At City of Hope, we are advancing immunotherapy as an approach to treat and cure devastating illnesses - from conducting innovative research in the laboratory to improving life-saving standard treatments in the clinic. Researchers in the Department of Cancer Immunotherapeutics & Tumor Immunology are pioneering medical science that harnesses the power of the human immune system and results in more powerful, less toxic cures for patients here and around the world.
Immunotherapy, a powerful weapon against cancer because of its potential to exploit the body's natural defenses against infection, has been called the "fourth modality" of cancer treatment by the American Cancer Society. The department’s goal is to make it a highly effective primary treatment option.
Currently, T-cell therapy and radioimmunotherapy offer renewed hope to people who have exhausted other treatment options. They are also effective for eliminating microscopic residual disease which can lead to cancer recurrence, even after chemotherapy, radiation therapy and surgery have been successful.
Peter Lee, M.D., Chair
Dr. Lee seeks to utilize immunotherapy as a less toxic approach to treating patients diagnosed with breast cancer. While many researchers focus on attacking the cancer cell itself, Dr. Lee aims to target the cancer cell as well as its ‘co-conspirators’ - support cells within the tissue stroma and tumor microenvironment. In order to survive, cancer cells recruit and manipulate these support cells, and as a result, a patient’s immune system is destroyed. Right now, Dr. Lee is studying these ‘co-conspirator’ cells to broaden his understanding of their interactions. By gaining a better understanding of the ways these co-conspirators help feed cancer cells, he may be able to develop therapeutics that target both malignant cells and their supporting cells - thereby, restoring and enhancing the immune function in patients with breast cancer.
David Colcher, Ph.D.
Dr. Colcher brings 20 years experience using radiolabeled mAbs, both in vitro and in vivo - in model systems and in numerous clinical studies. He developed a number of antibodies to tumor-associated antigens that are well recognized in the field.
Stephen J. Forman, M.D., F.A.C.P.
An international expert in leukemia, lymphoma and bone marrow transplantation, Dr. Forman helped build City of Hope’s Hematologic Malignancies Program into one of the largest and most successful programs in the world.
Dr. Forman's work also focuses on immune-based therapies for treating malignancies, specifically the potential of augmenting the antitumor response of T cells, the body's immune defense against infection and cancerous cells.
Dr. Kortylewski is studying the intracellular processing of CpG-siRNA to identify molecular mechanisms needed to make the silencing of cancer-causing genes more effective. As a part of this effort, Dr. Kortylewski is broadening his understanding of TLR9, the protein responsible for recognizing pathogens and infectious agents like cancer cells, and then, activating the body’s immune cells against those pathogens. In mouse studies, Dr. Kortylewski demonstrated that the TLR9 protein helps the foreign siRNA therapeutic escape endosomes (which are responsible for moving and sorting proteins throughout the body, specifically plasma) and reach cytoplasm. There, the therapeutic silences overexpressed Stat3 proteins. Dr. Kortylewski now seeks to verify whether TLR9 perform the same function for siRNA in human immune- and cancer cells. The results of this investigation will ultimately help improve the Cpg-siRNA therapeutic for clinical use.
Dr. Yu’s laboratory was the first to validate Stat3, a critical regulator of tumor cell survival and proliferation, as a molecular target for cancer therapy in animal models. Yu's team also discovered the critical role of Stat3 in tumor angiogenesis and tumor immune evasion.
She and her colleagues have devised a novel biologic-based drug called CpG-Stat3 siRNA that strikes a dual blow against cancer. It blocks the growth of tumor cells directly, and activates surrounding immune cells to attack the tumor. This drug takes advantage of two components, which block production of the cancer-promoting and immunosuppressive protein STAT3, and direct the therapy specifically to immune and tumor cells. Importantly, CpG-Stat3 siRNA overcomes the limitations of small molecule drugs, which are difficult to design against proteins such as STAT3 that have no enzymatic activity. It also serves as a unique therapeutic platform, as the siRNA can be designed to block virtually any protein of interest that is important for cancer growth and proliferation. In pre-clinical studies, CpG-Stat3 siRNA effectively stymies growth of aggressive lymphomas and the brain cancer glioma, two deadly cancers with no current viable therapies. A clinical grade CpG-Stat3 siRNA is scheduled to begin production at City of Hope’s facilities this year, and Dr. Yu and her colleagues are poised to take this leading-edge therapeutic strategy to first-in-human clinical trials within two years.
