“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

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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.

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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. 

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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.

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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.

World Cancer Day 2013: Dispelling Myths & Misconceptions About “The Enemy Within”

1.5 million premature cancer deaths could be prevented each year if targets set to reduce non-communicable diseases are met by 2025.  Today, on World Cancer Day, the Union for International Cancer Control and the International Agency for Research on Cancer reveal the real life impact of achieving this goal.

World Cancer Day 2013

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“… 1.5 million people saved from an early death due to cancer is equal to the entire populations of Philadelphia, Auckland, Barcelona or Maputo each and every year.”

World Cancer Day is the one initiative under which the entire world can unite in the fight against the global cancer epidemic.It takes place every year on February 4th. World Cancer Day aims to save millions of preventable deaths each year by raising awareness and education about cancer, and pressing governments and individuals across the world to take action against the disease.

World Cancer Day is an initiative of the Union for International Cancer Control (UICC), a leading international non-governmental organization dedicated to the prevention and control of cancer worldwide. Founded in 1933 and based in Geneva, UICC’s growing membership of over 765 organizations across 155 countries, features the world’s major cancer societies, ministries of health, research institutes, treatment centers, and patient groups. Additionally, the organization is a founding member of the NCD Alliance, a global civil society network that now represents almost 3,000 organizations in 170 countries.

Target “25 by 25:” Reduce 25% of Premature Non-Communicable Disease Deaths by 2025

The UICC and the International Agency for Research on Cancer (IARC) today announced that 1.5 million lives which would be lost to cancer, could be saved each year if decisive measures are taken to achieve the World Health Organization’s (WHO) “25 by 25” target; to reduce premature deaths due to non-communicable diseases (NCDs), including cancer, by 25% by 2025.

Currently, 7.6 million people die from cancer worldwide every year, out of which, 4 million people die prematurely (aged 30 to 69 years). So unless urgent action is taken to raise awareness about the disease and to develop practical strategies to address cancer, by 2025, this is projected to increase to an alarming 6 million premature cancer deaths per year.

“The estimate of 1.5 million lives lost per year to cancer that could be prevented must serve to galvanize our efforts in implementing the WHO’s ‘25 by 25’ target,” said Dr.  Christopher Wild, Director of IARC. “There is now a need for a global commitment to help drive advancements in policy and encourage implementation of comprehensive National Cancer Control Plans. If we are to succeed in this, we have a collective responsibility to support low- and middle-income countries who are tackling a cancer epidemic with insufficient resources.”

The 1.5 million lives lost per year represent 25% of the estimated 6 million premature cancer deaths that will occur by 2025, and the 6 million figure is itself based on population projections of current numbers and aging.

“Cancer — Did You Know?”

On World Cancer Day, UICC and its members are urging the public and governments alike to speak out with one voice to dispel damaging myths and misconceptions on cancer. Under the theme “Cancer – Did you know?” individuals and communities are encouraged to shed light on four key cancer “myths” and the corresponding “truth” via the UICC World Cancer Day Facebook App.

Myth #1: Cancer is just a health issue.

Truth #1: Cancer is not just a health issue. It has wide-reaching social, economic, development and human rights implications.

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Myth #2: Cancer is primarily a disease of the wealthy, elderly, and developed countries.

Truth #2: Cancer is a global epidemic, affecting all ages and socio-economic groups, with developing countries bearing a disproportionate burden.

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Myth #3: Cancer is a death sentence.

Truth #3: Many cancers that were once considered a death sentence can now be cured and for many more people their cancer can now be treated effectively.

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Myth #4: Cancer is my fate.

Truth #4: With the right strategies, at least 30% of cancer cases can be prevented based on current knowledge.

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Mr. Cary Adams, UICC Chief Exective Officer said:

“This World Cancer Day UICC, its members and partners urge everyone from individuals to governments to take a stand against damaging myths on cancer. By truly understanding this deadly disease, governments can develop appropriate strategies to reduce premature deaths and reach the WHO ‘25 by 25’ goal. The figures today announced by IARC and UICC reveal the fundamental human value of achieving this target. 1.5 million people saved from an early death due to cancer is equal to the entire populations of Philadelphia, Auckland, Barcelona or Maputo each and every year.”

What Can You Do?

In 2008, UICC developed the World Cancer Declaration as a tool to help bring the growing cancer crisis to the attention of government leaders and health policymakers. The 11 Declaration targets, designed to significantly reduce the global cancer burden by 2020, have served as the basis for UICC recommendations to the WHO. This year’s goal — #5 Declaration target — is to dispel damaging cancer myths and misconceptions. The Declaration, with more than half a million signatories, has also been instrumental in generating political will for cancer control targets both at the United Nations and grassroots levels. In close collaboration with the NCD Alliance, UICC played a key role recently in securing WHO’s global health target of a 25% reduction in premature deaths from NCDs by 2025 (known as “25 by 25”), at the World Health Assembly in May 2012 – demonstrating the important role advocacy plays in the global flight against cancer.

To sign the World Cancer Declaration, click here.

To download the World Cancer Day Facebook App, and play your part in reducing the unacceptable burden of cancer, visit https://apps.facebook.com/world_cancer_day.

Review and circulate the cancer truth fact sheets hyperlinked above under the “Cancer — Did You Know?” section of this article.

For more ideas on how you can get involved and take local action against the global crisis of cancer, visit worldcancerday.org.

Understanding Cancer:  “The Enemy Within” Documentary

In the documentary posted below, Vivienne Parry OBE tells the incredible story of our fight against cancer over the last 50 years. Through the eyes of scientists, researchers, and patients, we see how far we have come and how far we have yet to go, including contributions from Professor Robert Weinberg, Professor Umberto Veronesi, Lord Ara Darzi, Cancer Research UK, David Nathan, M.D., Brian Druker, M.D., and many more.

The film is a non-commercial, editorially independent piece of work which has been supported by Cancer Research UK and funded by an educational grant from Roche. The purpose is to educate and inform those who are affected by cancer. It’s now freely available to all who may want to use it, so please feel free to embed on your own websites and share as you see fit.