Advancing Immune Checkpoint Targeting in Cancer Treatment

A Conversation With James P. Allison, PhD


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James P. Allison, PhD

Ronald DePinho, MD

I think we have to focus on how to increase the durable effect of cancer therapies, and it’s going to require some thinking about how to combine immunotherapies with other agents to improve durable antitumor responses.

—James P. Allison, PhD

James P. Allison, PhD, Professor and Chair of the Department of Immunology, Executive Director of the Moon Shots Immunotherapy Platform, and Deputy Directory of the David H. Koch Center for Applied Research of Genitourinary Cancers at The University of Texas MD Anderson Cancer Center, Houston, is renowned for his groundbreaking research in cancer immunotherapy.

As a young investigator at The University of Texas in the early 1980s, Dr. Allison identified the antigen receptor CTLA-4 on the surface of T cells that functions as an ignition switch, turning on an immune response when it comes in contact with a foreign antigen. In 1992, while a professor at the University of California, Berkeley, Dr. Allison identified a second molecule on the surface of T cells, called CD28, which acts as the T cell’s gas pedal, accelerating immune response.

He and another investigator, Jeffrey Bluestone, PhD, Executive Vice Chancellor and Provost at the University of California, San Francisco, performed independent experiments and identified CTLA-4 as an inhibitory checkpoint molecule, which acted to restrict activated T-cell responses. Dr. Allison then proposed blockade of CTLA-4 as a way to enhance activated T-cell responses against cancer.

In laboratory studies with an antibody to CTLA-4, Dr. Allison found that 90% of cancers in treated mice disappeared. In 2011, ipillimumab (Yervoy), an antibody to human CTLA-4, proved successful in human clinical trials in the treatment of melanoma and was approved by the U.S. Food and Drug Administration as standard therapy for patients with metastatic melanoma. While statistics show that about 25% of patients with late-stage melanoma who took ipilimumab in clinical trials have lived 5 years or longer, Dr. Allison said that recent studies actually show prolonged immune response and longer overall survival in some patients. “That tail of the survival curve appears to be quite durable,” said Dr. Allison.

Today, immune checkpoint targeting in which the immune system is used to destroy cancer has become the new paradigm for cancer treatment and is a major component of MD Anderson Cancer Center’s “Moon Shots” program, an ambitious endeavor to reduce cancer deaths over the next decade. In an interview with The ASCO Post, Ronald DePinho, MD, President of MD Anderson Cancer Center, cited Dr. Allison’s research with helping to achieve that goal. “Thanks to the work of many, particularly Jim Allison’s, there is a solid likelihood that we will reach our goal of reducing mortality from advanced melanoma by at least 50% in the next 5 to 10 years,” said Dr. DePinho. (See “Conversation With Ronald DePinho, MD,” in the May 15, 2014, issue of The ASCO Post.)

Dr. Allison has been recognized for his contribution to cancer immunology with numerous awards. In 2013, Science magazine named cancer immunotherapy its Breakthrough of the Year, citing Dr. Allison’s work as crucial to immunotherapy’s rapid advancement, and The Economist honored him with its Innovations Award in Bioscience. This year, Dr. Allison was the recipient of the Szent-Györgyi Prize, the Canada Gairdner International Award, and the American Association for Cancer Research GHA Clowes Memorial Award.

The ASCO Post talked with Dr. Allison about the Moon Shots program and the role of the Immunotherapy Platform to achieve its goals, the promise of immune checkpoint targeting in a variety of cancers, and his unforgettable one-night gig playing harmonica with Willie Nelson.

Immunotherapy Platform Components

Please talk about the goals of the Immunotherapy Platform in MD Anderson’s Moon Shots program.

The whole purpose of the immunotherapy platform is to perform in-depth immune monitoring studies, including immunopathology analyses, in the context of patient samples obtained from clinical trials of immunotherapeutic drugs such as anti–CTLA-4 and anti–PD-1 agents. Data from these studies will generate hypotheses regarding mechanisms that contribute to tumor rejection, which can be tested in preclinical models. Studies in preclinical models provide data to help in the development of novel immunotherapy strategies to hopefully benefit even more patients with cancer.

We tried to put together a unified array of experimental approaches to understand—on the cellular and molecular level—the consequences of giving drugs that impact the human immune system. The goal of that is to guide the development of treatment combinations to increase therapeutic efficacy. We knew, for example, that CTLA-4 blockade and PD-1 blockade impacted antitumor immune responses differently in preclinical models, which indicated that combined blockade of CTLA-4 and PD-1 may be beneficial clinically.

The immunologic monitoring component is tasked with performing cytometry techniques to define different subsets of cells within the immune system and to perform functional studies on selected subsets. But this component also takes that process a step further, using expression arrays and NanoString technology to get an idea on the message level of the changes in specific cells, such as T cells. We are currently in the process of setting up a system to do mass cytometry analysis as well.

The second component is molecular pathology. We wanted to do very specialized immunopathology, not disease-based pathology, because it’s becoming apparent that there are multiple immune inhibitory pathway checkpoints, and the expression of these inhibitory molecules (such as PD-1 or LAG-3 on T cells and B7-H3 or B7-H4 on tumor cells) may be clues as to what combination treatments need to be considered for eliciting effective antitumor immune responses.

We also want to look for patterns of expression of different immunologic molecules in the different types of cancer. We want to know whether there are specific patterns associated with certain types of cancer or whether any patterns are random. Also, we want to know how treatment changes the tumor microenvironment.

