David L. Porter, MD
Antoni Ribas, MD, PhD
Suresh S. Ramalingam, MD
More than 100 years after William B. Coley, MD, used bacterial toxins to goad the immune system into recognizing cancer cells as foreign to the body and mount an immune response to go after and kill them, the recognition of immunotherapy as a powerful anticancer therapy is finally being realized. Just 5 years ago, data were presented at the ASCO Annual Meeting from a phase III study1 of the immunotherapy ipilimumab (Yervoy), which showed improved survival of patients with advanced melanoma. It was the first new treatment for metastatic melanoma in more than a decade.2 Ipilimumab is now also U.S. Food and Drug Administration (FDA) approved in the treatment of lung cancer.
Today, immunotherapy for the treatment of a variety of cancers is rapidly evolving from therapies that nonspecifically stimulate the immune system to more targeted ones that activate individual components of the immune system, increasing efficacy of the treatment while decreasing toxicity. These newer immunotherapies, including nivolumab (Opdivo) and pembrolizumab (Keytruda), both approved in the treatment of non–small cell lung cancer and melanoma, inhibit interaction between programmed cell death protein 1 (PD-1, present on the surface of activated lymphocytes) and its ligand (PD-L1, present on the surface of tumor or antigen-presenting cells).
In addition to checkpoint inhibitors, other types of immunotherapies, such as adoptive cell transfer therapy and chimeric antigen receptor (CAR)–T-cell therapy are also proving to be effective in the treatment of some cancers, especially B-cell malignancies like chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).
In the 5 years since the FDA approved ipilimumab, more than 20 other antibody-based drugs, including new immunotherapies for colorectal cancer, neuroblastoma, renal cell carcinoma, and multiple myeloma, have been approved by the FDA,3 prompting ASCO to name cancer immunotherapy its 2016 Advance of the Year.4 The continued success of immunotherapy in providing durable remissions for some patients with advanced cancers has led to the therapy becoming the “fifth pillar” in cancer treatment, following radiotherapy, surgery, chemotherapy, and molecularly targeted therapy.
To gain a better understanding of the current state of immunotherapy progress and what advances are expected over the next decade, The ASCO Post held a roundtable discussion with three experts in the field of immunotherapy: David L. Porter, MD, Jodi Fisher Horowitz Professor in Leukemia Care Excellence and Director of Blood and Marrow Transplantation at the Abramson Cancer Center of the University of Pennsylvania; Suresh S. Ramalingam, MD, Assistant Dean for Cancer Research and Deputy Director of Winship Cancer Institute of Emory University; and Antoni Ribas, MD, PhD, Director of the Tumor Immunology Program at Jonsson Comprehensive Cancer Center, Chair of the Melanoma Committee at SWOG, and team leader of the SU2C Scientific Research Team in Immunologic Checkpoint Blockade and Adoptive Cell Transfer in Cancer Therapy.
Potential of Immunotherapy
How is immunotherapy already changing clinical practice in the treatment of a variety of cancers, and what is its potential in cancer care?
We are now using completely new approaches in the treatment of [cancer]. It took a long time to get here, although it seems so logical to try stimulating and manipulating the immune system to attack cancer cells. The potential in oncology right now is enormous and seemingly limitless.— David L. Porter, MD
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Dr. Porter: Immunotherapy is revolutionizing cancer care. We are now using completely new approaches in the treatment of the disease. It took a long time to get here, although it seems so logical to try stimulating and manipulating the immune system to attack cancer cells. The potential in oncology right now is enormous and seemingly limitless. Some of the issues we are grappling with are how to control the immune system and how to target it to go after specific types of tumors.
Dr. Ramalingam: Clearly, immunotherapy is already part of routine care for patients with lung cancer. Last year, two immunotherapy agents, nivolumab and pembrolizumab, were FDA approved in the treatment of lung cancer, and as a result, the second-line or salvage therapy paradigm for lung cancer has already changed. This speaks to how quickly these agents have made an impact from the time the initial phase I study reported promising responses.
We now know that these agents are active in a subset of patients with lung cancer, and that brings about a lot of interesting questions, including how do we identify these patients before we start therapy, and what can we do to convert a nonresponding patient into a responding one? These questions are just beginning to be asked, and a number of preclinical and clinical efforts are underway, seeking to extend the benefits of immune checkpoint inhibitors to a greater number of patients and to see whether we can move these drugs from the metastatic disease treatment setting to the curative setting for early-stage disease.
Dr. Ribas: For over 100 years, we had anecdotal findings that immunotherapy with either a vaccine or injections of a bacterial or viral toxin or a cytokine led to cancer regression. But these therapies only worked in a minority of patients.
Because the findings were mostly anecdotal and the therapy worked only occasionally, for a long time immunotherapy was not taken seriously as a viable cancer treatment. I think the conceptual change in the potential for immunotherapy came with the idea promoted by Dr. James Allison [Chairman of Immunology at The University of Texas MD Anderson Cancer Center] that what was limiting the immune system to fight the cancer was not its inability to be turned on, but its being turned off by regulators of the immune system or checkpoints.