Identifying the Connection between Stat3 and Diabetes - It has long been established that obesity is a major cause of type 2 diabetes, due in part to specific cells in fat tissue that promote pathogenic T cells and blunt the activity of insulin. Dr. Yu is exploring the connection between Stat3 and the development of diabetes. In efforts to learn more about this potential link, her lab has used genetically-engineered mice whose T cells lack the Stat3 gene. When these mice became obese through forced consumption of a fatty diet, they showed better glucose tolerance compared with comparably overfed normal mice, as well as a shift in the balance of pathogenic T cells toward regulatory T cells. These intriguing findings suggest that Stat3 is common to both cancer and diabetes and suggest that anti-Stat3 therapies, which have thus far been considered primarily for cancer, might also be effective against type 2 and perhaps type 1 diabetes.
The cellular immunotherapy program, led by Dr. Stephen J. Forman, Clinical Manager, Department of Cancer Immunotherapeutics & Tumor Immunology, develops innovative treatments that reduce the need for harsh radiation and chemotherapy. One of the most exciting programs underway at City of Hope, Cellular Immunotherapy is developing technology to take T-cells from a cancer patient and reprogram them through genetic engineering to target and eradicate the patient’s cancer.
Using pioneering technology, we have been able to isolate immune cells from a person’s blood sample and then engineer them to express an artificial receptor that will seek out and attack cancer cells. Our researchers then grow billions of identical, reprogrammed T-cells outside the body and re-infuse them into the patient, where they go to work eliminating the cancer.
City of Hope had the first-ever FDA-authorized clinical trials using reprogrammed T-cell therapy for lymphoma, neuroblastoma and glioma. Additionally, we have exported this technology to other medical and research centers and actively share our advancements through close collaboration.
City of Hope is a national leader in cancer immunotherapeutics and tumor immunology research, with an infrastructure unmatched by any other biomedical institution in the United States:
City of Hope is a pioneer in cancer radioimmunotherapy, a therapeutic strategy in which radiation is targeted to tumors using monoclonal antibodies. City of Hope received a National Cancer Institute grant to support trials to evaluate radioimmunotherapy of colorectal, breast and lung cancers. The quality of our research in the field of molecularly engineered antibodies is reflected by 11 years of National Cancer Institute (NCI)-supported grants.
City of Hope is the only institution with four FDA-authorized clinical trials using genetically reprogrammed T cells; and the first institution to use re-engineered T cell therapy for lymphoma, malignant brain tumors, and for neuroblastoma in children. Researchers were also able to prototype the zetakine chimeric receptor in human clinical trials, which arms us with a new way to target T cells to cancer cells, and expands potential targets from tens to hundreds.
City of Hope offers more clinical studies than any other facility of our size in the nation, with 30 to 40 percent of our patients enrolled in clinical trials at any one time — the national average is less than 5 percent. . This extensive institutional infrastructure for clinical trials maximizes patient safety and the acquisition of information.
City of Hope received a five-year, $11.5 million Specialized Program of Research Excellence (SPORE) grant from the NCI to fund translational research studies that focus on lymphoma, including an emphasis on immunotherapy.
The largest freestanding biologic production facility in the nation, the Center for Biomedicine & Genetics, allows researchers to bypass pharmaceutical and biotech corporations to speed the development of viral vectors, DNA plasmids, and engineered and customized cellular products for phase I and II clinical trials.
