At the Princess Margaret Cancer Centre, Dr. Pamela Ohashi and her group are leading efforts to harness the power of the immune system to treat cancer. Cancer immunotherapy is an emerging frontier that focuses on boosting the host’s immune response to cancer as a form of treatment. Pam and her group are developing and refining the use of tumour-infiltrating lymphocytes (TILs) as a targeted and durable way of treating cancer.
From the thymus to tumour immunity
Pam began her laboratory with long-standing interests in understanding how the T cell receptor can signal different cell fates: from positive versus negative selection in the thymus to T cell activation versus tolerance in the periphery.
At the time, Pam knew that her immediate research interests in T cell activation and tolerance had broad applicability to autoimmunity and tumour immunity. In recent years, she has been taking a more active approach in applying knowledge from basic science research to developing an immune therapy program for cancer.
With the strong support of the Institute directors Drs. Tak Mak and Benjamin Neel, and the tremendous energy and support from the Princess Margaret Cancer Foundation and their donors, the expertise to develop adoptive T cell therapy in Toronto was initiated. This approach was chosen because it was the most efficacious immune therapy reported to date. The immune therapy program could not have been done in any other setting because traditional granting structures would not provide the sustained support necessary to build a stable program. With the beginning of the TIL program in 2004, Pam began a new stage in her journey to tackle one of the most dangerous killers in the developed world.
The malevolence of cancer
Cancer is one of the most complex and formidable diseases that we may encounter during our lifetime. Translated into Latin from the Greek word kronamos, cancer, meaning “crab”, was accordingly named because early Greek physicians observed a hard, stony centre with radiating blood vessels like crab legs that is characteristic of many solid tumours.
Likened to a clawed parasite eating into its host, cancer seeks to grow and multiply, draining nutrients from its surroundings and choking healthy tissue around it. Cancer is a disease that commands respect, but respects no commands and follows no rules. Defying the basic laws of cell life and death, cancer cells are immortal, perpetually dividing and growing as long as they have sufficient nutrients to do so. Despite advances in research and medicine, cancer remains a powerful and ancient enemy to which countless lives have been, and continue to be lost.
In 2012 alone, there were 14.1 million new cancer cases and 8.2 million deaths worldwide due to cancer. It is the leading cause of death in Canada and the UK, and the second leading cause of death in the US as of 2013. At current incidence rates, it is estimated that one in three people will develop cancer at some point during their lifetime. With an overall aging population, longer average lifespan, and increasingly sedentary population, the incidence of cancer will continue to rise in the near future.
Current strategies of intervention
Great strides have been made in understanding the biology of cancer, its origins, and how to treat it. Improved detection and better interventional strategies have significantly improved patient survival. The five-year survival rate, averaged across all cancer types, has jumped dramatically from approximately 20% in the early 1930s, to over 63% in 2008. Despite these advances however, a significant gap remains in the effectiveness of current treatments for cancer. The complex nature of cancer requires a tailored approach that traditional therapies do not yet offer.
Harnessing and improving our body’s own defenses against cancer
Only recently have scientists begun to fully appreciate the role of the immune system in battling cancer. Our immune system fights tirelessly to protect us from viruses, bacteria, parasites and other agents that may cause disease. The immune system is also able to recognize cancer cells as harmful to the body and in a healthy individual, these cancer cells are targeted and eliminated.
However, cancer cells can develop mutations that allow them to escape immune detection or evade destruction by our immune cells. They can also often subvert the immune system by producing chemical signals that neutralize immune cells, or by recruiting specialized suppressive immune cells such as regulatory T cells and myeloid derived suppressor cells. These cell populations normally function to limit an immune response and prevent autoimmunity. However, their recruitment by cancer cells also inhibits the immune response. In this manner, cancer cells can continue to grow, and eventually metastasize, worsening the progression of disease and leading to a poor prognosis.