How Immunotherapies Work
How do PD-1/PD-L1 checkpoint inhibitors and other emerging immunotherapeutic strategies, such as therapeutic vaccines and T-cell therapies, work to control tumor growth and/or eradicate cancers?
Dr. Porter: For an immune reaction to work, it has to be stimulated. However, what we have learned over the past several years is that this process has to be tightly regulated.
We often use a car analogy to describe how to rev up the immune system to attack cancer cells by turning on the ignition switch on a T cell and pressing the gas pedal, but you also have to be able to apply the brakes, because you can’t have an effective immune system that is out of control.
The T-cell therapies that have gotten so much attention recently are trying to take the human immune system and manipulate it so it can target specific tumor cells. If a patient has cancer, by definition, his or her immune system is not capable of killing that cancer for a variety of reasons. It may be that the immune system is blocked or, using the car analogy, the brakes are on. Or it may be that the immune system is not recognizing that the cancer cells are abnormal.
One of the exciting advances over the past 7 years has been in our ability to manipulate T cells so that they can recognize tumor cells and kill them. That process is the basis of our research in CAR–T-cell therapy for patients with CLL and ALL, which involves isolating a patient’s own T cells and genetically modifying them to express chimeric antigen receptors or even novel T-cell receptors that recognize tumor cells. The modified cells are designed to attack the CD19 protein expressed on the surface of B-cell malignancies. The reengineered cells are expanded and then injected back into the patient.
The PD-1/PD-L1 inhibitors are appealing because of their ability to achieve anticancer effects in the form of durable responses, improvements in survival, and less toxicity for patients. Checkpoint inhibitors have opened the door to other novel ways to stimulate the immune system and upregulate anticancer immunity.— Suresh S. Ramalingam, MD
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Dr. Ramalingam: The PD-1/PD-L1 inhibitors are appealing because of their ability to achieve anticancer effects in the form of durable responses, improvements in survival, and less toxicity for patients. Checkpoint inhibitors have opened the door to other novel ways to stimulate the immune system and upregulate anticancer immunity. For example, if we were to use a vaccine in conjunction with PD-1/PD-L1 inhibitors, one might hypothesize that the antitumor effect would be greater.
For a long time, vaccine approaches have not been successful. But by using vaccines with immune checkpoint inhibitors, we may begin to see success stories emerge.
Dr. Ribas: PD-1 and PD-L1 turn off T-cell activation, preventing T cells from attacking the cancer. These T cells make interferons, and the tumor has a mechanism to protect itself from a T cell that makes interferons in the vicinity, which is the expression of PD-L1.
Many immunotherapies developed in the past may not have made it to FDA approval because once the T cells made their way into the tumor, the tumor had a way of protecting itself. Now, a variety of immunotherapies that were thought to be either inactive or marginally active are getting another look because they might have new life when used in combination with the checkpoint inhibitors.
Increasing Lung Cancer Survival Rates
How can the success of pembrolizumab and nivolumab in increasing survival rates for patients with advanced lung cancer be increased? Are there novel approaches to enhance their effectiveness?
Dr. Ramalingam: Yes. These immune checkpoint inhibitors are currently used in lung cancer in the salvage setting. Clinical trials underway are comparing checkpoint inhibitors to platinum-based chemotherapy in newly diagnosed patients with advanced lung cancer. The results of those trials could usher in a new era in which first-line therapy—at least for a subset of lung cancer patients—would be immunotherapy and not chemotherapy. So movement to the front-line setting for these agents is a potential advance that is coming.
The second area for advancement is in the use of checkpoint inhibitors in conjunction with proven targeted therapies in the treatment of lung cancer. We know that for patients with EGFR mutations and ALK translocation, there are very effective targeted therapies that are standard of care. Now, there are efforts to combine these targeted agents with checkpoint inhibitors. While we do not have clinical data yet, it is conceivable that we may see that the benefits of targeted therapies may be extended with the use of immune checkpoint inhibitors.
Potential for Curing CLL and ALL
In studies of CTL019 (a CAR–T-cell therapy) in patients with CLL and ALL, some patients have experienced sustained remissions, in some cases lasting years. What is the current status of those patients, and is curing these cancers possible?
Dr. Porter: We now have patients with CLL, who had largely exhausted all conventional therapies, in remission for more than 5 years after treatment with CAR–T-cell therapy. There is no evidence of leukemia on any measure of residual disease, and the leukemia seems to have been eradicated. We have found similar long-term remissions in some patients with ALL.
We don’t know if they have been cured; it will take longer follow-up with these patients to know that for sure. But it is encouraging to see that there is no detectable tumor in patients who would have been expected to relapse a long time ago. Certainly, our intent is to try and develop this T-cell therapy as a possible cure for patients, and I must say that I am optimistic that this is going to be possible.
Combining Immunotherapies in Advanced Melanoma
Current investigations are exploring factors limiting the efficacy and wide applicability of tumor immunotherapy and how the combination of checkpoint blockade and adoptive cell transfer might be more effective in treating advanced melanoma and other solid tumors. What have these studies revealed so far?