Close collaborations with other centers add value to the advances made at City of Hope and capitalize on sharing expertise and capacity with our academic peers such as Baylor University, Memorial Sloan-Kettering, Mayo Clinic, University of Pennsylvania, Johns Hopkins University and the Fred Hutchinson Cancer Research Center.
Molecular immunotherapy, a collaboration between Drs. Andrew Raubitschek andStephen J. Forman,supports and enhances the other cancer immunotherapy programs through the genetic engineering of biological products. In particular, this area of research is pioneering the science of creating “designer” proteins, which fuse two types of molecules — one that seeks out the tumor and one that triggers the immune system to attack the cancer.
These pharmaceutical-grade proteins are currently being used for clinical trials at City of Hope, including a study utilizing an antibody directed against non-Hodgkin’s lymphoma, as well as at collaborating institutions throughout the nation. Their potential uses range from boosting patients’ immune response to controlling the proliferation of engineered, exogenously administered cells.
Two additional immunofusions are being evaluated for patient studies; one directed against melanoma/neuroblastoma and the other directed against a common antigen in breast, lung, colon and prostate cancer. In addition, a group of investigators has been exploring the concept of immunizing patients with DNA to elicit an immune response against an altered protein that is associated with the malignant transformation of normal cells.
Dr. Andrew Raubitschek’s work in this ground-breaking area of medicine has resulted in new treatments - and new hope - for cancer patients. Radioimmunotherapy attaches radioactive isotopes to genetically engineered monoclonal antibodies (mAbs), which carry the radiation directly to tumor cells. A major advancement has been the identification of the carcinoembryonic antigen (CEA) in more than 60% of colorectal, breast, and lung cancers. We have developed technology that utilizes anti-CEA antibodies for imaging and therapy.
Among the patients benefiting from this technology are those receiving bone marrow transplants (BMT), who currently receive total body irradiation (TBI) in combination with high-dose chemotherapy as part of their treatment. Though intended for the patient’s cancer, TBI affects the entire body and causes harsh side effects. Radioimmunotherapy offers a more targeted treatment by focusing radiation on the cancer while only minimally affecting surrounding tissues. These efforts have led to the development of a variety of molecularly engineered antibodies, culminating in clinical trials.
Our radioimmunotherapy program is investigating a new area of medicine that combines radiation and immune therapy using monoclonal antibodies to:
Locate cancer within the body, known as radioimmunoimaging (RII) and
Treat cancer, called radioimmunotherapy (RIT).
RII uses a radioactive material attached to specially designed antibodies to locate cancer within the body. Antibodies are naturally produced by the body's immune system. They are normally used to fight infections caused by bacteria and viruses. The antibodies used in RII are monoclonal antibodies (MAbs). These antibodies are developed in the laboratory and recognize substances on the surface of tumor cells. These antibodies are further "engineered" in the laboratory to improve their efficacy. The MAbs are then modified to bind radioactive metals (Indium-111 or Copper-64) or radioactive iodine (Iodine 123, Iodine 131, or Iodine 124) which can be visualized with a special camera in Nuclear Medicine. Images from these cameras show areas where the MAbs have localized in the body.
RIT uses the same MAbs for therapy but switches the radioactive metal to Yttrium-90, which delivers higher levels of local radiation to the tumor. The radiolabeled MAb is administered through a vein and then circulates through the body to the surface of tumor cells. The tumor cells are destroyed by the radiation given off from the localized radiolabeled MAbs.
Three different antibodies are being used in our current clinical trials. One binds carcinoembryonic antigen (CEA), a tumor antigen found in certain patients with breast, colon, lung, thyroid and ovarian cancers. The second antibody binds to CD20, an antigen found on the surface of certain lymphomas. The third antibody binds to HER2 (human epidermal growth factor receptor 2) which is overexpressed in approximately 25% of breast cancer patients.
City of Hope pioneered immunotherapy with groundbreaking work in bone marrow transplantation. Within our Beckman Research Institute, we also developed the genetic processes for rendering monoclonal antibodies (mAbs) more effective in fighting cancer, processes critical for making products such as Avastin, Erbitux, Herceptin and Rituxan. Poised to maximize our world-class expertise, CITI's focus is on six key areas:
Radioimmunotherapy: using genetically engineered mAbs to carry radioactive isotopes directly to tumor cells. City of Hope pioneered radioimmunotherapy when researchers developed an antibody recognizing a marker on the surface of cancer cells and used it to target tumors.
Cellular Immunotherapy: genetically reprogramming immune cells to seek out and destroy specific cancers. We were the first to conduct Food and Drug Adminstration-authorized clinical trials with genetically reprogrammed T cells for lymphoma, neuroblastoma and glioma.
Molecular Immunotherapy: "designer" proteins that fuse two molecules — one that seeks out the tumor and another that triggers the immune system to attack it. CITI researchers were the first group to apply this technology to lymphoma treatment, with clinical trials beginning in 2006.
Vaccine Immunotherapy: vaccines targeting the p53 protein that result in elimination of cancers by supercharging the body's immune system. CITI scientists are at the forefront of developing and testing new p53-targeted vaccines against breast, prostate, lung and gastrointestinal cancers.
Tumor Immunology: studying the mechanisms tumors use to evade the immune system. In one example at City of Hope, researchers hope to target Stat3, a powerful protein found in 60 percent of cancer cells. Stat3 not only has the ability to control cell growth — and as a result, tumor growth — but it also helps cancer cloak itself from immune cells and may even disable the immune system itself.
Lymphoma (SPORE Grant): City of Hope has been awarded the Specialized Program of Research Excellence (SPORE) grant by the National Cancer Institute (NCI) for translational research studies for Hodgkin’s and non-Hodgkin’s lymphoma. The Lymphoma SPORE grant brings together a number of investigators across four projects, one of which investigates the use of radioimmunotherapy to specifically seek out and destroy malignant cells.
Drs. Richard Jove and Hua Yu are pioneers in the understanding of the function and possible therapeutic targeting of Stat3, a protein essential to regulating cell growth. In ground-breaking research, Dr. Jove found that under normal circumstances, Stat3 “turns on and off” as needed to stimulate the normal growth of cells. However, in cancer cells, Stat3 remains turned on and stimulates unregulated growth in tumors.
Dr. Yu proved that Stat3 is a promising target for cancer therapy, and in laboratory studies has shown that it can be safely blocked in the entire hematopoietic system. Her research has also found that Stat3 serves as a cloak, keeping the immune system from detecting the tumor cells and allowing the cancer cells to continue growing. In laboratory studies she has blocked Stat3 and found that this causes the immune system to recognize and attack the tumor cells. Ongoing research is devoted to understanding the complexities of Stat3, its structure, mechanisms and effects so that drugs can be developed for use in patients that will specifically target it, shut it off and stimulate the immune system to kill the cancer.
Because Stat3 is found in approximately 60 per cent of all cancer cells, (including virtually all breast cancers), targeting this molecule may provide a broadly applicable and highly effective therapy that could treat many cancers without the need for chemotherapy or radiation.
Research, led by surgeon Dr. Joshua Ellenhorn, is exploring a vaccine that could kill solid cancer tumors by supercharging the body’s immune system. About half of all cancer is the result of a mutation that turns off a cell’s ability to regulate growth, resulting in rapid growth of the solid tumors responsible for the most common forms of lung, breast, prostate and colon cancer.
P53 is a naturally occurring protein that is overabundant in tumor cells. Dr. Ellenhorn’s lab is developing a vaccine that targets this over-expression by stimulating the body’s immune system to attack the p53 protein and the cancer cells in which it is over-expressed. Already, researchers are moving to the next step of preparing and evaluating the vaccine for human cancer patients a few years from now.
City of Hope’s research into the relationship between breast cancer and p53 has garnered an NIH grant to develop a vaccine based on this research. While much of the current cancer vaccine research in people focuses on individualized vaccines, this is the first that suggests a more generalized approach could be
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