There’s been a lot of buzz recently about cancer immunotherapy, including its selection as Science Magazine’s 2013 Breakthrough of the Year. Immunotherapy has introduced a new class of drugs that harness your immune system’s ability to fight off cancer cells. While traditional cancer drugs act by directly attacking cancer cells, immunotherapies instead stimulate your immune cells to kill the cancer themselves. Immunotherapy has been gaining traction in recent years as a promising new answer to cancers such as melanoma. There are many different categories of immunotherapy (see this previous Signal to Noise Article ), and clinical success has been especially rapid in melanoma for a type of immunotherapy called an immune checkpoint blockade [].
How does your immune system function?
Your body’s immune system is a collection of organs and cells that protect you from foreign invaders that threaten your health. Each immune cell battles these threats, which include bacteria, viruses, parasites, and even cancer cells. A dendritic cell (DC) constantly surveys your body to identify foreign invaders. When a DC finds one, it takes a unique protein from that invader and uses it to alert another component of your immune system, the cytotoxic T cell. The protein that is presented to the T cell is referred to as an antigen, and it identifies the threat. A T cell can then go to the site of the threat and destroy it.
For a T cell to be properly activated, its T cell receptor must interact with the presented foreign antigen. Furthermore, a T cell co-stimulatory protein, CD28, must interact with proteins on the DC called CD80 and CD86. Since such binding interactions are only possible for known foreign antigens, this step helps to prevent these T cells from harming your normal body cells by mistake. Such self-tolerance is aided by the presence of inhibitory proteins known as immune checkpoints, which can send signals to dampen T cell activity when it is no longer needed. Immune checkpoint proteins act as ‘brakes’ on T cell activation – they modulate the reaction of the immune system to minimize collateral damage [].
How does your immune system battle cancer?
Cancer represents a unique challenge to the immune system. Unlike foreign invaders like bacteria, cancer cells have antigens that are similar to your normal body cells, which makes recognizing cancer cells as enemies more difficult. Even worse, cancer cells have found ways to utilize some immune checkpoint proteins to put the brakes on T cell activity, protecting them from a T cell attack. For these reasons, the immune system does not always fight off cancer effectively. In order to enhance the immune system’s ability to fight off cancer, we can actively block immune checkpoints, effectively removing the brakes on the T cell attack.
Blocking immune checkpoints has proven most successful in the treatment of melanomas. Melanoma is the deadliest form of skin cancer and once it spreads from the initial primary tumor to distant parts of the body, the five-year survival rate for patients is only 15-20% []. Melanoma is considered an immunogenic cancer, meaning that its cancer cells are able to elicit an immune response, possibly because its high mutation rate could be creating high amounts of mutant proteins that can act as antigens. Considering its immunogenic properties, it makes sense that scientists focused on melanoma for this treatment as they aimed to enhance the body’s existing response to melanoma cancer cells [1,2].
How can we block immune checkpoints in cancer treatment?
Recall that DCs promote T cell activation when its proteins CD80/86 bind to the co-stimulatory protein CD28. One immune checkpoint protein, CTLA-4, is found in high amounts on the surface of T cells and it competes with CD28 to interact with CD80/86. When it interacts with CD80/86, CTLA-4 sends a signal to the T cell to dampen the amplitude of its activation. This inhibitory signal counteracts the stimulatory activity of CD28 (see Figure 1A). While good at preventing overactivation of the immune system, the signal can also prevent the T cell from attacking the offending cancer cell [].
Figure 1 ~ CTLA-4 inhibits T cell activation by dendritic cells
Ipilumamab is the first approved drug to block this inhibitory interaction. It uses a type of protein called an antibody, which binds directly to CTLA-4 so that there is no space for an interaction with CD80/86. This removes a natural check on the immune response and allows the body to mount a more effective battle against cancer cells (see Figure 1B). The exact mechanism of ipilumamab’s action is still under active investigation and likely involves the regulation of a whole host of immune processes, including the destruction of your body’s immune cells that are known to dampen the immune response. It is the first treatment to improve overall survival in patients with metastatic melanoma, with 10% of patients showing decreased tumor size in a recent study []. Furthermore, the study showed that those that did respond to ipilimumab showed improvement lasting up to two years, compared to patients on traditional therapy that often have only a matter of months before tumor relapse.
With the success of anti-CTLA-4 treatments, researchers sought to identify other immune checkpoint proteins to target. One such protein is PD-1, which like CTLA-4 is expressed on the surface of T cells. While CTLA-4 is involved in the initial activation of T cells, PD-1 modulates the activity of T cells after they have already become activated at the site of the cancer cell. Some cancer cells have proteins on their surface (PD-L1/2) that interact with PD-1, which then sends an inhibitory signal back to the T cell to put the brakes on its activity [1,4, Figure 2A].
