian Cancer Remission in 30% of Women Who Received a NY-ESO-1 Vaccine

Three of nine patients (33%) remain in complete clinical remission at 25, 38, and 52 months, respectively.

The cancer-testis antigen NY-ESO-1 is expressed in greater than 40% of advanced epithelial ovarian cancers and represents a promising immunotherapeutic target. In a small Phase I (safety and immunogenicity) clinical trial conducted by Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, nine “high-risk” epithelial ovarian cancer patients, who were in first clinical remission after primary surgery and chemotherapy, received NY-ESO-1b peptide and Montanide ISA-51 every 3 weeks in the form of five vaccinations. The “high risk” ovarian cancer patient criterion was defined as a patient who (i) received suboptimal primary debulking (remaining tumor masses with diameter of 1.0 cm or greater), or (ii) experienced a failure to normalize the CA 125 blood tumor marker by the end of the third cycle of first-line chemotherapy. In addition, each patient enrolled in the trial was required to test positive for (i) human leukocyte antigen 2A (HLA-2A) in the blood, and (ii) NY-ESO-1 or LAGE-1 tumor expression. NY-ESO-1 tumor expression was evaluated for each patient by immunohistochemistry (IHC). LAGE-1 tumor expression was evaluated for each patient by reverse transcriptase and polymerase chain reaction (RT-PCR) analysis. For each patient, NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed pre-vaccination and at week #1, week #4, week #7, week #10, week #13, and week #16 of the vaccination period.

The nine patients experienced treatment-related adverse events including: grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism; and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. The results of the Phase I trial are set forth below.

• Three of four patients (75%) with NY-ESO-1-positive tumor showed T-cell immunity.
• Four of five patients (80%) with NY-ESO-1-negative tumor showed T-cell immunity.
• At median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival (PFS) of 13 months.
• Three of nine patients (33%) remain in complete clinical remission at 25, 38, and 52 months, respectively.

At the end of the Phase I trial, the trial investigators concluded that vaccination of high-risk, HLA-A2-positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1-positive and NY-ESO-1-negative tumors. Also, the trial investigators noted that additional study is necessary. For a copy of the clinical trial protocol associated with this trial, click here.

[Source: “Safety and Immunogenicity Study of NY-ESO-1b Peptide and Montanide ISA-51 Vaccination of Patients with Epithelial Ovarian Cancer in High-Risk First Remission;” Diefenbach, C.S. et. al.; Clin Cancer Res. 2008 May 1;14(9):2740-2748.]

Comment: Prior cancer vaccines targeting NY-ESO-1 overexpression in ovarian cancer tumors produced moderate success in terms of an increase in PFS. This study is particularly provocative because patients who tested positive and negative for NY-ESO-1 tumor expression experienced T-cell immunity, and “high risk” patients (including suboptimally debulked patients) experienced PFS benefit.

Related Information:

• See “Five Years Later, Patient Participating in Vaccine Trial Remains Free of Ovarian Cancer,” H*O*P*E* Blog post, April 7, 2008.
• Open Ovarian Cancer Clinical Trials Utilizing a NY-ESO-1 vaccine.

Avax Technologies Announces Initiation of Clinical Study With Autologous Ovarian Cancer Vaccine

“AVAX Technologies, Inc. (OTC Market:AVXT.OB) today announces it has received FDA approval to begin enrollment into a Phase I-II clinical trial of OVax® for patients with advanced, chemotherapy-refractive ovarian cancer. [For a copy of the clinical trial inclusion/exclusion criteria refer to “OVax®: A Feasibility Study Using a DNP-Modified Autologous Ovarian Tumor Cell Vaccine as Therapy in Ovarian Cancer Patients After Relapse.”]. The study will be performed in collaboration with Cancer Treatment Centers of America, Inc (CTCA). It will be centered in the CTCA hospital in Zion, Illinois, although patients also will be referred from other CTCA hospitals in Tulsa and Philadelphia, and its out-patient clinic in Seattle.

Up to 42 eligible patients with stage III or IV ovarian carcinoma will be enrolled. These patients’ cancers will have progressed despite initial surgery and chemotherapy and failed to respond to one or two salvage chemotherapy regimens. They will undergo debulking surgery, and tumor tissue will be sent to AVAX for production of vaccine. Post-operatively, they will receive intraperitoneal chemotherapy with a taxane and then will be enrolled into the protocol.

Three doses of OVax will be tested, and each of the three doses will be analyzed for immunological efficacy with the goal of optimizing the dose for treatment of patients in future trials.

‘We are enthusiastic about receiving FDA clearance to start this important clinical trial and with the opportunity it affords us to collaborate with CTCA,’ stated Dr. David Berd, Chief Medical Officer of AVAX. ‘Clearly, better treatments for ovarian cancer are needed and we hope that OVax will eventually find its place as a relatively non-toxic therapeutic alternative for these patients. This alliance with CTCA will allow us to expand the therapeutic utility of the AC Vaccine platform along with our ongoing Phase I/II program in non-small cell lung cancer and our recently launched Phase III pivotal registration study in melanoma (MVALDI).’

As part of the business collaboration CTCA has made an up-front payment of $250,000 and will begin to make monthly payments of $25,000 upon the initiation of production of vaccines at AVAX’s Philadelphia manufacturing facility.

‘We are very excited to be part of a new chapter in the fight against ovarian cancer,’ said Dr. Edgar Staren, Chief Medical Officer at Cancer Treatment Centers of America. ‘Ovarian cancer is a very complex cancer that is often resistant to chemotherapy, radiation and surgery. At Cancer Treatment Centers of America, our commitment to cancer patients is to help fight their cancer with the most advanced medical technology available. This partnership with AVAX gives hope to ovarian cancer patients who are told far too often that there is nothing more that can be done for them. This treatment option will work well with our unique integrative care model that combines state-of-the-art traditional medicine with scientifically-based complementary therapies such as aggressive nutritional management and support, naturopathic medicine, physical therapy, mind-body medicine and spiritual support to go beyond treating the tumor and supporting the needs of the whole person – all under one roof.’

About the AC Vaccine Therapeutic

The AC Vaccine is an immunotherapy prepared by attaching a small chemical to the patient’s tumor cells in a process known as haptenization. This hapten modification allows the tumor cells to stimulate a T cell-based immune response to a patients own tumor cells. An early indicator of T cell immune activity is Delayed Type Hypersensitivity (DTH).

An understanding of what AVAX calls the immunopharmacology of the AC Vaccines is critical to their effective use. AVAX believes that the optimal dose, schedule of administration, and route of administration of human cancer vaccines must be established before they enter advanced phase studies, and that some competing vaccine technologies have failed because their developers ignored one or more of these parameters in early phase development. The optimum schedule and best route of administration (intradermal) to be used for OVax were determined by extensive phase I-II studies of MVax. The latest phase I-II trial was completed last year and the results will be presented at the 2008 [Annual] meeting of the American Society of Clinical Oncology (ASCO).”

[Quoted Source: “AVAX Technologies Announces Initiation of Clinical Study with Autologous Ovarian Cancer Vaccine (OVax®),” BusinessWire news release dated April 9, 2008.]

Comment: The OVax®vaccine clinical trial carries great promise. The trial will combine three potent approaches to battling ovarian cancer: (i) debulking surgery, (ii) intraperitoneal chemotherapy with a taxane drug, and (iii) a custom made vaccine created from the ovarian cancer survivor’s own tumor. Please watch the video below regarding the OVax® vaccine for ovarian cancer.

Five Years Later, Patient Participating in Vaccine Trial Remains Free of Ovarian Cancer

“Like most women with ovarian cancer, 44-year-old Christine Sable of Lancaster, Pennsylvania, did not discover she had the disease until it was in the advanced stages and had spread to other areas of the abdomen. ‘I knew my chances of recurrence were very high-75 to 80 percent at that particular stage-and that the disease would likely recur within a year or two,’she says. ‘Once it recurs, it is difficult to cure.’

