- Personalized Immunotherapy: Attacking Prostate Cancer with Improved T Cell Engineering
- Clinical Testing of the Radiolabeled Anti-PSMA Antibody J591 in Patients with Non-Metastatic Castrate Resistant Prostate Cancer
- Improving Therapy for Advanced Prostate Cancer Using Nanoparticle-driven Drug Delivery
- The Prostate Cancer Biorepository Network (PCBN): A Valuable Resource for Prostate Cancer Researchers
- Detection of Prostate Cancer with a Non-Invasive Blood Assay
Personalized Immunotherapy: Attacking Prostate Cancer with Improved T Cell Engineering
Posted April 30, 2013
Christopher Kloss, Weill Medical College of Cornell University
Invasion of the body by harmful foreign bodies, such as bacteria and viruses, triggers an immune response that signals an attack and removal of the "non-self" invader. Cancerous cells can also be invaders of the body, but because of their origination from normal cells, the same immune response is not triggered, thereby allowing cancer cells to grow unchecked and eventually metastasize. Researchers believe that harnessing the ability of our immune system to specifically recognize and remove cancer cells would serve as a very potent therapy for prostate cancer patients. Under the mentorship of Dr. Michel Sadelain at Memorial Sloan Kettering Cancer Center, Christopher Kloss, a PhD student at Weill Medical College of Cornell University and a Predoctoral FY10 Prostate Cancer Training Award recipient, has been investigating a new method for engineering a patient's own T cells to target their prostate cancer.
Clinical trials have already showed promise with the method of engineering T cells to express a single artificial receptor that targets the T cells to cancer cells; however, this method is still not specific enough to prevent the T cells from also targeting normal cells. To solve this problem, Mr. Kloss engineered human T cells to express two artificial receptors instead of just one; one that induces CD3zeta signaling and a second that induces CD28 and CD137 signaling. This allows the T cells to target two antigens associated with the cancerous cells for their elimination while sparing normal cells that might express neither or either protein alone. The results from this study were recently published in Nature Biotechnology.
The ultimate goal would be to translate these findings into clinical trials for patient benefit. Similar studies in other cancer types have cured some patients, so this type of therapy shows great promise for prostate cancer treatment. However, it will likely be a challenge to make personalized medicine a cost effective therapy for patients. Mr. Kloss' career goals therefore extend beyond prostate cancer research to finding ways to make these therapies a reality. He plans to pursue an MBA degree once he has obtained his PhD from Cornell University so that he can become a more integral part of facilitating mergers between business and academia to support the trials and infrastructure necessary to make these personalized therapies a reality for patients.
T cells with dual artificial receptors (chimeric antigen receptors, or CARs) are shown attacking other cells. Only cells with both tumor antigens (A and B) are eliminated.
References:
Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. 2013. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nature Biotechnology 31:71-75.
Clinical Testing of the Radiolabeled Anti-PSMA Antibody J591 in Patients with Non-Metastatic Castrate Resistant Prostate Cancer
Posted March 20, 2013
Dr. Scott Tagawa, Weill Cornell Medical College
Many men with prostate cancer suffer from biochemical relapse (rising PSA) after surgery and/or radiation. Hormonal therapy can control this state of disease temporarily, but most men will continue to have PSA levels that continue to rise. This state represents micro-metastatic disease, meaning tiny tumors that are in the body but too small to see by traditional imaging (CT, MRI, or bone scans). To address this, and to also address the need for better treatments for advanced prostate cancer, Dr. Scott Tagawa, using support from his FY08 PCRP Clinical Trial Award, has collaborated with a research team led by Dr. Neil Bander at Weill Cornell Medical College to develop an antibody, called J591, which specifically recognizes prostate specific membrane antigen (PSMA), allowing prostate cancer cells to be targeted in a very specific manner.
PMSA is a cell-surface protein expressed by the vast majority of prostate cancer cells and generally not present elsewhere in the human body. By attaching J591 to a tiny radioactive particle (177Lu), a small amount of radiation is delivered to the cancer cells and can be used for treatment of tumors or for imaging to visualize tumors. The research team has been utilizing J591 in patients with metastatic prostate cancer for over a decade, with success in targeting metastatic tumors and benefitting patients with decreases in PSA, tumor size, and pain symptoms. Their Clinical Trial Award has allowed them to expand on the clinical testing of J591 through a multi-site, phase 2 clinical trial combining hormonal therapy with targeted J591 radiation, bringing the radiation particle to unseen tumors. They are also testing to see if a specialized type of a scan using the radiolabeled antibody can visualize these small sites of cancer that can't be seen on standard scans.
