Dr. Raoul S. Concepcion presented “What’s New in Immunotherapy for Prostate Cancer?” at the 27th annual International Prostate Cancer Update meeting on Thursday, January 26, 2017.

 

 

Keywords: prostate cancer, antigen, CTLA-4,  immunotherapy, metastatic, prostatectomy, PSA, Sipuleucel-T, T-cell, immunotherapy for prostate cancer

How to cite: Concepcion, Raoul S. “What’s New in Immunotherapy?” January 26, 2017. Accessed Aug 2020. https://grandroundsinurology.com/whats-new-immunotherapy

Summary:

Dr. Raoul S. Concepcion discusses the shift in urology practices toward using immunotherapy for prostate cancer and bladder cancer, and the rise of checkpoint inhibitors. He cites trials of sipuleucel-T and PROSTVAC-Tricom.

Edited Transcript

 

Immunotherapy is the newest approach for treating and preventing prostate and bladder cancer.

To explore this topic, I will move the focus away from individual drugs. I feel it is more important to discuss checkpoint inhibitors, CTLA-4, PD-1, PD-L1, and costimulatory molecules when it comes to developing a full understanding of immunotherapy. In order to understand how these drugs work, we need to go back to immunology 101. A couple of years ago, immunology could be taught in a two-week course. Now, it would take two years to teach the subject.

Immunotherapy Diagram
So, let’s talk about current therapeutics that can be used for the management of metastatic castration-resistant prostate cancer. There are traditional therapies, such as cytotoxic chemotherapy, including docetaxel and cabazitaxel. There is also hormonal therapy. We know bone targeting therapy, including anti-resorptive agents like denosumab or zoledronic acid, receives a lot of attention lately. Furthermore, we have an Alpharadin pharmaceutical agent that’s FDA approved with a survival benefit. It’s also called Radium-223, or Xofigo.
But what about immunotherapy? This is where we’re going to concentrate most of the efforts for this lecture. Again, this is going to be more theoretical than specific, but hopefully educational. We’ve been looking at cancer immunotherapy for a number of years. It’s becoming more and more effective across all tumor types. While not much has been going on with bladder cancer, immunotherapy has been able to make a mark on that front.
Renaissance of Immunotherapy
In the early days, immunotherapy started with Dr. Coley noticing an association in patients undergoing treatment for sarcomas and infections. He took extracts of strep and Serratia and injected them into tumors, then saw the tumors regress to some degree. This was the original Coley’s toxin. Just a bit of trivia: Coley brought his attention to this practice after one of his patients died of an infection. I believe this woman was somehow related to John D, Rockefeller. Because of this, Rockefeller developed an interest for medical research and made large donations to the cause. At any rate, as urologists, we’ve been using BCG for management of non-muscle invasive bladder cancer for many years. We’ve seen a whole proliferation of agents with various types. Really, it’s all immunotherapy. It’s a rather encompassing term.
Tumor Cells
Moving on, here is what the micro-tumor environment looks like. There are cancer cells, macrophages, natural killer cells, T-cells, which are responsible for cell mediated response, dendritic cells, which are part of the APCs, myeloid-derived suppressor cells, and B-lymphocytes, which are responsible for antibody production. These are all the cells that make up part of your immune response.

In the category of lymphocytes, T cells and B cells are all antigen specific. Then, natural killers, or NK cells, are cytotoxic lymphocytes. They recognize and kill stress or malignant cells independent of antigen activity. Next, there are androgen presenting cells, or myeloid cells, that are important for T-cell mediated response.

Here is a diagram of what these processes look like:
Cells of the Adaptive Immune System
On the left, you see B lymphocytes driving the Adaptive Immune System, which results in antibody production. On the right, you see the T-cell-driven process.
Initiation of Immune Response
So how does the Immune Response start? Antigens are presented in the lymph nodes or lymphoid tissue. However, the antigen doesn’t cause a response by itself. It has to be presented to the immune system. When the antigen gets taken up by antigen presenting cells, the activation and priming of T cells begins. In other words, the antigens get expressed, T cells get activated, and those activated T cells goes into the peripheral tissue. These are now replications of antigen specific T cells. This triggers a whole downstream effect. There is both a B-cell response and a T-cell response. It is important to understand this moving forward.
FDA Approved Immunotherapies

In terms of immunotherapy, over a dozen different immunotherapy agents have been approved since 1986. Most of these agents were approved after 2010. The currently approved agents target over ten different cancer types. Keep in mind this data is mildly outdated. These numbers are expanding rapidly. However, the only approved therapeutic vaccine for prostate cancer is in metastatic castration-resistant disease. It’s called sipuleucel-T, and it was approved in April of 2010.

 

Unfortunately, there are no therapies approved for M0 that have a significant survival benefit.