After aggressive surgery and chemotherapy, the only other option her doctor could offer was more chemotherapy. But the first round had been ‘very hard,’ Sable recalls. ‘I wanted to find something that would work with my own immune system and not be so harsh on my body.’

Then she learned about a Phase I clinical research study of an ovarian cancer vaccine developed by Kunle Odunsi, MD, PhD, Surgeon in Gynecologic Oncology and Co-Leader of the Tumor Immunology and Immunotherapy Program at Roswell Park [Cancer Institute]. The vaccine is designed to trigger an immune response in the significant number of women who have tumors that test positive for the antigen NY-ESO-1.

The study was open to patients who had completed their initial treatments and who had no further evidence of disease; Sable fit the profile. She says the day she was accepted into the study was ‘one of the most exciting days of my life.’ She began treatment at Roswell Park in February 2004, and her immune system responded so strongly to the first five doses of vaccine that she received another five, then another five, each time experiencing a better response-with no side effects. Now 49 and still cancer-free, she returns to Roswell Park just once a year for continued monitoring.

Odunsi is currently leading a team of Roswell Park researchers who are working to improve the vaccine’s effectiveness. The vaccine is an important new focus in the search for better treatments for ovarian cancer, which is often difficult to treat. Sable says participating in the trial ‘was a very good experience; I was very well cared for. Dr. Odunsi is a gentle, kind man, brilliant and dedicated and very compassionate.’ In May of 2008, Sable will mark the fifth anniversary of her diagnosis and survival. ‘To have had this many years cancer-free is really amazing.’

The study in which she participated was supported by the Cancer Vaccine Collaborative Program of the Cancer Research Institute and Ludwig Institute for Cancer Research, and results were reported in the … [NY-ESO-1 Peptide Vaccine Phase I Clinical Trial Results, Odunsi, K et. al., Proceedings of the National Academy of Sciences, Vol. 141, no 31, July 31, 2007].” [Quoted Source: Science Daily News Release dated April 7, 2008.]

In March 2008, The Ovarian Cancer Research Fund (OCRF) awarded a $900,000 research grant to Dr. Odunsi and his colleagues at the Roswell Park Cancer Institute (RPCI) to fund a collaborative study with the stated goal of developing a promising vaccine to unleash the power of the immune system against cancer. The prestigious award will allow Dr. Odunsi and the RPCI research team to combine four different immunotherapy approaches, all designed to enhance the immune system’s response to ovarian cancer. [Source: “Roswell Park Cancer Institute awarded three-years funding for ovarian cancer vaccine,” a News-Medical.Net News Release dated April 7, 2008.]

Comment: Vaccine or immunotherapy can play an important role in an ovarian cancer survivor’s overarching treatment strategy. This aspect of treatment is often overlooked. It is important to be aware of the availability of vaccine therapy as early as possible in treatment because most clinical trials utilizing vaccine therapy require an extremely low disease “tumor burden” or no (macroscopic) evidence of disease as a prerequisite for patient eligibility. Low tumor burden or no evidence of disease is generally present immediately after chemotherapy treatment(s) resulting in “complete remission,” and/or surgery resulting in “optimal debulking/cytoreduction.” Christine Sable is an excellent example of an ovarian cancer survivor who is proactively managing her care through enrollment in a beneficial clinical trial.

The Roswell Park Cancer Institute, as of this writing, is currently recruiting Stage II through IV ovarian cancer participants for a Phase II vaccine clinical trial involving the use of “Recombinant Vaccinia-NY-ESO-1 (rF-NY-ESO-1) and Recombinant Fowlpox-NY-ESO-1 (rF-NY-ESO-1) in Patients With Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma Whose Tumors Express NY-ESO-1 or LAGE-1 Antigen.” For more information with respect to this clinical trial, contact the Roswell Park Cancer Institute Clinical Trials Office at 877-275-7724.

I encourage you to watch the video segment below which addresses Christine Sable’s case, including an interview with Kunle Odunsi, M.D., Ph.D.., the Co-Leader of the Tumor Immunology and Immunotherapy Program at Roswell Park.

MediaSourceTV Video Segment Re

Christine Sable and Roswell Park Cancer Institute Clinical Trial Vaccine Program