Immunotherapy will define new era of GU cancer care

Dr. BelldegrunCancer immunotherapy offers myriad advantages, including specificity and durability of response, but questions remain about its cost and what role the urologist should play in treatment. In this interview, Arie Belldegrun, MD, discusses the benefits of immunotherapy, the importance of a multidisciplinary treatment approach, and what the future holds for this treatment. Dr. Belldegrun is professor of urology, The Roy and Carol Doumani Chair in Urologic Oncology, and director of the UCLA Institute of Urologic Oncology at the David Geffen School of Medicine at UCLA. He is founder and CEO of Kite Pharma, a biopharmaceutical company dedicated to the development of immune-based and engineered autologous T-cell therapies.

Please provide an overview of cancer immunotherapy and how urologists are using it.

Cancer immunotherapy, named as the 2013 “Breakthrough of the Year” by Science magazine, is a treatment modality that harnesses the power of the immune system to fight and reject the patient’s own cancer. Urologists were among the first to apply the power of immunotherapy in the clinic by using instillation of bacillus Calmette-Guérin (BCG) into the bladder for the treatment of superficial bladder cancer, and BCG is all about local immunotherapy.

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Two decades later, in 1985, interleukin-2 (IL-2), the first immunotherapy capable of mediating complete tumor regression of metastatic tumor deposits, was described. Urologists became familiar with IL-2 after its historic approval in 1992 for the treatment of patients with metastatic kidney cancer. It then remained the only approved drug for advanced renal cancer for the next 15 years, until the emergence of targeted therapy.

In 2010, patients with hormone-refractory prostate cancer who received an immune cancer vaccine called sipuleucel-T demonstrated improved survival over placebo; sipuleucel-T was approved by the FDA later that year. At the same time, a huge step forward in the field of cancer immunotherapy was achieved when clinical evidence emerged that the administration of an antibody targeting inhibitory T-cell costimulatory molecules CTLA-4 and/or PD-1 could generate significant regressions of metastatic cancer in patients, including kidney and bladder cancers. This gave birth to a new field of clinical investigation called checkpoint modulators or inhibitors.

Urologists have therefore been deeply entrenched in immunotherapy for over 5 decades now. The last several years, however, have witnessed a huge revolution in the field with dramatic clinical advances yet to come.

Next: Advantages over other treatments

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You’ve alluded to one advantage of immunotherapy, which is that it’s very targeted. What are some other advantages it has over other systemic treatments?

Specificity is the most important characteristic; immunotherapy attacks the cancer cells and spares normal cells. Durability is next: T-cell memory cells continue to circulate in the blood for many years and once they identify new cancer cells in the body, even in the form of mutated cancer cells, they will launch an attack and destroy these newly formed cancer cells. Third, although cancer’s heterogeneity evolves over time, the immune system still recognizes the cancer as foreign. Heterogeneity creates a problem for targeted cancer therapy since these treatments are directed against a specific target; immunotherapy overcomes this issue.

What is most impressive with immunotherapy is that once a complete response has been achieved, it sustains for many years. In my personal experience, it is very rare for these patients to have cancer recurrence; I have patients who have had metastatic kidney cancer for two decades and are still responding to their original immunotherapy. Unfortunately, these success cases are still in the minority and therefore the question is how to increase that percentage of patients.

What do you consider the most exciting area now where immunotherapy would be most effective?

That’s a very timely question. For years, metastatic kidney tumors were considered the best responders to immunotherapy among the urologic cancers. In addition, there’s the superficial bladder tumor, which can be treated with BCG.

However, at the 2014 American Society of Clinical Oncology annual meeting, much-anticipated data was presented about a new immunotherapy agent called anti-PD-L1. It is a monoclonal antibody, a member of the checkpoint modulators growing family, that has demonstrated impressive clinical activity against advanced bladder cancer. It was a small study, with only about 40 patients, but it showed, for the first time, the power of immunotherapy to eradicate metastatic bladder cancer in patients who previously failed chemotherapy. Seventy-one percent of these patients had failed two prior treatments. The response rate was quite astounding at about 50%, with one complete responder and nine partial responders.

Eventually, if it pans out the way this small study showed, we’ll see immunotherapy replacing chemotherapy as first-line therapy for bladder cancer in the very near future.

Next: The importance of multi-disciplinary clinics

As a urologist, these kinds of treatments raise some questions and concerns. How will these treatments be delivered, and by whom? Will the patient need to travel to an infusion center and, if so, will a medical oncologist be then in charge of the patient’s care? Is there any change in the delivery of immunotherapy that might be more practical to the urologist?

That’s a very good question. Urologists must face the fact that most of the new generation of selective anti-cancer therapies are not going to come in the form of an oral pill that is easy to prescribe. Delivery might be more complex and require a different type of training. In my mind, as those new therapies will make their way to first-line treatments, multidisciplinary clinics will be the only way for the urologist to stay involved in the care of the patient and help in the decision-making process.

At UCLA, we have separate clinics for kidney, bladder, and prostate cancers all under one roof of the Institute of Urologic Oncology. The joint clinics include urologists, medical oncologists, and radiation therapists working together and making joint recommendations regarding surgery, immunotherapy, chemotherapy, or radiation, including the sequence of these therapies. In such a way, the urologist maintains full control on his part of the patient’s care. In any other format, urologists will start losing control of the patient and decisions to delay surgery will be done without him. We are already witnessing this trend in the management of kidney cancer in the community.