Understanding TIL therapy
Researchers have discovered that there are immune cells that can be found within a tumour. Some of these immune cells have recognized that the tumour needs to be eliminated to protect the host. The term “tumour-infiltrating lymphocytes”, or TILs, generally refers to the T cells that infiltrate tumours. Although the population of TILs is likely to be enriched for those that are specific for tumour cells, these TILs might have been deactivated by the cancer cells, or there may not be enough of them present to destroy the rapidly growing tumour. The idea behind TIL therapy is to grow these TILs in the laboratory, removing them from the suppressive tumour microenvironment, and expanding them to large numbers before re-infusing them in an autologous manner (meaning that they are transferred back into the same person from whom they were initially derived).
A turning point in TIL therapy
In 2002, Dr. Steven Rosenberg at the National Institutes of Health (NIH) in Bethesda, Maryland, USA, published a landmark study in Science describing the use of autologous TILs for the treatment of metastatic melanoma. In the study, all of the metastatic melanoma patients had failed standard therapies. Amazingly, after administration of a large number of TILs, Rosenberg’s group saw positive clinical responses in 6 out of the 13 patients (46%) in the study. In the years following this initial report, additional patients were treated using the same protocol, with a similar clinical response rate of 49% out of a total of 43 patients across all studies. Moreover, not only was there a high clinical response rate, but the patients who experienced tumour regression continued to remain disease free for many years.
These impressive results were in part attributed to an additional step that the Rosenberg group introduced prior to infusion of TILs. This preparative step was chemotherapy-based lymphodepletion, a process that involves giving a patient drugs that kill off white blood cells (including lymphocytes). Although counterintuitive because lymphodepletion kills the very immune cells that may be fighting the tumour, lymphodepletion is thought to have the beneficial effect of preferentially depleting any suppressive immune cells that may be found within the tumour. It also serves the function of “making room” in the body for the huge number of T cells (approximately 10 to 100 billion in the Rosenberg study) that are re-infused into the patient and increases the T cells’ chances of survival after they have been transferred.
In the Rosenberg protocol, after the patient receives the re-infusion of their TILs, the patient is given high-dose interleukin-2 (IL-2) therapy. IL-2 is a soluble factor that acts on T cells which helps them to multiply. Therefore the aim of the IL-2 therapy is to help improve the persistence of the transferred TILs. Several other groups have now performed clinical trials using the same approach and have had comparable results as the Rosenberg group.
Using TIL therapy to bolster immune function
Based on Rosenberg’s protocol, Pam used it as a starting point for developing a TIL-based immune therapy program at the Princess Margaret. She decided to bring on one of her former graduate students, Dr. Linh Nguyen, who is currently the Head of the Translational Immunotherapy Laboratory at the Campbell Family Institute for Breast Cancer Research, to develop TIL therapy for cancer.
When Linh started, she was faced with the enormous task of building a new program from scratch. Obtaining institutional ethics board approvals, performing the necessary preclinical studies and overseeing technology transfer from the Rosenberg group were just some of the first steps that had to be taken. As the work progressed, she set up a process to obtain blood products from healthy donors to support TIL growth, developed Health Canada-approved manufacturing procedures for the production of cells for clinical use and was involved in planning the clinical trial.
Developing the TIL platform also required the collaborative efforts of many researchers and clinicians to get the program off the ground. Pam credits several key individuals including medical oncologists Drs. Ian Quirt and David Hogg, surgeons Drs. Alexandra Easson, Wey Leong, David McCready, Michael Reedijk and Director of Dermatopathology, Dr. Danny Ghazarian, and Dr. Hans Messner, all at the Princess Margaret Cancer Centre in Toronto, for their roles in helping start and develop the TIL program. Dr. Malcolm Moore, Director of the Drug Development Program at the Princess Margaret Cancer Centre, was crucial in coordinating the clinical network for the program, as was Marcia Flynn-Post, Nurse Manager for clinical trials at the Princess Margaret. More recently, Dr. Anthony Joshua and Dr. Marcus Butler, both medical oncologists at the Princess Margaret, and Drs. Michael Crump and Norman Franke, have also joined and are important figures in the TIL therapy group.