To date, the trial has opened at various sites across the country and has shown that some of the men with non-metastatic prostate cancer treated with 177Lu-J591 have benefitted in terms of PSA reduction, with good tolerance to the treatment. It is hoped that the treatment will either prevent or delay the onset of metastatic disease. The investigators have leveraged the funds from the PCRP clinical trial award amass a large group of collaborative researchers (see photo) to move this exciting new treatment forward. Plans are underway to initiate a phase 3 study to move radiolabeled J591 closer to possible FDA approval.
Improving Therapy for Advanced Prostate Cancer Using Nanoparticle-driven Drug Delivery
Posted February 21, 2013
Dr. Benyi Li, University of Kansas, Medical Center Research Institute
One of the main limiting factors for effective prostate cancer drugs is toxicity - where normal cells and tissues are damaged by the drugs as well as cancerous cells and tissues, and Dr. Benyi Li of the University of Kansas, Medical Center Research Institute is using support from his FY08 Idea Development Award to address this problem in men with advanced prostate cancer.
Over the past several years, numerous approaches have been under development to target anticancer drugs specifically to only cancer cells so that the drugs can be used at their maximally effective doses. One such approach is the use of nanoparticles, which can carry drugs and release them for activity only upon nanoparticle contact with cancer cells. Dr. Li, a prostate cancer physician-scientist, in collaboration with Dr. Laird Forrest, a pharmaceutical chemist expert in nano-scale delivery of therapeutics, has been working to develop such agents for targeted therapy of prostate cancer and specifically targeting castration-resistant prostate cancer. This advanced form of prostate cancer, which typically progresses to lethality, arises in some men after hormone therapy that is given to limit the growth and progression of the disease. For these patients, treatment beyond hormone therapy is necessary, and so Drs. Li and Forrest's groups created a nanoparticle that targets a protein called PSMA, which is increasingly expressed on prostate cancer cells as they progress to more advanced stages. This nanoparticle could therefore deliver drugs specifically to advanced prostate cancer, sparing normal cells and tissues. Since Dr. Li's previous work had showed that the protein PI3K-p110beta plays a critical role in prostate cancer development and progression, he chose to load their PSMA-targeted nanoparticle with the pro-drug BL05, which is derived from TGX-221, a small chemical that specifically inhibits PI3K-p110beta activity and thus would be predicted to block tumor growth. The BL05-loaded nanoparticle was tested in a mouse model, where it completely abolished the growth of both hormone-sensitive and hormone-resistant tumors, indicating significant promise for further development of the agent. Dr. Li plans to continue developing the BL05-loaded nanoparticle, as well as other nanoparticle-driven approaches to targeted therapy (such as specifically delivering small interfering RNA against the androgen receptor in prostate cancer cells, also supported by the DoD PCRP), with the goal of eventually conducting clinical trials that would bring new and less toxic options for therapy to patients with advanced prostate cancer.
The Prostate Cancer Biorepository Network (PCBN): A Valuable Resource for Prostate Cancer Researchers
Posted February 7, 2013
Bruce J. Trock, PhD, Johns Hopkins University
Jonathan Melamed, MD, New York University
The Prostate Cancer Biorepository Network (PCBN), supported by the Department of Defense (DoD) Prostate Cancer Research Program (PCRP), is working toward meeting a critical need in prostate cancer research - the need for human tissues and other biospecimens.
To reduce or eliminate the impact of prostate cancer, researchers need a better understanding of the disease so that new approaches to preventing or treating it can be achieved. Advancements in understanding the disease occur primarily through discoveries made at the basic science, translational, and clinical levels. To bring to patients these discoveries, such as identification of a novel biomarker for detection or diagnosis, a critical component is to determine the relevance of the findings by studying them in human tissues. Unfortunately, there is currently a major roadblock to this in that many researchers do not have access to prostate cancer patient populations and high-quality human tissues, limiting their ability to translate their discoveries into improvements for patients. This critical need for providing high-quality prostate cancer biospecimens to the research community was a focus of discussion during the Fiscal Year 2009 DoD PCRP Vision Setting meeting, and led to a new award mechanism that would support a pilot effort to begin addressing this need. Thus, the Prostate Cancer Pathology Resource Network Award was openly competed and ultimately awarded in June 2010 to the Johns Hopkins University (JHU) and the New York University (NYU) Schools of Medicine for a total investment of approximately $3.2 million, and the PCBN was initiated.