The role of, and the need for, surgery in the management of urologic cancers in the era of these new immunotherapies and targeted therapies is currently being redefined. Urologists must take a seat at the table where these critical decisions are being made. This will also require the urologists to participate in the design of meaningful clinical trials. Without clear and well-defined surgical endpoints for these new combination therapies, urologists will be left out and new practice guidelines will be created that will defer many of our mainstream surgical cancer procedures.

We are already witnessing it in the need for, and timing of, radical nephrectomies in patients with advanced kidney cancer. The role of radical cystectomy in invasive bladder cancer will come next. For example, radical cystectomy is still the Holy Grail for the management of muscle-invasive bladder cancer. But if early anti-PD-L1 data is confirmed in larger studies, it can become first-line therapy with or without surgery. Urologists must be involved in these clinical decisions.

Next: Immunotherapy in the next 5 to 10 years

Where do you see immunotherapy in the next 5 to 10 years? Do you see other cancers and other disease sites where this might be appropriate?

My prediction is that in the next 5 years, at least half of all oncologic cases will be managed by, or in combination with, immunotherapy. Immunotherapy will replace many existing treatments. Chemotherapy will be relegated to salvage therapy. Cancer therapy will be managed by immunotherapy, hormonal therapy, and targeted cancer therapy. How surgery will be incorporated in this treatment paradigm is yet to be defined and therefore, again, urologists must be active participants in the process.

As for the second part of your question, hundreds of clinical trials are currently exploring other potential avenues for immunotherapy. Undoubtedly, the utility of immunotherapy will expand beyond our current thinking. One example is sarcoma, a very aggressive type of cancer. For years, at the National Cancer Institute, we tried immunotherapy with interleukin-2, and other types of therapy with very poor responses. However, at the 2014 American Association for Cancer Research annual meeting, Dr. Steven Rosenberg presented data showing that two-thirds of the sarcoma patients he treated with a new form of adoptive cell therapy called engineered TCR experienced significant responses, some of which lasted for several years. This therapy requires only a single infusion of activated T-cells engineered to express a tumor antigen called NY-ESO-1.

More recently, in a paper published in Science (2014; 344:641-4), the same group was able to successfully treat a patient with cholangiocarcinoma, a rare type of cancer, using autologous T-cells directed against a specific mutation that occurred in this particular tumor. These examples highlight the great potential for new versions of personalized immunotherapy that are currently being investigated for multiple cancer indications.

Next: "I personally believe that tumor volume will play an important role in response to immunotherapy"

Do you think that tumor volume is going to be an important factor in the delivery of immunotherapy? Will surgery play a part at least in de-bulking some of these tumors?

I personally believe that tumor volume will play an important role in response to immunotherapy, and I can see the utility for de-bulking ahead of immunotherapy onset. The evidence, however, will have to be established in controlled clinical trials. I recommend starting to ask these questions now; otherwise therapies like anti-PD-1, PD-L1, anti CTLA-4, and others will be advanced to earlier and earlier disease stages without ever fully understanding the role of de-bulking.

A decade ago, as IL-2 and interferon were introduced for the therapy of advanced kidney cancer, Dr. Robert Flanigan and others conducted an important study investigating the role of cytoreductive nephrectomy for these patients. The data, published in the New England Journal of Medicine (2001; 345:1655-9), established the rationale for performing radical nephrectomy before immunotherapy; this became standard of care for many years. The same questions will need to be addressed for the newer forms of immunotherapy.

In immunotherapy with vaccines, you have to have a boost. Is that true with cancer immunotherapy as well?

Checkpoint inhibitors are monoclonal antibodies that need to be given repetitively every 2 to 3 weeks by IV administration. The newer immunotherapies, in the form of engineered activated T-cells, are currently being tested as single-infusion therapy with no need for additional therapy. These T-cells continue to proliferate in the body and retain memory for many years. Therefore, unlike with vaccines, this is a living treatment that does not require any additional boost. In the future, however, as the field continues to evolve, I can foresee the introduction of combination immunotherapy with intermittent administration of cancer vaccines as boosts. Again, this will have to be tested in clinical trials.

One of the arguments against immunotherapies is the high cost. Are these treatments going to be sustainable from a cost standpoint?

Yes, these treatments are expensive. But even the best targeted therapies have to be taken chronically and rarely lead to complete cancer remission. With the newer types of immunotherapy, we are facing a growing population of patients with complete response that do not need continuous therapy. Engineered T-cells are given once as a single infusion. So the cost proposition makes more sense as you start to think about the annualized cost of therapy. I also believe as the process is further optimized and automated, the cost will be reduced dramatically over time.

Next: "What’s most important is for young urologists to get involved"

Do you have anything else that you’d like to add?

What’s most important is for young urologists to get involved. Twenty-seven years ago, I was a fellow at the National Cancer Institute and started to work on immunotherapy. At that time, we talked about mouse experiments; there was no human data. Flashing forward, Science named cancer immunotherapy its 2013 “Breakthrough of the Year.”

So we’ve come a long way, but the progress continues to accelerate and the field will keep evolving. This is the most exciting time in my academic career and I’m witnessing rapid changes on almost a daily basis. After many years of basic and molecular research, we are finally equipped with all the right tools to create new therapies and for the first time, we are starting to talk about cancer cures rather than just persistent long remission. The bottom line is this is one of the hottest areas in urology, and young urologists should get involved.

It sounds like we will need to have more postgraduate courses and instructional courses on immunotherapy and practical deliveries of targeted immunotherapy.

Yes, we will and the Society of Urologic Oncology should take the lead in conducting clinical trials, integrating surgery with other forms of therapy, and educating the members and practicing urologists of all the new developments in the field.

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