This article was first published in the 2016/17 edition of Brain Tumour, the IBTA's annual magazine that is distributed globally and free of charge in 113 countries and at international neuro-oncology and cancer conferences around the world. Read the full issue online and find out more here. The authors of this article are Dr David Reardon and Professor Michael Weller (more details at the foot of this page).
HISTORICALLY, three pillars have served as established approaches for the treatment of cancer, including surgery, radiation therapy and chemotherapy. Based on exciting results achieved over the past few years, immunotherapy is now established as a fourth pillar of cancer therapy.
This article provides a brief introduction to immunotherapy and its application for patients with brain cancer. Its advantages and challenges are summarized and potential considerations for future development are outlined.
What is Immunotherapy?
The primary goal of our body’s natural defenses, the immune system, is to protect us against attack from anything foreign that could be harmful. Immunotherapy refers to treatments that utilize the immune system to attack cancer. Currently there are three main types of cancer immunotherapy treatment: vaccines; adoptive cell therapies; and immune checkpoint modulation.
Cancer vaccines work in a manner similar to infectious disease vaccines that protect us against harmful infections such as tetanus, polio and diphtheria. They consist of injected proteins that sensitize the immune system against an intended target. Once successfully sensitized, the immune system is actively on guard and will attack that target should it invade us. Cancer vaccines attempt to sensitize the immune system to components of cancer cells.
Most cancer vaccines are therapeutic in that they help the immune system attack existing cancers, but some cancer vaccines are also preventive, for instance, against viral proteins linked to cervical cancer.
Adoptive cell therapies are sophisticated treatments in which specific immune cells (usually T cells) are collected from the patients’ blood and sensitized in the laboratory against tumor target proteins. These sensitized cells are then infused back into the patient with the goal of activating other immune cells in the body to launch a successful attack against the cancer. One type of adoptive cellular therapy called CAR (chimeric antigen receptor) T cells has been widely publicized for inducing durable remissions among leukemia patients who have exhausted all treatment options.
The third type of immunotherapy includes molecules that are designed to enhance the overall activity of the immune system and are called immune checkpoint molecules.
Immune checkpoints are normally turned on whenever the immune system is activated and signal the immune system to stop reacting in order to help prevent damage to normal body organs. Unfortunately many cancers activate these protective immune checkpoints as a strategy to protect themselves by disarming the immune system especially in the immediate area where the tumor is growing.
Two important immune checkpoints which have been successfully targeted to treat cancers include CTLA-4 (cytotoxic lymphocyte antigen 4) and PD-1 (programmed death 1). Exciting results have led to approval of agents that inhibit CTLA-4 (Yervoy) or PD-1 (Opdivo and Keytruda) for a number of cancers including melanoma, lung cancer and kidney cancer while additional approvals for other types of cancer are expected soon.
What are the advantages of immunotherapy?
Our immune system is remarkably designed. Two of its important strengths are specificity and memory.
The immune system is highly specific and will only be sensitized against a precisely defined target. As a cancer therapeutic, such specificity is highly advantageous in that it should protect against damage to normal cells in the body. In contrast, chemotherapy and radiation therapy, while very potent against dividing cells, lack specificity and often indiscriminately affect normal as well as cancer cells.
Memory refers to the immune system’s ability to remember what it has been sensitized against and retain the ability to mobilize in the future should it be exposed to that target again, even years later. Thus if memory is successfully activated, the immune system could prevent future relapse or recurrence of cancer.
Immunotherapy has additional advantages that may allow it to overcome two important hurdles that have limited the effectiveness other cancer treatments: delivery and tumor heterogeneity.
Delivery is a major issue for brain cancer because the blood supply to the brain has a protective aspect known as the blood brain barrier (BBB). Inadequate penetration of the BBB has likely been a major contributor to many drugs that have failed to improve outcome for brain cancer patients. The immune system has the ability to successfully navigate the BBB and thus the effective delivery of immunotherapies to tumors in the brain is not a major issue.
Heterogeneity refers to critical differences that define different cells in a tumor. These differences can occur geographically, meaning that cells in different areas of the tumor can be very different in many ways including their sensitivity to treatment. These differences can also occur over time in that tumor cells can change as they adapt to become resistant to treatment. Tumor geographic and temporal heterogeneity has been an insurmountable hurdle in the development of successful brain cancer treatment to date. Immunotherapy has the potential to overcome heterogeneity as long as it can be successfully sensitized against variations that exist regionally within the tumor or are induced over time.
What are the challenges for immunotherapy?
Although exciting progress has been made in the last few years, we are only beginning to understand and utilize the power of our body’s natural defenses against cancer. Additional laboratory and clinical research is desperately needed. Even among tumors where immunotherapies have been approved, only a minority of patients achieve durable benefit.
Why do some patients respond and others do not? Similarly why do some types of cancer respond better to immunotherapy than others?
The answers to these questions likely involve two factors: optimization and resistance.
There are a host of variables that must be optimized for successful sensitization of the immune system. For example, several variables can impact the effectiveness of a cancer vaccine including: when, how and where to administer it; which patients are best candidates; does the amount of resected tumor matter; and what is the impact of other therapies such as radiation or chemotherapy.
Another critical challenge for immunotherapies are mechanisms of resistance that tumors can use to evade attack by the immune system. Many cancers, and especially brain cancers, are remarkably adaptive in their ability to develop resistance capabilities that allow them to flourish despite our best attempts at treatment.
Ongoing research has identified a wide array of protective resistance mechanisms cancers can exploit to protect themselves from immunotherapies as well.
The reason for the disappointing negative results recently reported for rindopepimut, a glioblastoma vaccine against EGFRvIII, in the large phase 3 ACT IV study, is not clear, but it is likely that tumor resistance mechanisms designed to suppress immune responses, probably were a major contributing factor. Due to the existence of resistance mechanisms, combination treatments that bring together complementary approaches will likely be required.
There are additional practical challenges for immunotherapy that are particularly relevant for brain cancer patients.
First, immunotherapies typically stimulate inflammation as an inevitable part of the immune system’s attack against cancer. Inflammation can cause brain swelling which can temporarily worsen neurologic deficits. Second, steroids such as dexamethasone which are commonly used to decrease brain swelling can cripple the ability of immune cells to attack cancer. Third, inflammation caused by immunotherapies can make accurate interpretation of MRI changes difficult because such reactions can mimic tumor growth. Expert panels are developing guidance for the neuro-oncology community to help deal with these challenges.
Thanks to much intensive research, a variety of immunotherapies have achieved exciting success across a spectrum of cancers recently. Hopefully, these successes are just the beginning. Nonetheless, in order to realize the potential benefit of immunotherapy for brain cancer patients, much work remains to maximize the powerful advantages of the immune system while overcoming challenges including resistance mechanisms exploited by cancer.
Dr David Reardon is Associate Professor in Medicine at Harvard Medical School, and
Clinical Director at the Center for Neuro-Oncology, Medical Oncology, Dana-Farber Cancer Institute. Professor Michael Weller is Chairman for the Department of Neurology, University Hospital Zurich, Zurich, Switzerland