The third component—the preclinical studies part—is meant to achieve two goals. One is to determine the impact of different agents, such as targeted therapies and chemotherapies, on the immune system. The second is to test hypotheses that are generated as a result of data obtained from the immune monitoring studies performed in the context of the different clinical trials, as previously mentioned.

 

Can you offer an example of the preclinical studies component?

My colleague, Padmanee Sharma, MD, PhD [Scientific Director of the Immunotherapy Platform], noticed in one of her presurgical trials that there was a great amplification of a kind of T cell (CD4-positive/ICOS-high) that expresses a molecule called ICOS (inducible T-cell costimulator). Dr. Sharma designed a presurgical study to treat 12 localized bladder cancer patients with anti–CTLA-4 to evaluate the impact of anti–CTLA-4 on human immune responses in both peripheral blood and tumor samples obtained from scheduled surgeries that removed the patients’ bladders.1 The purpose of the study was to obtain data regarding human immune responses after treatment with anti–CTLA-4 and, most importantly, to understand the impact of the drug on the immune responses with the tumor microenvironment.

In her study, Dr. Sharma found that these ICOS-positive cells can act as effector T cells, which produce the Th1 cytokine interferon-gamma. In collaboration with Dr. Sharma, we found that melanoma patients who had sustained levels of ICOS-positive cells had longer survival rates than patients without sustained levels of CD4-positive/ICOS-high T cells. This raises the possibility that ICOS-positive cells might be important in the therapeutic effects of anti–CTLA-4 agents.

To test that hypothesis, Dr. Sharma studied ICOS or its ligand (ICOSL) in mouse models treated with CTLA-4 and found that the treatment was much less effective in mice that lack either ICOS or ICOSL.2 These data raised the possibility that targeting ICOS might enhance the efficacy of anti–CTLA-4, which we recently showed to be the case.

These types of studies that combine expertise in clinical trials, translational research, and basic science form the foundation of the Immunotherapy Platform. We are taking an integrated scientific approach to really understand what is going on in the immune system and tumor microenvironment and see if we can gain insight into biomarkers and new targets. We are also working with several drug manufacturers to develop immunology-based therapies and study them in both preclinical models and clinical trials.

Clinical Trials

As part of the Immunotherapy Platform initiative you are launching clinical trials in melanoma, breast, lung, colon, and pancreatic cancers. What is the goal of those studies?

To determine whether the blockade of CTLA-4 or PD-1, or both, is efficacious in all those tumor types. That’s one goal. Another goal is to investigate the combination of an immunotherapy with other drugs, such as a tyrosine kinase inhibitor, or treatment modalities, such as radiation therapy.

Role of Ipilimumab

Ipilimumab is effective in about one-quarter of patients with late-stage melanoma. Do you know why the drug works really well in some patients and not in others?

One possibility is that there are multiple checkpoint molecules in melanoma, so some patients who do not respond to ipilimumab do respond to nivolumab, an investigational anti–PD-1 antibody, and vice versa. For patients who don’t respond to either agent alone, combining the two drugs might be more effective. A study presented at last year’s ASCO Annual Meeting found that patients with advanced melanoma who were treated with a combination of ipilimumab and nivolumab had a nearly 50% response rate.3

Some melanoma patients have very long, durable responses. While “cure” is a loaded term, I know a patient from an early phase I trial of ipilimumab who has been in remission for almost 14 years after just a single injection. Is she cured? I don’t know, but she thinks she is cured. Another melanoma patient, while not in complete remission, has had stable disease for 9 years without subsequent treatment and has had two children during that time.

Since ipilimumab treats the immune system rather than the tumor directly, it is also showing effectiveness in the treatment of other cancers, including prostate, renal, and some lung cancers. We also have anecdotal evidence that the drug may work in ovarian and pancreatic cancers, but we have to do the clinical trials.

Long-Term Goal

What is the long-term promise of immune checkpoint targeting in cancer therapy? To increase durable remissions?

Yes, that’s the goal. To be slightly controversial, I think the goal of cancer clinical trials should not be to get an increase in median survival of just a few months. We know we can do much better than that with both anti–CTLA-4 and anti–PD-1 therapies since they can provide durable antitumor responses. I think we have to focus on how to increase the durable effect of cancer therapies, and it’s going to require some thinking about how to combine immunotherapies with other agents to improve durable antitumor responses. We also need to consider what endpoints need to be evaluated for a drug or drug combination to become approved, because we can’t take a lot of years to test all the combinations for survival benefit.

The bigger point becomes, if you have a therapy or combination strategy that is showing objective responses in a phase I trial, there has to be an acceptable way of shortening the study process, so that the drugs can get to patients faster.

Musical Sidelight

In 1975, during your postdoctoral fellowship at Scripps Clinic and Research Foundation, you found yourself on stage playing harmonica with country legend Willie Nelson. Was that experience as exciting as the research you were doing?

Oh, yes. I had been a Willie Nelson fan for years—and I still am. For a couple of years, I had played harmonica with Clay Baker and the Texas Honky Tonk Band at the Stingaree bar in San Diego. I got an invitation to a party Willie’s record label was throwing to celebrate the sale of over a million copies of his hit album The Red Headed Stranger. When Willie asked me where he could play some music the next night, I suggested Stingaree. I joined Willie on stage, accompanying him on “Blue Eyes Crying in the Rain.” It was only that one song and that one night, but I’ll never forget it. ■


References

1. Carthon BC, Wolchok JD, Yuan J, et al: Preoperative CTLA-4 blockage: Tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 16:2861-2871, 2010.

2. Fu T, He Q, Sharma P: The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res 71:5445-5454, 2011.

3. Wolchok, JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9012. Presented June 3, 2013.



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