Much like ipilimumab, an anti-PD1 drug called Nivolumab boosts T cell activity by binding to the T cell’s PD-1 to block this inhibitory interaction (see Figure 2B). Early results of a phase II clinical trial of the drug indicate that half of patients exhibit tumor shrinkage. A phase III trial comparing anti-PD-1 to ipilimumab will begin soon []. Other trials include looking at the combination of anti-PD-1 and anti-CTLA-4 drugs to see if two immune checkpoint blockades are better than one. Early-stage trials indicate that more than half of patients treated with the maximum dose of both immune checkpoint blockade drugs show a greater than 80 percent reduction in tumor mass []. Because of its high clinical promise and the successful path previously paved by the ipilimumab, the FDA has fast-tracked the review of anti-PD1, and physicians are hopeful it will become available for expanded use soon. Antibodies are also in development to block the PDL1 found on cancer cells [].
Figure 2 ~ The PD-1 and PD-L1 interaction dampens T cell activity at the site of the cancer
The success of these two drugs is promising, but there are consequences to suppressing the body’s natural mechanism for moderating immune system overactivation. As you may imagine, removing the brake on T cells throughout the body could have detrimental effects in some patients if the immune system begins to attack normal body cells in addition to the cancer cells. In fact, two of the most common side effects in clinic for ipilimumab are diarrhea and skin rashes, both a result of aberrant immune system activation against a patient’s own cells. If treatment is continued despite such side effects, colitis, hepatitis and other serious autoimmune issues may develop. Fortunately the anti-PD1 drug appears to exhibit better tumor response and less intense side effects than ipilimumab, and could therefore represent a less risky immune checkpoint blockade [].
Future questions for immune checkpoint blockades
Despite such rapid initial success, it is important to learn more about how best to apply these therapies.
Immunotherapies alone have been successful in patients that have already received other types of treatment. The next logical step is to determine if immunotherapies could act in concert with other treatments for better patient survival. One such class of treatments is called targeted therapy, which acts to directly attack the cancer cells. Physicians are interested in seeing whether this direct attack will be enhanced if the immune system is also recruited to the battle and trials are currently underway.
With the success of these drugs in melanoma, a number of trials are in progress to determine whether a survival benefit extends to other cancers. Early indications are that renal cell carcinoma and non-small cell lung cancer may respond to these drugs, which makes sense, as these two cancers, like melanoma, are considered immunogenic. Trials testing ipilimumab for classically less immunogenic cancer types such as breast, ovarian, kidney, and prostate cancers are also in progress. If effective, immune checkpoint blockades will represent a way to elicit responses from the immune system that may not already exist for these cancers.
Finally, the identification of biomarkers to predict which patients will respond to this class of immunotherapy drugs is an area of active investigation []. A biomarker is a measurable characteristic that indicates some biological state, in this case, the ability for that tumor to respond to immune checkpoint blockades. Early results indicate that high levels of PD-L1 in the tumor may correlate with a better response to the drug that targets PD-1 []. Logically, if a tumor has no PD-L1, you would expect that a drug blocking the PD-1/PD-L1 interaction would not show any therapeutic response. This and other biomarkers will be studied extensively in the future as the field of personalized medicine continues to expand (see seminar on personalized medicine). Success in this field will allow treatment choices to be tailored to a patient’s ability to respond.
While there are still unanswered questions in the field, immune checkpoint blockades have demonstrated that sometimes one of the best defenses against cancer cells may be your body’s own army of immune cells bolstered by therapies that keep cancer cells from bypassing their response.
Steph Guerra is a Ph.D. student in the Biological and Biomedical Sciences Program
References
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. http://www.nature.com/nrc/journal/v12/n4/full/nrc3239.html
2. Skin Cancer- Melanoma, Immunotherapy. American Cancer Society. http://www.cancer.org/cancer/skincancer-melanoma/index, http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-what-is-immunotherapy
3. S. Hodi et al., “Improved survival with ipilimumab in patients with metastatic melanoma,” N Engl J Med, 363:711-23, 2010.
4. Ribas, A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012 Jun 28;366(26):2517-9. http://www.nejm.org/doi/full/10.1056/NEJMe1205943
5. New Combinations and Immunotherapies for Melanoma. Medscape. http://www.medscape.com/viewarticle/810688_3
6. S.L. Topalian et al., “Safety, activity and immune correlates of anti–PD-1 antibody in cancer, ” N Engl J Med, 366:2443-54, 2012. http://www.nejm.org/doi/full/10.1056/NEJMoa1200690
For more reading
Information about Immunotherapies from the American Cancer Society: http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-what-is-immunotherapy
Recent article from The Scientist:
http://www.the-scientist.com/?articles.view/articleNo/39511/title/Deploying-the-Body-s-Army/
Recent article from The Boston Globe: