Immune Therapy Program

Transcription

1 Immune Therapy Program Princess Margaret Cancer Centre One of the top 5 cancer research centres in the world. Leading the way with the most comprehensive Immune Therapy program in Canada.

2 Leading the Way in Immune Therapy for Cancer Overview The Immune Therapy Program at the Princess Margaret Cancer Centre draws from the basic science and clinical strengths of one of the top 5 cancer research centres in the world. Led by an award-winning team of researchers and physicians, The Princess Margaret is positioned to become one of the global leaders in Immune Therapy for cancer treatment. This program is the most comprehensive Immune Therapy Program in Canada. This report provides an overview of our program and addresses the following: Section I: The Immune System and Cancer (Page 3) To appreciate the power of Immune Therapy, it is important to begin by understanding the immune system itself and the relationship between cancer and the immune system. Section II: What is Immune Therapy? (Page 6) Immune Therapy is based on the principle of using the body s own immune system to combat disease. Immune Therapy is not just one type of treatment; it includes a variety of strategies. Section III: Immune Therapy at The Princess Margaret (Page 7) The Princess Margaret has invested in the development of a broad spectrum of Immune Therapy treatments in order to benefit the widest range of patients. This section discusses a few examples of the top quality care we deliver to our patients by translating the science of cancer and immunology into practice. Section IV: What is the future of Immune Therapy? (Page 14) There is enormous momentum in the field of Immune Therapy. Supporting our Immune Therapy Program will ensure that our patients continue to benefit from leading-edge breakthroughs. Section V: Why is The Princess Margaret positioned for success? (Page 15) The success of the Immune Therapy Program is due to our deep knowledge base and cuttingedge expertise in clinical trials, as well as valuable partnerships with external centres. Section VI: Who are the leaders in Immune Therapy? (Page 16) Our award-winning team of researchers and clinicians are leading contributors to the field of Immune Therapy. The Princess Margaret strategically supports different areas of cancer research such as Immune Therapy in order to provide patients with access to state-of-the-art therapies. We believe that the best clinical treatments for curing cancer will be achieved by combining different cancer treatments. The Princess Margaret Cancer Foundation Page 2

3 Section I: The Immune System and Cancer What is the immune system? In order to understand the power of Immune Therapy for cancer, it is helpful to know how the immune system works. The immune system exists to protect our bodies from disease-causing germs, such as viruses and bacteria. This complex and remarkable defense network can be broken into two categories: the innate immune system and the adaptive immune system (shown in Figure 1). Each system is made up of different types of cells and molecules. The innate immune system is important as a first line of defense against germs. It plays an important role by alerting and initiating the adaptive immune response. However, this first line of defense does not provide long-lasting protection against foreign invaders (or organisms) or tumours. The adaptive immune system is responsible for providing the lifelong immunity that can follow exposure to a disease. As it is exposed to various germs, the adaptive immune system acquires information and is able to remember that it has already encountered these agents so that it can better protect our bodies from similar attacks in the future. Immune therapies for cancer often involve the adaptive immune system because this memory can apply to cancer as well as disease-causing germs. Another advantage of the adaptive immune response is that it can specifically destroy particular targets (germs or cancer cells), while sparing healthy tissues from attack. Innate immune system: First line of defense Rapid response Alerts the adaptive immune system of threats No memory Adaptive immune system: Second line of defense Slower response Mounts a long-lasting response against threats Development of memory Figure 1. Key differences between the innate immune system and the adaptive immune system. One of the key players in the adaptive immune system is the T-cell. T-cells are the chief type of immune cell that can directly attack and destroy cells that are infected with viruses. T-cells can also attack and destroy cancer cells. There are many different sub-types of T-cells, each of which bears their own unique T-cell receptor on their cell surface. Each T-cell receptor has the unique ability to recognize different things. For example, some T-cell Receptors recognize parts of viruses, some recognize parts of bacteria, and others recognize abnormalities in cancer cells. The discovery of the T-cell receptor by Princess Margaret s own Dr. Tak Mak provided, in many ways, the Rosetta Stone for all subsequent work on the adaptive immune system. Dr. Mak s landmark discovery allowed researchers to define many critical properties of how T-cells develop and function, which provided new ways to treat diseases including cancer. The Princess Margaret Cancer Foundation Page 3

