Five years ago, at the American Society of Clinical Oncology (ASCO) Annual Meeting (June 3-7, 2011; Chicago, IL), investigators presented data on the immunotherapy drug ipilimumab, the first treatment to improve the survival of patients with advanced melanoma.1 Today, there are now over 20 immunotherapy regimens approved by the Food and Drug Administration (FDA),2 and breakthroughs in the field were considered by ASCO to be the top advancement in cancer research in 2015.3
Immunotherapy is an approach to treatment that harnesses the immune system to attack cancerous cells. This can be done by either inhibiting the mechanisms by which cancerous cells hide from the immune system, such as with checkpoint inhibitors, or by aiding the immune system with monoclonal antibodies to help it fight the cancer. Beginning with ipilimumab in 2011, immunotherapies were primarily developed for the treatment of melanoma, a disease state in which standard therapies mostly failed.
More recent studies of immunotherapies have shown great success for treating other forms of cancer as well. Nivolumab, which was approved in 2014 as a treatment for advanced melanoma that had stopped responding to ipilimumab,4 received additional approvals for the treatment of lung cancer5,6 and renal cell carcinoma.7 Pembrolizumab, another immunotherapy drug that started as a treatment for advanced melanoma,8 received approval for the treatment of advanced non-small cell lung cancer9 after demonstrating improved response rate with manageable side effects in certain patient populations.10
Both nivolumab and pembrolizumab are part of a new class of immunotherapies called programmed cell death protein 1 (PD-1) pathway inhibitors. PD-1 is a marker of exhaustion of T cells. When PD-1 on T cells engages its ligand, called PD-L1, the T cell is eliminated. Thus, tumor cells express PD-L1 as a way to destroy functioning T cells.11 Therefore, therapies that inhibit the PD-1 pathway can enable an antitumor response from the immune system in order to destroy cancer cells while preserving healthy tissue.11
Although promising, PD-1 inhibitors and other immunotherapies are only just beginning to arrive on the scene in cancer care, meaning that there is still limited information about how these new treatments should be applied to different clinical scenarios and the risks that might be associated with them. According to a study recently published in Nature, acquired resistance to immunotherapy with PD-L1 inhibitors is one challenge that must be addressed.12
To clarify the ambiguity surrounding immunotherapies, Journal of Clinical of Pathways spoke with Howard L Kaufman, MD, FACS, an accomplished surgical oncologist who has received numerous honors for his work in cancer care and immunology, specifically for melanoma and oncolytic viruses. Dr Kaufman discussed what the future holds for these promising new treatments and the role they will likely play within oncology pathways.
Tell us about your experience with immunotherapy research.
I’m trained as a surgical oncologist and also have had a long-standing interest in tumor immunology, specifically the development of oncolytic viruses as a treatment for cancer. I did a lot of work with an oncolytic herpes virus and led the clinical trial that resulted in the recent FDA approval of talimogene laherparepvec (t-vec) for the treatment of melanoma. So, this is exciting because it’s the first approved oncolytic virus and really the first approved gene therapy for the treatment of cancer. And I think immunotherapy is something that could apply to almost any cancer.
Can you give us a background in immunotherapies and their role in improving cancer treatment?
The most important advantage of immunotherapy is that it has been associated with durable responses. In some patients, it appears that we can even start talking about having cured the cancer—and these are patients with widespread metastatic disease in some cases. So, I think that the real advance here is that we have a therapeutic approach that can buy us a significant amount of time when it works properly. Understanding how that works and, perhaps even more importantly, why it doesn’t work in some cases is going to be really important as we move forward.
Additionally, several studies in immunotherapy have suggested that some of the standard therapies we’ve had for many years, such as chemotherapy and radiation therapy, have immunologic components in how they are working. Understanding those immune components is giving rise to new ideas about how to combine therapies a little bit better. There is no question that the field is going to be focused on combination therapies, and, while I think it makes sense to combine immunotherapies together—we have data now that suggests that is a very successful way to go in many situations—I think combining immunotherapies with non-immunotherapies may also offer some real advantages.
Can you tell us more about the discoveries that led to the development and implementation of immunotherapies for oncology?
First of all, for many years, it was dogma that chemotherapy, which is known to cause cytopenia, likely inhibits the body’s ability to produce an immune response. While we all accepted that dogma, there was essentially very little data to actually support it. There were some early studies that began to take a look at chemotherapy agents and their impact on the immune system, and it just did not pan out that chemotherapy was uniformly suppressive of at least tumor-specific immune responses. We understand today that there are a variety of different types of immune cells, some that have effector functions and other that have suppressor functions. So, sometimes being able to deplete the suppressive cells may be as important as stimulating the effector cells. That’s the first major advance in our thinking.
The second was the outcomes of the clinical trials using more contemporary immunotherapy agents, which have suggested that there might in fact be other mechanisms by which chemotherapy could help to promote immune responses. Over the last year or two, one of the really important findings has been that mutation load is a critical correlative of good response to immunotherapy. What that means is that the more mutations you have in a cell, the more potential neoantigens may exist for generating an immune response. And we think there is a process called immunoediting in which the cancer cells and the immune system seem to coevolve, which may help cancer cells evade the immune system over time by eliminating an antigen-specific response. But those tumor cells that have a large number of mutations may be able to generate a new immune response that has not been immunoedited out of clinical activity. So, chemotherapy may be an agent that helps to generate more mutations in a tumor cell, making it more susceptible to an immune response. Similarly, radiation is notorious for causing DNA damage and likely resulting in new mutations; it’s only recently that we’ve discovered that part of the potential mechanism of activity of chemotherapy and radiation therapy may be in generating new mutations.
Can identifying the number of cancer cell mutations help to determine which patients are ideal candidates for immunotherapy treatment?
Right now, I think this is a hypothesis that still needs to be proven, but there is certainly data supporting it. If you look at non-small cell lung cancer, it has been very interesting that patients with a history of tobacco use, where the mutation rate is high, are responding better to some of the immunotherapies. So, that’s supportive of the fact that mutation load by itself may be an important biomarker of patients likely to respond to treatment. A similar pattern is being reported in melanoma in which mutation rates are high due to chronic UV light exposure.
In the field, the search for a predictive biomarker of response has been a very high priority. Validating these markers would be an enormous advantage for identifying patients likely to respond to various treatments. I don’t think we’re quite ready yet to use any particular biomarker for selection purposes, but we certainly have a lot of interesting leads. For example, the expression of PD-L1 appears to be an important predictor in many cases. And the other biomarker that’s been of particular interest has been the number of lymphocytes within the tumor microenvironment. When you have a lymphocyte-rich environment, the tumor is much more likely to respond to immunotherapy than if there are very few lymphocytes. What we don’t yet understand is why some tumors have lymphocyte-rich environments and others don’t. However, one of the advantages of the oncolytic viruses is that it generates lymphocytes in the tumor, which can be critically important for treatment with other immunotherapies. So, combinations of oncolytic viruses with immunotherapy should be a very high priority.
Are there any risks involved with using immunotherapies?
Yes. Immunotherapy treatment does have a different adverse event profile than standard cancer therapeutics, and it is important to be aware of them. The most common side effect that we’ve seen is the emergence of what are called “immune-related adverse events.” These are a result of activating the immune system and having it react against normal tissues. For the T cell checkpoint inhibitors, most commonly, this presents as skin rashes due to a localized dermatitis, but other reactions such as autoimmune colitis, pneumonitis, and hypophysitis, have been reported. It is possible to get immune-mediated reactions against almost any tissue in the body; we have seen reactions against the liver, the kidneys, the endocrine organs, and even peripheral and central nerves. The adoptive T cells have led to a different sort of side effect, where you can have a release of cytokines; this has been called cytokine release syndrome. There have also been some unusual neurologic complications that have been reported. On the other hand, oncolytic viruses actually have had a very favorable safety profile. The most common side effects of those have been fever, chills, fatigue, and minor injection site reactions.
So, the adverse event profile is a bit more favorable in some cases and mandates careful monitoring in others. We have developed ways to control side effects if they occur—steroids, for example, seem to help manage a lot of these side effects—but early identification obviously is important for symptom management.
There has been increased focus on involving patients in discussions about their care. With the growing interest surrounding immunotherapies and consumer-targeted television ad campaigns such as Opdivo’s “Longer Life” ads, is there a concern that patients might be inclined to ask for these treatments when they may not be right for them? How can physicians guide their patients in these situations?
Well, of course, we encounter patients every day who want these treatments, and I think sometimes it isn’t good to be overhyping things. All patients need is to be carefully evaluated by an expert in the field. Sometimes immunotherapy is going to be a good option, and sometimes it isn’t; it’s highly dependent on the individual. It is good to stay educated, though, and just like with any other new treatment, patients are educating themselves about immunotherapies. But physicians also need to be learning about these treatments, because, in many cases, they may not be up-to-date. So, there’s a really important role for providing objective education.