The TIL generation process that Pam and Linh set up in Toronto involves many steps. To culture TILs, eligible patients first undergo blood tests and also have a sample of their cancer surgically removed. The TILs are then grown out from the tumour specimen and assessed for their suitability to produce a therapeutic product. These TILs are then stored in a cryopreserved state and samples are also tested to ensure that there is no microbial contamination.
Once it has been decided that a patient will undergo investigational treatment with TILs, a culture step is carried out using the cryopreserved TILs to rapidly expand the number of TILs to the levels required for infusion. During this time, the patient would undergo the lymphodepleting chemotherapy that was part of the Rosenberg protocol. After the patient completes the preparative chemotherapy, the TILs are infused fresh without additional cryopreservation.
Why TIL therapy
TIL therapy harnesses the specificity that the immune system offers, as standard chemotherapies are not specific to cancer cells. TIL therapy also carries the advantage that the TIL population is polyclonal, meaning that they collectively recognize many different tumour antigens, thus improving the chances that the immune system will effectively eliminate the tumour. In addition, TIL therapy has the potential to establish immunological memory and persist in the patient without additional treatments.
In theory, TIL therapy should be amenable to many different cancers as long as TILs can be obtained. According to Linh, there are “probably many solid tumours from which one can grow TILs…so many [cancers] might be amenable to TIL therapy – the question is whether you can expand enough TILs in the lab and whether these TILs are enriched for tumour-specific lymphocytes.” Current targets being studied for TIL therapy in Pam’s laboratory include melanoma, ovarian, breast and prostate cancer, and mesothelioma.
Current challenges and the future of TIL therapy
At the moment, TIL therapy is still in its nascent stages and much work remains to be done to optimize and refine treatment strategies. Only a handful of centres around the world are currently conducting TIL clinical trials. These centres include the NIH, Moffitt Cancer Center and MD Anderson in the US, Copenhagen University Hospital in Denmark, and the Chaim Sheba Cancer Research Center in Israel. Currently, the Princess Margaret Cancer Centre is the only institution in Canada with a TIL therapy program, largely in part due to the efforts of Pam, her collaborators and the Princess Margaret Cancer Foundation.
One aspect of TIL therapy that remains largely unknown is determining which characteristics of TILs predict a good clinical response. At the moment, there are still no clear criteria that can be used to determine how effectively TILs will function after they are re-infused into a patient. Understanding the specific parameters that govern TIL function will allow the field to dramatically enhance the effectiveness of TIL therapy in the future.
Recently, immune therapy for cancer has made significant leaps forward, represented by the approval of a new type of immunological agent called ipilimumab (anti-CTLA4; Yervoy®). Ipilimumab falls under the category of immune therapies called “checkpoint blockade”. Another checkpoint blockade target known as PD-1 has also shown promising results in early phase clinical trials. Combining TIL therapy with other immune therapies such as these checkpoint blockade agents, as well as with standard cancer therapies such as chemotherapy and radiation therapy may enhance its overall efficacy and much work remains to be done to explore this avenue of research.
Research by Pam and other investigators at top institutions across the world are opening up new avenues for the treatment of cancer. TIL therapy will augment the methods we have to conquer cancer and Pam believes that TIL therapy will one day become a standard line of care. It is a revolutionary approach; one that relies on a system that has been forged by millions of years of evolution. With advances in TIL therapy, we are gaining ground on treating cancer and may one day be able to completely cure a disease so aptly named as “The Emperor of All Maladies”.
Special thanks to Drs. Linh Nguyen, Pamela Ohashi and Marcus Butler for helpful comments and edits to this article.
Dudley et al. Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes. 2002. Science 298(5594): 850-854.
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