4 By continuing to invest in research like this, we can develop treatments that will have a greater impact on cancer outcomes in the future. What happens during an immune response? After disease-causing germs enter the body, the immune system leaps into action to eliminate them. T-cells are often the key players in this process, which involves a complex series of events. Similarly, in order for T-cells to eliminate cancer cells, the following steps must occur (depicted in Figure 2): Step 1: Alerting T-cells to a threat. In order for T-cells to be effectively activated, a specialized cell type in the innate immune system, the dendritic cell, needs to take a small piece of the germ (or the cancer cell) and display it to T-cells. These small pieces of germs (or cancer cells) are called antigens. The job of the T-cell receptor is to recognize specific antigens present on the surface of dendritic cells. When a T-cell encounters its unique antigen, the T-cell is alerted to the presence of that specific threat to the body and becomes activated. Step 2: T-cell multiplication and attack. After T-cells are activated, they rapidly multiply in the body so that there are many T-cells available to attack the threat. T-cells then work to destroy the cells of the body that are infected with a germ. Once these infected cells are killed off, the germs die along with them. In a similar way, T-cells can work to kill cancer cells. Step 3: End of the T-cell response. Once the threat to the body is gone, excess T-cells that participated in the immune response die off. However, some of these T-cells are converted to memory T-cells and stay in the body. The next time the body is infected with that same germ, these memory T-cells stand ready to rapidly destroy the threat. Therefore, memory T-cells can provide durable, even permanent, protection against foreign invaders or cancer cells. Figure 2. The main steps during an immune response against cancer. Negative regulation: putting the brakes on the T-cell response. The immune system also has the ability to limit the strength or magnitude of T-cell responses. This can be useful in some The Princess Margaret Cancer Foundation Page 4

5 situations. For example, it would be harmful if T-cells that recognize healthy tissues were to become activated and then proceed to destroy healthy tissues; in fact, this is exactly what happens in auto-immune diseases. The body might also be harmed if there are too many T-cells in overdrive, even after germs have been destroyed. There are many types of cells and molecules that act to inhibit the T-cell response, just like the brakes in a car. In the case of Immune Therapy for cancer treatment, however, these brakes are not desirable. Part of Immune Therapy is aimed at discovering ways to release these brakes, so that we can unleash the power of T-cells to effectively destroy cancer cells. The Princess Margaret Cancer Foundation Page 5

6 Section II: What is Immune Therapy? Immune Therapy is based on the principle of using the body s own immune system to combat disease. Although our bodies can attack many of the germs that we encounter, our immune system is often unable to fight cancer by itself. Many people with healthy immune cells are still diagnosed with cancer. Yet, it has been shown that treatments that manipulate the immune system can assist in controlling cancer. As described in Section I, there are many steps during an immune response and many ways that the response can be blocked. Accordingly, a variety of strategies can be used for Immune Therapy. For instance, growth stimulants for immune cells or agents called antibodies can be administered to promote the growth or activity of specific immune cells. Alternatively, tumourkilling immune cells from a patient, such as T-cells, can be multiplied in the laboratory to increase their numbers and enhance their ability to attack cancer cells. These cells can then be given back to the patient. Vaccines are another form of Immune Therapy, in which small parts of cancer cells are used to stimulate the immune system to attack the cancer. T-cells attacking a cancer cell (Source: Mesotheliomalungs.org). The type of strategy (or combination of strategies) that turns out to be the most effective will depend on the type of cancer and the individual patient. Our goal is to carefully evaluate each patient and develop a personalized cancer treatment plan, which would strategically include the most suitable combination therapies. Immune Therapy can also be used in combination with other cancer treatments such as surgery, chemotherapy or radiation therapy. In fact, there is evidence that these combinations may enhance the effectiveness of Immune Therapy. For example, when certain types of chemotherapy kill off cancer cells, this helps specialized immune cells (dendritic cells) to engulf pieces of dead cancer cells and alert T-cells to the threat of cancer. Although Immune Therapy harnesses the body s natural defense mechanisms, it can still have side effects. For example, think of how sick you feel when you get the flu (caused by the influenza virus). The negative side effects that you get are partially due to the virus, but are mostly due to the power of the immune system. However, one of the key features of the immune system is its ability to destroy specific targets, which lowers the risk of collateral damage to healthy tissue. Scientists are dedicated to developing treatments that take advantage of the specificity of the immune system. By contrast, most of today s chemotherapies cannot discriminate between killing off fast-growing cancer cells versus other healthy, fast-growing cells such as blood cells. The Princess Margaret Cancer Foundation Page 6