It’s a very exciting time in oncology—not just in immunotherapy, but in general. We have more drugs than we’ve ever had before. The likelihood of having positive results in clinical trials is higher because we understand the science better and we’re designing these trials more rationally. I was telling someone that, 10 years ago when I would be in the clinic, if we had one patient responding to something, we would get very excited. Today, it’s not unusual for me to have every single patient responding to a variety of different treatments. So, to some degree, I think there’s some justification for the excitement surrounding immunotherapies, but that can never take the place of good education and good clinical judgment.
In January 2015, you wrote an article reviewing some of the industry standards for immunotherapies, barriers to their use, and benefits of their implementation.13 Now, 1 year later, how has the field evolved and how do you see it continuing to evolve over the coming months?
Oh, it’s definitely evolving. Just like precision medicine, precision immunology seeks to understand the specific mutation of a patient’s tumor and build a therapeutic plan around selecting the right type of immunotherapy. The goal of precision immunology is to really understand what the guiding immunologic principles are that govern or suppress immune response in a given patient’s tumor, and then better guide them into the right therapy. The problem is that I don’t think we’ve yet been able to validate any of the immunological markers. The good news is that we have several leads. As I mentioned, PD-L1 expression, the presence of lymphocytes in the tumor, and mutation load are all very interesting as potential biomarkers, they just still require validation in trials—many that are already underway. And if those trials come back with good results, we’ll be able to not only take a look at the mutations of a patient’s tumor, but also understand the immune response of the patient to better design therapies that make sense.
You’re the president of the Society for Immunotherapy of Cancer. Can you provide some information about what your organization’s goals are and how you hope to propel immunotherapy research forward?
The Society for Immunotherapy of Cancer is the only organization that’s dedicated to improving patient outcomes through the use of tumor immunotherapy. The Society is open to a variety of professionals who have an interest in the field, including academia, industry, and government. The society works to foster networking and provide state-of-the-art education to both the expert in immunology and the non-expert. Increasingly, we’ve grown to being a source to inform the clinical community and patients. We’re now a key source of information and are getting increasingly involved in medical guidelines for the treatment of cancer. We were just appointed to the [American College of Surgeons] Commission on Cancer, which accredits hospitals and medical centers for cancer care, so that we can ensure high-quality delivery of tumor immunotherapy. Finally, the value proposition of immunotherapy is very different from other types of cancer therapies because of the durability of response we see. The Society hopes to gather some of the experts in immunotherapy and take a very careful look at the value of immunotherapy.
Is there anything else you would like to add?
Part of the real excitement of immunotherapies over the last year has been understanding that this is working not just in melanoma but in many types of cancer as well. So, I think the future is going to be expanding to other cancers. In theory, there is no cancer that would not be amenable to some form of immunotherapy. So, the potential impact of this can be really profound. And we’re just at the beginning of looking at immunotherapy as an adjuvant therapy and for prevention in high-risk individuals. These possibilities are potentially unlimited.
References:
1. Wolchok JD, Thomas L, Bondarenko IN, et al. Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma. J Clin Oncol. 2011;29(suppl): abstr LBA5.
2. Immunotherapy Approvals in 2015. Cancer Research Institute Web Site. https://bit.ly/1VzTbka. Published December 24, 2015. Accessed February 10, 2016.
3. Dizon DS, Krilov L, Cohen E, et al. Clinical cancer advances 2016: annual report on progress against cancer from the American Society of Clinical Oncology [published online ahead of print February 4, 2016]. J
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4. FDA News Release: FDA approves Opdivo for advanced melanoma. U.S. Food and Drug Administration Web Site. Published December 22, 2014. Accessed February 10, 2016.
5. FDA News Release: FDA expands approved use of Opdivo to treat lung cancer. U.S. Food and Drug Administration Web Site. https://1.usa.gov/1zKmqUl. Published March 4, 2015. Accessed February 10, 2016.
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7. FDA News Release: FDA approves Opdivo to treat advanced form of kidney cancer. U.S. Food and Drug Administration Web Site. https://1.usa.gov/1IbDRTh. Published November 23, 2015. Accessed February 10, 2016.
8. FDA News Release: FDA approves Keytruda for advanced melanoma. U.S. Food and Drug Administration Web Site. Published September 4, 2014. Accessed February 10, 2016.
9. FDA News Release: FDA approves Keytruda for advanced non-small cell lung cancer. U.S. Food and Drug Administration Web Site. https://1.usa.gov/1hgkNfa. Published October 2, 2015. Accessed February 10, 2016.
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12. Restifo NP, Smyth MJ, Snyder A. Acquired resistance to immunotherapy and future challenges. Nat Rev Cancer. 2016;16:121-126.
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