Dr. Ribas: If we can determine why these therapies work in some patients but not in others, then we will be better at developing the next generation of studies. The advances we have seen so far have not been random. They have been achieved by applying scientific knowledge to developing drugs that are supposed to do a particular thing. Understanding the immunobiology of cancer has allowed us to make this progress.
The advances we have seen so far have not been random. They have been achieved by applying scientific knowledge to developing drugs that are supposed to do a particular thing. Understanding the immunobiology of cancer has allowed us to make this progress.— Antoni Ribas, MD, PhD
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What we are learning is that PD-1 blockade immunotherapy works in patients whose immune system was turned off by the cancer. The patients in whom the therapy does not work lack preexisting T cells in the tumor. With this knowledge, the logical next step is to test combinations that could bring T cells into tumors or, in cases where there are no T cells to be brought in, to genetically engineer the T cells to target the cancer and then infuse them in an adoptive cell transfer protocol.
What advances do you see happening in the development and use of immunotherapy in the treatment of cancer over the next 5 to 10 years?
Dr. Porter: Identifying which patients would benefit most from this therapy is one area. I think we will learn what features make immunotherapy effective, and it may have to do with the health of a person’s immune system. If we can identify the factors that allow someone’s T cells to be more effective against cancer compared to someone else’s, we can identify those patients who are most likely to respond. We would also be able to try repairing immune defects in a specific patient so the therapy is more likely to work.
Another area for advancement is the ability to identify targets in a variety of tumors to make immunotherapy an effective therapy for many types of cancer. CD19 is an almost ideal tumor target, but ideal tumor targets are not found on many other cancers. There is a great deal of work being done to identify tumor-specific targets on different cancers, and once you are able to do that, you can apply this type of immunotherapy technology to those other cancers.
Over the next 5 to 10 years, we will see a lot of activity targeting different antigens on different tumor types. It is also logical to start using combination immunotherapies in the treatment of cancer. For example, CAR–T-cell therapy requires the T cell to recognize its target and become activated. But you may be in a situation where T-cell activation is suppressed, perhaps by checkpoint molecules, and that may be one reason why CAR–T-cell therapy does not work in some patients.
I can easily envision a combination of a CAR–T cell and a checkpoint inhibitor that allows the T cell to be more activated in the tumor environment, so combinations of both T-cell immunotherapy with checkpoint blockade is one logical step. The idea of combining different modalities in different molecules is very exciting, and hopefully, it will be very fruitful for many patients.
Dr. Ramalingam: I agree with Dr. Porter. We are going to see a lot of combination approaches over the next decade. We now have a better understanding of various other checkpoints that are involved in recognizing the tumor and an antitumor immune response against the tumor, so novel combinations that take advantage of these checkpoints to maximize the benefits of immunotherapies is an area where I am very optimistic about progress being made.
The other area is the setting in which disease burden is minimal—for example, in a patient with resected lung cancer—where the immune checkpoint inhibitors can do what conventional treatment modalities could not do, which is to cure a greater proportion of patients. Our goal is to cure patients’ cancer, and if immunotherapy can take us closer to attaining that goal, or at least achieve cure for a subset of patients, then we would have done a great deal of service for our patients.
This is an exciting time to be an oncologist specializing in lung cancer because there are so many promising and proven options for patients now. We are seeing significant improvement in patient outcomes for patients with lung cancer, and it is very encouraging.
Dr. Ribas: I also agree. We will make a lot of progress over the next 5 to 10 years in immunotherapy for cancer. We will figure out which patients are best served by being treated with immunotherapy and which patients are unlikely to benefit.
For those patients unlikely to benefit by immunotherapy alone, we have the potential of creating an immune system that is targeted to the cancer through adoptive cell transfer therapy or genetically engineered T cells. Other times, the immune system is not turned on but the tumor is immunogenic, so we just need to unleash the T cells inside the patient’s immune system to attack the cancer. ■
Disclosure: Dr. Porter receives research support from Novartis and is listed as an inventor on a patent for CTL019 technology, entitling him to future royalties. Dr. Ramalingam is on the advisory board of Abbie, AstraZeneca, Bristol-Myers Squibb, Celgene, Lilly, Genentech, Novartis, Merck, and Boehringer Ingelheim. Dr. Ribas is a consultant or advisor for Amgen, Genentech, Merck, Novartis, and Pierre Fabre and is on the scientific advisory board of and owns stock in Acteris, Arcus, Compugen, Five Prime, Flexus Bio, and Kite Pharma.
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. 2011 ASCO Annual Meeting. Abstract LBA5.
2. Melanoma Research Foundation: FDA approval of new melanoma therapy changes landscape for patients. Posted March 25, 2011. Available at melanoma.org. Accessed April 5, 2016.
3. Cancer Research Institute: Immunotherapy approvals in 2015. Available at cancerresearch.org/news-publications/our-blog/december-2015/immunotherapy-approvals-in-2015. Accessed April 5, 2016.
4. 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. J Clin Oncol 34:987-1011, 2016.