7 Section III: Immune Therapy at The Princess Margaret The Princess Margaret Cancer Centre has invested in the development of a broad spectrum of Immune Therapy treatments in order to benefit the widest range of patients. This section of the report discusses a few examples of the top quality care we deliver to our patients by translating the science of cancer into practice. First Clinical Trial in Canada of Adoptive T-cell Therapy Drs. Pamela Ohashi, Linh Nguyen and Marcus Butler at The Princess Margaret have recently opened the first clinical trial in Canada using a specific kind of Immune Therapy called Adoptive T-cell Therapy. This type of therapy is currently in clinical trials at select centres around the world and has a track record of success. In Adoptive T-cell Therapy, T-cells from a sample of the patient s cancer are isolated in the laboratory. T-cells that are found right inside tumours often have a built-in ability to kill off cancer cells, but often are too few in number to efficiently kill the tumour. Scientists use growth stimulants to dramatically increase the number of these anti-tumour T-cells, and then transfer them back into the patient. The goal is, in many ways, to provide a larger army (or a larger number of soldiers) to fight the tumour in the hopes of launching a stronger immune attack against the patient s cancer. This process is depicted in Figure 3. Figure 3. The steps involved in Adoptive T-cell Therapy (Source, modified: Genetic Engineering & Biotechnology News). As part of the process of generating a T-cell product in the laboratory, a growth stimulant called IL-2 is used. After the T-cells have been given back to the patient, IL-2 is also administered to the patient to keep the T-cells growing in their body. Adoptive T-cell Therapy shows high rates of cancer regression in centres such as the National Cancer Institute (in Bethesda, MD), MD The Princess Margaret Cancer Foundation Page 7

8 Anderson Cancer Center in Texas, and the Sheba Medical Center in Israel. However, patients often have severe side effects after receiving high doses of IL-2. To address this concern, Drs. Ohashi, Nguyen and Butler at The Princess Margaret have been modifying this approach by using a lower amount of administered IL-2 in a Phase II clinical trial. Adoptive T-cell Therapy is a personalized approach, and the complex technology needed to produce T-cells for clinical use can only be developed in comprehensive cancer centres like The Princess Margaret. Creating Next Generation Artificial Antigen-Presenting Cells (APCs) In some cancers, and in some patients, the type of Adoptive T-cell Therapy described above may not be an option. For example, some tumours may not have any T-cells in them, or the T- cells may not be fit enough to multiply in the laboratory. But what if we could teach new T- cells to attack tumour cells? As innovators in cancer care, researchers at The Princess Margaret are working on this very idea to deliver a solution to this obstacle. Drs. Naoto Hirano and Marcus Butler have Adoptive T-cell Therapy developed a biological tool called artificial This form of Immune Therapy is based on taking APCs. Similar to the dendritic cells described a sample of T-cells from a cancer patient. T-cells in Section I, these artificial APCs can teach that are able to attack tumours are then multiplied T-cells how to recognize and attack cancer in the laboratory. They may also be manipulated cells. This approach was proven by Drs. in the laboratory to improve their tumour-fighting activity. The T-cells are then given back to the Hirano and Butler while they were at Harvard cancer patient. Adoptive T-cell Therapy is a truly Medical School. Once taught, these personalized medicine since the T-cells are educated T-cells were given to patients in a matched to each individual patient. clinical trial of Adoptive T-cell Therapy. No drugs additional were given to the patients during treatment, which meant that patients were able to avoid hospitalization and instead, could be treated safely as outpatients. Drs. Hirano and Butler have brought their expertise to The Princess Margaret to create new and more potent cancer-targeting T-cells that have been educated by specialized artificial APCs. Their first generation of artificial APCs took over five years to develop due to the novelty of the process. With a deeper knowledge base as a result of that earlier work, they anticipate that the second generation of artificial APCs created at The Princess Margaret will only take approximately one year. They are also developing strategies to genetically modify T-cells to help them become tumour-attacking T-cells. Leaders in Treatment Using Checkpoint Blockade What is Checkpoint Blockade? The immune system has developed important ways to control or regulate the immune response, so that it is strong enough to rid the body of invaders without harming normal tissues. At a certain point during an immune response, specific molecular switches are engaged to act like brakes to slow down or stop the immune response. The points at which the brakes are applied are called checkpoints. Another type of cancer Immune Therapy blocks these checkpoints. The Princess Margaret Cancer Foundation Page 8