Johns Hopkins University entered into the collaboration with the dual role of being both a Pathology Resource Network Site, with the task of contributing specimens, and the Coordinating Center, led by Dr. Bruce Trock. With the combined efforts of investigators at the NYU site (Dr. Jonathan Melamed, Principal Investigator, and Dr. Peng Lee) and other prominent pathologists at JHU (Drs. Angelo De Marzo and George Netto), the PCBN has utilized PCRP support to facilitate the development of a biorepository whose goal is to facilitate the collection, processing, storage, and distribution of high-quality, well-annotated prostate cancer biospecimens. To date, the specimens available in the PCBN include tissues from prostatectomies (formalin-fixed, paraffin-embedded and fresh-frozen), tissue microarrays (TMAs), body fluids (serum, plasma, buffy coat, prostatic fluid), and derived specimens such asDNA and RNA. Importantly, a large subset of the specimens in the PCBN are also linked to clinical, pathological, and outcome data, and are supported by an informatics infrastructure with the capability to deposit data into currently available systems at the respective institutions. In addition, the PCBN actively investigates improved methods for obtaining, processing, and derivatizing biospecimens, and the impact of such methods on biomarker research. The PCBN website (http://prostatebiorepository.org) provides additional information regarding access to samples for the research community.
Both the DoD PCRP and the PCBN work with additional subject matter experts, including patient advocates, who help to provide critical input for the overall direction of the PCBN. These efforts have helped to produce specific policies and procedures for requesting biospecimens, including review criteria for applications, collaboration requirements for certain types of specimens, and the preservation of confidentiality and intellectual property. The PCBN investigators continually reach out to scientists at national scientific meetings and other venues in an effort to publicize the availability of this valuable resource. One such focused effort is a workshop being held on February 13, 2013 for biorepository experts and leaders in prostate cancer research to come together to discuss topics that will facilitate the use of PCBN biospecimens in the most important areas of prostate cancer research, such as understanding and preventing metastatic disease.
Over 400 samples including TMAs (including those for race-disparity or metastasis studies), DNA, RNA, protein, serum samples, and paraffin sections have been delivered thus far to the scientific community and are producing results that are being published in peer-review journals. In one particular study, PCBN samples enabled urologists at Johns Hopkins to discover that reduction of a specific protein is correlated with the aggressiveness of the disease, acting as a red flag to indicate an increased risk of cancer recurrence. Their study, reported in the Proceedings of the National Academy of Sciences on Aug. 27, 2012, focused on a gene called SPARCL1, which appears to be critically important for cell migration during prostate development in the embryo and becomes active again during cancer progression1. Their findings should allow physicians to not only pinpoint those patients whose cancers are destined to return after surgery, but could also reveal potential new options for treatment.
It is the hope of the DoD PCRP and the PCBN investigators that this resource will continue to gain in utility for the prostate cancer research community, and will continue to enable discoveries toward achieving the PCRP vision of conquering prostate cancer.
Publications:
1. Hurley, PJ et al. Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome. PNAS Sept, 109(37):14977-14982.
Detection of Prostate Cancer with a Non-Invasive Blood Assay
Posted January 24, 2013
Dr. Amin I. Kassis, Harvard University
The prostate specific antigen (PSA) is the primary marker used for the early detection of prostate cancer. However, the high frequency of false-positives and false-negatives and the inability to differentiate between aggressive and non-lethal forms of cancer has led to extensive over-treatment, making improved methods for the early detection of prostate cancer greatly needed. Dr. Amin I. Kassis and his research group at Harvard University received a FY08 Idea Development Award to support their development and testing of a new, non-invasive genomic assay for the early detection of prostate cancer using blood samples.
The genomic assay relies on the presence of tumor cells that have been shed into the body's circulatory system, called circulating tumor cells (CTCs). Since most of these CTCs undergo programmed cell death, Dr. Kassis hypothesized that the removal of such cells from circulation by phagocytic white blood cells will lead to the expression of prostate cancer-specific signatures by these cells. The subsequent assay developed by Dr. Kassis' group was able to successfully differentiate, with 100% accuracy, between mice with prostate cancer and those without. Furthermore, since these gene signatures were undetectable in the blood of mice that had their tumors surgically removed, the assay can readily and accurately monitor therapeutic efficacy.
Dr. Kassis currently has multiple U.S. and world-wide patents pending for the new assay. Additional funding support from an NIH Challenge Grant enabled him to show that the assay is able to detect the gene signatures in cancer patients with high accuracy (>99%). The technology has now been licensed to Cell MDx, Inc., through which the diagnostic potential of the assay will be tested in larger numbers of prostate cancer patients. Dr. Kassis also noted, "We strongly believe that the blood assay we have been developing will have an unprecedentedly high impact on, and contribute significantly to, the goal of early detection and eradication of prostate cancer in the U.S. and worldwide. I am most grateful to the DoD PCRP for their willingness to fund a highly risky idea. Without their support, I seriously doubt that this technology's potential could have been assessed and established."
Diagram of assay used to differentiate gene expression profiles of white blood cells that have or have not cleared (via phagocytosis) prostate cancer cells from the circulation.