9 This releases the brakes and gives a go signal so that T-cells can continue to effectively attack the cancer until it is completely gone. This approach is known as checkpoint blockade and has been tested with impressive results as a form of treatment for certain cancers. Worldleading researchers at The Princess Margaret are at the frontier of this approach. In addition to using checkpoint blockade as part of standard treatment at The Princess Margaret, there are a large number of clinical trials for multiple types of cancer being conducted to investigate improvements in the field of checkpoint blockade. Blocking the CTLA-4 molecule One major molecule that acts as a brake on the immune response is called CTLA-4. Researchers have found a way to block the function of CTLA-4, using a monoclonal antibody. Ipilimumab* is a monoclonal antibody drug that specifically blocks CTLA-4. Thus, ipilimumab acts to release the brakes and allows cancer-fighting immune responses to keep going. Dr. David Hogg, Medical Oncologist at The Princess Margaret, co-authored a major paper describing the Phase III clinical trial using ipilimumab that has allowed this approach to move forward into standard clinical practice. Ipilimumab is acknowledged as the first and only treatment clinically proven to extend the lives of melanoma patients. Currently, however, the cost of ipilimumab is only covered if it is given as the second line of treatment for patients. Medical Oncologist Dr. Anthony Joshua and Senior Scientist Dr. Pamela Ohashi are studying ipilimumab in a clinical trial as a first line treatment for patients to help improve the standard of care and further understand which patients would benefit the most from this drug. Medical Oncologist Dr. Marcus Butler was involved with some of the very first ipilimumab Phase I clinical trials. He is about to open a clinical trial testing ipilimumab versus a class of drugs known as interferon, given to patients after their surgery with the aim of preventing the cancer from coming back. In addition, Dr. Naoto Hirano, Scientist at The Princess Margaret, has a track record of success in developing treatments using ipilimumab in combination with Adoptive T-cell Therapy for metastatic melanoma. Researchers at The Princess Margaret are also studying the effects of ipilimumab as a way of treating cervical cancer. Blocking the PD-1 molecule Monoclonal Antibodies Antibodies are molecules that are made in the body by a specific type of immune cell called a B-cell. Antibodies are able to bind to other molecules. Each monoclonal antibody has a unique structure and thus has the remarkable ability to recognize and bind only to its specific corresponding target molecule. Some monoclonal antibodies are used to target and kill certain types of cancers of the blood (lymphoma) or breast cancer; others are used to release the brakes on the cancer-fighting immune response. *The suffix -mab is used to indicate that a drug is a monoclonal antibody. PD-1 is another molecule that acts as a brake on the immune response. T-cells will display PD-1 on their surfaces under different circumstances. Because of this, there are many ways to The Princess Margaret Cancer Foundation Page 9

10 influence the function of T-cells when patients are treated with agents that block PD-1. One particular way is at the site of the tumour. What happens is that, when T-cells with PD-1 molecules on their surface enter a tumour, cancer cells trigger the PD-1 molecule causing the T-cells to shut off. Therefore, even though there are T-cells in the tumour that are capable of recognizing and killing cancer cells, they are paralyzed on the spot. This process is depicted in Figure 4: T-cells receive signals to migrate into the tumour. Cancer cells protect themselves by making a molecule on their surfaces called PD-L1. The PD-L1 molecule on the cancer cells engages PD-1 on the T-cells. The T-cells are shut off and cannot destroy the cancer cells. Figure 4. Flow chart illustrating how the PD-1 molecule acts as a checkpoint molecule, blocking the immune response against cancer cells. In order to prevent the shutdown of the T-cell response, various monoclonal antibodies that disrupt PD-1 activity have been developed. While Immune Therapy is already considered a targeted treatment, blocking PD-1 is even more specific because it selectively targets the immune cells that are attacking the tumour. As a result, strategies based on blocking PD-1 have demonstrated a high rate of tumour regression with a low rate of side effects. One example of a PD-1 monoclonal antibody that Drs. Anthony Joshua and David Hogg are studying is nivolumab. It has shown promising results in lung cancer, one of the deadliest types of cancer. Dr. Joshua has also co-authored an important paper describing another PD-1 blocking drug called MK-3475, which was given to patients with metastatic melanoma. Together with Medical Oncologist Dr. Natasha Leighl, Dr. Joshua has opened a Phase I clinical trial studying the effects of MK-3475 in lung cancer patients. Dr. Marcus Butler is preparing to open a clinical trial investigating a PD-1-blocking drug known as MEDI4736 in melanoma patients, as well as another clinical trial studying the effects of the same drug in patients with melanoma, The Princess Margaret Cancer Foundation Page 10

11 uveal melanoma, lung cancer, liver cancer, pancreatic cancer, triple negative breast cancer, head and neck cancer and gastroesophogeal cancer. Moving Towards Personalized Immune Therapy and Combination Therapies With the recent surge of new types of Immune Therapies, it will be important to evaluate and determine which therapies are appropriate for each individual patient. Because each person is unique and each cancer also develops in a unique way, we expect that successful Immune Therapy strategies will have to be tailored to each person. The Personalized Cancer Medicine platform at The Princess Margaret includes finding targeted treatments for each individual patient. Our researchers are committed to defining a road map that will reveal the optimal strategies for each patient. In order to do this, we must begin to compare different therapies and determine which combinations of therapies work best together. Dr. Marcus Butler will open a clinical trial comparing a PD-1-blocking drug (MK-3475) versus a CTLA-4-blocking drug (ipilimumab) in patients with metastatic melanoma. In a Phase III clinical trial for metastatic melanoma, Dr. David Hogg is investigating the effects of the PD-1-blocking drug nivolumab as a treatment alone and as a treatment in combination with ipilimumab. The purpose of this study is to investigate whether these approaches will extend survival in certain patients compared to treatment with ipilimumab alone. Similarly, Medical Oncologist Dr. Lillian Siu, the Co-Director of the Robert & Maggie Bras and Family New Drug Development Program at The Princess Margaret, has opened a Phase I clinical trial studying nivolumab as a treatment alone and in combination with ipilimumab in patients with renal cancer. Cancer Vaccines The goal of cancer vaccines is to alert T-cells to the presence of cancer and to initiate a strong T-cell response against the tumour. There are different ways that this can be achieved. Dr. Amit Oza, Medical Director of the Cancer Clinical Research Unit at The Princess Margaret, is leading a clinical trial using the vaccine DPX-Survivac for the treatment of ovarian cancer. The design of this trial draws upon Dr. Oza s expertise as Co-Chair of the Gynecology Site Committee of the NCIC Clinical Trials Group and as a member of the Gynecologic Cancer InterGroup. Dendritic cells growing in the laboratory. Dr. Jeffrey Medin, Senior Scientist at The Princess Margaret, has established the expertise to alter viruses so that they can potentially be used as cancer vaccines. Working with Dr. Christopher Paige, Senior Scientist and Vice President of Research at UHN, and Medical Oncologists Drs. Mark Minden and Andre Schuh, Dr. Medin has made viruses which secrete molecules called cytokines which tip off the immune system that cancer cells are present. A clinical trial to test this vaccine in patients with acute myeloid leukemia is currently being designed. The Princess Margaret Cancer Foundation Page 11

12 Another promising cancer vaccine strategy is to use dendritic cells (described in Section I) to display small pieces of cancer cells (called antigens) in order to effectively activate T-cells. In this approach, dendritic cells that display cancer antigens are made in the laboratory using a patient s own blood cells. The dendritic cells are then injected into the patient with the aim of turning on a cancer-fighting immune response in the patient. The Princess Margaret is currently building a team that will be able to produce dendritic cells from individual patients to test as a vaccine strategy. The Princess Margaret Cancer Foundation Page 12

13 Examples of Immune Therapy at The Princess Margaret: A Summary Type of Immune Therapy: Investigators: Description: Adoptive T-cell Therapy Drs. Ohashi, Nguyen, Butler One approach of Adoptive T-cell Therapy relies on extracting cancer-fighting T- cells from a patient s tumour, multiplying them in the laboratory, and then giving them back to the patient. It is a type of personalized medicine using T-cells that are matched to each individual patient. Artificial Antigen- Presenting Cells (aapcs) Drs. Butler, Hirano aapcs can be used to teach a patient s T-cells to develop into cancer-fighting T- cells. These T-cells can then be used in a type of Adoptive T-cell Therapy. Checkpoint Blockade Drs. Butler, Joshua, Hogg, Ohashi, Siu and Leighl Checkpoint blockade uses monoclonal antibodies to release the brakes on the immune response against cancer. Cancer Vaccines Drs. Oza, Medin, Paige, Minden, Schuh Cancer vaccines work by alerting T-cells in the body of a cancer threat and stimulating them to destroy cancer cells. The Princess Margaret Cancer Foundation Page 13

14 Immune Monitoring Laboratory An essential component of any world-class Immune Therapy program is the establishment of an Immune Monitoring Laboratory. Dr. Marcus Butler has established this facility at the Princess Margaret Cancer Centre and is expanding and developing the current expertise with his research team. By monitoring changes in the immune response to tumours in the blood and in tumour biopsies, our researchers can begin to evaluate in detail the responses of each patient to therapy. This process is critical in helping us understand why a given type of therapy does or does not work, and ultimately allows us to predict which drug would be the most effective for each individual patient. The Princess Margaret Cancer Foundation Page 14

15 Section IV: What is the future of Immune Therapy? Unprecedented momentum in Immune Therapy for Cancer Treatment The total number of currently active clinical trials listed by the U.S. National Cancer Institute (NCI) is over 12,000. Of these trials, 3,374 1 involve experimental Immune Therapy treatments. This means that approximately 30% of all active clinical trials currently run through the NCI involve Immune Therapy. Clinical trial phase: Number of trials involving Immune Therapy in each phase 1 : Phase I 1,047 Phase II 2,094 Phase III 443 Phase IV 67 1 As of November 20, 2013 In November 2013, the Society for Immunotherapy of Cancer (SITC) held its 28 th Annual Meeting, with a record number of 1,100 attendees. With the recent landmark achievements in the field of Immune Therapy, and the growing number of immune-based drugs in various phases of testing and standard medical use, Immune Therapy is poised to make a lasting impact in the fight against cancer. The Future of Immune Therapy at The Princess Margaret Accelerating our advancements in immune-based therapies is a top priority for The Princess Margaret. Recent developments in understanding the immune system, including those led by the world-class researchers at The Princess Margaret, make this an area of great promise. As Immune Therapy research becomes more widely studied, it is increasingly important that we empower our team to translate leading-edge Immune Therapy discoveries to clinical patient care as effectively as possible. In order to maintain our position as one of the top 5 cancer research centres in the world and to realize the full potential of our world-class Immune Therapy Program, there are specific areas that we need to invest in: 1) Supporting novel clinical trials that use different strategies to improve the immune response against cancer. 2) Creating teams of experts to comprehensively evaluate the immune response that patients have against cancer. This will be critical to provide a framework to predict which type of treatment will benefit each patient the most. 3) Supporting the development of new ideas that may lead to innovative strategies to improve the immune response against cancer. The Princess Margaret Cancer Foundation Page 15

16 Section V: Why is The Princess Margaret positioned for success? Leading features of Immune Therapy at The Princess Margaret Cutting-edge research expertise spanning from basic immunology discoveries though clinical trials of Immune Therapies. Established technologies to produce various types of T-cells for clinical use that can destroy cancer cells. Dedicated team of researchers for detailed analysis of patients immune responses against cancer. World-class teams to support all aspects of the development and implementation of clinical trials. Access to agents sponsored by the U.S. National Cancer Institute Cancer Therapy Evaluation Program for use in early phase clinical trials. Large patient population size, allowing the evaluation of Immune Therapies in many different types of cancers and individuals. A specialized facility for manufacturing cell products for clinical use under Good Manufacturing Practices (GMP). Participation in a wide variety of industry-sponsored clinical trials. Extensive, proven expertise in drug development and conduct of practice changing trials. Full repertoire of complementary modalities (chemotherapy, clinical genomics, epigenetics) to enable rapid testing of combination therapies. Leveraging our partnership with Immune Therapy across North America In addition to fostering our own leading-edge researchers, the Immune Therapy Program has forged partnerships with numerous external organizations involved in Immune Therapy. These partnerships include: The Cancer Immunotherapy Trials Network (CITN). The CITN is a U.S. National Cancer Institute initiative that allows us to collaborate with member institutions and industry sponsors to advance the progress of Immune Therapy. The Princess Margaret is the only Canadian site in the CITN. The Canadian Cancer Immunotherapy Consortium (CCIC). Dr. Pamela Ohashi was one of the founding members of the CCIC, whose mission is to support the development, advancement and promotion of cancer immunotherapy in Canada. Surgery Branch, U.S. National Cancer Institute (NCI). The technology to produce clinical grade cells for Adoptive T-cell Therapy at The Princess Margaret was established in collaboration with the world-renowned Dr. Steven Rosenberg at the NCI. The Oncology Clinical and Translational Consortium (OCTC): Princess Margaret Cancer Centre is among the six cancer centres worldwide selected by GlaxoSmithKline (GSK) one of the world s largest oncology drug companies as a preferred centre of excellence to accelerate translation of research into new therapies for patients. The Princess Margaret was the only Canadian institution chosen for this important initiative. In forming the consortium GSK The Princess Margaret Cancer Foundation Page 16

17 and The Princess Margaret will gain expertise in anti-cancer therapeutics including targeted therapies and immunotherapies. The Princess Margaret Cancer Foundation Page 17

18 Section VI: Who are our leaders in Immune Therapy? Dr. Pamela Ohashi, PhD, FRSC Director, Immune Therapy Program Co-Director, The Campbell Family Institute for Breast Cancer Research Senior Scientist, Princess Margaret Cancer Centre Expertise: T-cell Activation versus Tolerance, Immune Surveillance of Cancer, Tumour Immune Therapy Dr. Ohashi trained in the laboratory of a Nobel Laureate in Medicine. Her laboratory at The Princess Margaret has made key contributions to our understanding of the immune response against healthy tissues and cancer cells. Dr. Ohashi spearheaded the establishment of the first clinical trial in Adoptive T-cell therapy for cancer in Canada. Dr. Ohashi has received a number of prestigious awards and honours, including the American Association of Immunologists (AAI) Pharmingen Investigator Award, the National Cancer Institute of Canada s William E. Rawls Award, The Canadian Society of Immunology s Investigator Award, as well as a Canada Research Chair. She has also been elected as a member of the Royal Society of Canada, and was selected to give a Distinguished Lecture at the AAI Annual meeting. Dr. Marcus Butler, MD Medical Oncologist Clinical Site Group Membership: Melanoma & Skin, Gynecologic Before joining The Princess Margaret, Dr. Butler was an Instructor in Medicine at Harvard Medical School and a Clinical Fellow in Medicine at the Dana-Farber Cancer Institute. His expertise includes clinical trials in a variety of Immune Therapies including Adoptive T-cell Therapy and Checkpoint Blockade. He is the Director of the Immune Monitoring Laboratory at The Princess Margaret. In , Dr. Butler was recognized with the Dunkin Donuts Rising Stars Program Award at the Dana-Farber Cancer Institute, Harvard Medical School. The Princess Margaret Cancer Foundation Page 18

19 Dr. Naoto Hirano, MD, PhD Associate Director for Research, Immune Therapy Program Scientist, Princess Margaret Cancer Centre Expertise: Adoptive T-cell Therapy, Human T-cell Biology Dr. Hirano was an Assistant Professor at Harvard Medical School at the Dana-Farber Cancer Institute before moving to The Princess Margaret. Among his contributions to the field of Immune Therapy, he developed a human artificial antigen-presenting cell system that has been used to produce cancer-fighting T-cells for Immune Therapy. In 2009, he was awarded the American Society of Hematology Scholar Award and the Dunkin Donuts Rising Stars Program Award. He was recognized by the Ontario Institute for Cancer Research with the Investigator Award in Dr. David Hogg, MD, FRCP(C) Medical Oncologist Clinical Site Group Membership: Melanoma & Skin, Sarcoma Dr. Hogg has been an attending physician in the Division of Medical Oncology since He has been the principal investigator of many clinical trials at The Princess Margaret. Dr. Hogg participated in the pivotal clinical trial that led to the approval of ipilimumab Immune Therapy for metastatic melanoma. Dr. Hogg has been the recipient of many awards including the Murray Muirhead Award, The Issei Scholarship in Medicine and Surgery and the Chappell Prize in Clinical Medicine. Dr. Anthony Joshua, MBBS, FRACP, PhD Medical Oncologist Clinical Site Group Membership: Genitourinary (GU), Melanoma & Skin, Endocrine Dr. Joshua co-authored a landmark study in the New England Journal of Medicine in 2013 describing a novel Immune Therapy treatment based on blocking signals that inhibit an immune response. He has also participated in developing Immune Therapy using Tumour-Infiltrating Lymphocytes at The Princess Margaret. The Princess Margaret Cancer Foundation Page 19

20 Dr. Joshua received the 2013 Rising Star in Prostate Cancer Research from Prostate Cancer Canada. He was also awarded the Pier Luigi Tolaini CCPC Young Investigator Award from the Coalition to Cure Prostate Cancer in Dr. Tak Mak, OC, PhD, DSC, FRSC, FRS Director, The Campbell Family Institute for Breast Cancer Research Senior Scientist, Princess Margaret Cancer Centre Dr. Mak is one of the most cited medical researchers in the world. He discovered the T-cell receptor, known as the Rosetta Stone of immunology. Dr. Mak has won international recognition in the form of the Emil von Behring Prize, the King Faisal Prize for Medicine, the Gairdner Foundation International Award, the Sloan Prize of the General Motors Cancer Foundation, the Novartis Prize in Immunology and the Paul Ehrlich Prize and Ludwig Darmstaedter Prize of Germany, among many others. He also holds Honorary Doctoral Degrees from universities in North America and Europe, is an Officer of the Order of Canada, and has been elected a Foreign Associate of the National Academy of Sciences (USA), a Foreign Associate of the American Academy of Arts and Sciences, as well as a Fellow of the Royal Society of London (UK). Dr. Mak was recently awarded the Order of Ontario. Dr. Jeffrey A. Medin, PhD Senior Scientist, University Health Network (OCI, TFRI, TWRI appointments) Dr. Medin s lab focuses on the development and implementation of gene therapy by integrating viral vectors for inherited and acquired disorders. Dr. Medin heads 2 independent, multidisciplinary teams that are implementing first-in-human gene therapy trials involving lentiviral vectors for correction of Fabry disease and to generate potent anti-cancer vaccines. Dr. Medin has won a National Research Council Associateship Award, a USDOD Prostate Cancer New Investigator Award, and the 2011 Distinguished Alumni Award for Achievement from the University of Wisconsin-Parkside. Dr. Medin founded the Vector Core Facility at the TWH. The Princess Margaret Cancer Foundation Page 20

21 Dr. Malcolm Moore, MD Director, Bras Drug Development Program Director, McCain Centre for Pancreatic Cancer Medical Oncologist Dr. Moore is Head of the Division of Medical Oncology and Hematology, Department of Medicine at Princess Margaret Cancer Centre. He is also the Co-Director of the Pancreatic Cancer Research Initiative at the Ontario Institute of Cancer Research and a Scientist in the Division of Experimental Therapeutics at the Ontario Cancer Institute. Dr. Moore s major research interest over the past 10 years has been innovative drug development for cancer therapy, and he has been a Principal Investigator for many Phase I, II and III studies in gastrointestinal and genitourinary cancer. Dr. Moore has published over 200 peer-reviewed manuscripts, review articles, and book chapters and is on the editorial board of the Journal of Clinical Oncology. He has presented nationally and internationally, having given over 150 invited lectures worldwide. Dr. Christopher J. Paige, PhD, FCAHS Vice President, Research, University Health Network, Toronto General Hospital, Toronto Western Hospital, Princess Margaret Cancer Centre, Toronto Rehabilitation Institute Ronald Buick Chair in Cancer Research, Ontario Cancer Institute Since 1998, Dr. Paige has been Vice President, Research of the Ontario Cancer Institute and has since assumed his current position of Vice President, Research at the University Health Network, which comprises four hospitals: Toronto Rehab, Toronto General Hospital, Toronto Western Hospital and Princess Margaret Cancer Centre. Dr. Paige is an internationally recognized leader in the area of lymphocyte development and antibody formation, with an active research program in training the immune system to recognize cancer cells. He is the recipient of the Cinader Award of the Canadian Society of Immunology, Salute to the City Award of the City of Toronto, and the UFCW Canada Research Award of the Leukemia Society of Canada. He is a Fellow of the Canadian Academy of Health Sciences. The Princess Margaret Cancer Foundation Page 21

22 Dr. Li Zhang, MD, PhD Research Director, University of Toronto Transplantation Institute Inaugural Maria H. Bacardi Chair in Transplantation Senior Scientist, Toronto General Research Institute, University Health Network Dr. Zhang currently holds a Maria H. Bacardi Chair in Transplantation and is also the Research Director of the University of Toronto Transplantation Institute. Her research has been focused on understanding the cellular and molecular mechanisms involved in immune tolerance and its applications in various diseases including graft rejection, graft versus host disease, autoimmune diseases and cancer. Dr. Zhang s laboratory was the first to discover and characterize a subset of T lymphocytes termed double negative (DN) T-cells. Her group and other laboratories have demonstrated that DN T-cells can prevent transplant rejection, inhibit graft versus host disease and autoimmune disease, and eliminate cancer cells. Dr. Zhang s group is currently dissecting further the molecular mechanisms involved in DN T-cell action and building a critical bridge between new concepts originating from her laboratory and novel immunotherapy for cancer patients. The Princess Margaret Cancer Foundation Page 22

23 To donate or find out more information about the Immune Therapy Program, please contact: Shannon Stuart Director, Major Gifts (416) The Princess Margaret Cancer Foundation Page 23