That’s why we have all these great M0 trials as we move forward, especially with early hormonal agents. Some companies are trying to move some therapeutic vaccines into this M0 space. For now, this is a real problem, because they remain in either clinical trial or observation. But, I think with some newer imaging agents, including FACBC, PSMA, choline, we might see more evidence of metastatic disease. This opens up our play book, if you will, to many newer drugs.

It suffices to say that systemic therapy in the M1, or for castration-resistant prostate cancer patients, the current management maintains castration levels of serum testosterone less than 50. Or, they need to stay on LHRH therapy. Consider bone anti-resorptive therapy with denosumab, zoledronic acid. If the patient is asymptomatic or minimally symptomatic, with no liver metastasis (mets), a life expectancy greater than 6 months, and a ECOG performance status less than 1, you should really consider the use early on of sipuleucel-T. Again, this is the only currently approved immunotherapy in metastatic castration-resistant prostate cancer. If the patient is symptomatic, then consider palliative radiation for painful bony mets, as well as the best supportive care.
NCCN Guidelines Prostate Cancer
From there, the question is whether or not they have visceral disease. For that, here is the whole menu of drugs that we’ve been talking about.
Sipuleucel-T
Let’s return to sipuleucel-T. Remember, it was approved in April of 2010. It is an autologous immunotherapy. You may know this already, but the drug works by exposing itself to an antigen presenting cell based upon prostatic acid phosphatase. This basically all happens ex vivo.

We send the patients for an apheresis. We pull out about 5% of their antigen presenting cells.

Then, we incubate the patient’s own antigen presenting cells, or their APCs or their dendritic cells, with this fused antigen of PAP and GMCSF. The APCs then take up the antigen and the antigen is processed and presented on the surface of the antigen presenting cell. These cells are now fully activated. Now sipuleucel-T, the drug itself, is the patient’s own white blood cells, or dendritic cells, that have been activated by the uptake of prostatic acid phosphatase. Then, the Infuse Patient process takes place. It’s the most difficult part of delivering sipuleucel-T. The apheresis portion of this process takes about three hours. After that, it gets back to our clinic three days later. Then, the patients sit in a recliner and they get an IV. Sipuleucel-T is infused over one hour and the patient goes home. At that point, you get T-cell proliferation that attack the cancer cells. It’s completely driven by prostatic acid phosphatase that’s been taken up by the patient’s own antigen presenting cells.
Next, we have a prime boost regimen that improves the size and the quality of the anti-cancer immune response. The prime boost regimen strategy is that first, you get a priming dose which triggers the expansion of a  pool of activated T cells. Then, you get a boosting dose of sipuleucel-T every two weeks for three cycles to make a memory effect. The memory effect generates long-lived memory T-cells for long-term, active anti-cancer results. Next, you get a cascade effect of antigen spread, which I will talk about later.
There was a registry trial for Sipuleucel-T called the IMPACT trial, which stands for IMmunotherapy Prostate AdenoCarcinoma Treatment. It tested 512 patients. It tested 512 patients with metastatic castration-resistant prostate cancer, asymptomatic or minimally symptomatic. They were randomized 2:1 to either receive Sipuleucel-T every two weeks for three cycles, versus a placebo. After monitored progression, the primary endpoint was overall survival. If the patients did progress, they could be treated at the physician’s discretion. According to the overall IMPACT survival data, the median survival in the sipuleucel-T arm was 25.8 months, while in the placebo arm, this was 21.7 months. That’s a 4.1 month survival difference, which was statistically significant. And again, sipuleucel-T was approved by the FDA here in the United States in April of 2010. It’s only available in the United States.
Interestingly, Paul Schellhammer, a good friend and a prostate cancer survivor, was involved in taking this data. The median PSA in IMPACT was about 55. Paul’s team divided the patients in PSA quartiles. There were 128 patients per quartile. The first quartile had PSA’s less than 22, the second 22 to 50, the third 50 to 134, and the fourth greater than 134. The question this study tried answer was, “What’s the benefit if patients have lower volumes of disease, or lower PSAs?”

This brings up a problem urologists get into. We have created a generation of PSA addicts.

The problem with this trial is that there was not a PSA effect. The PSAs did not go down after treatment, but the patients lived longer. This study showed that patients with lower PSAs, or lower volume of disease, have a longer survival benefit. While the survival benefit held for all four, the most responsive group were people with lower PSAs. Remember that a PSA is an androgen driven event. It is a protein that’s a function of transcription and translation that’s driven by testosterone binding to the androgen receptor. So if we take out testosterone, simply, the cells are making less PSA. Think of this way. Think of two patients with three things in common: they’ve had a radical prostatectomy, they have PSAs of 3, and they have prostate cancer. What they don’t have in common is the first patient has never been on hormone, he’s hormone naïve, and the second patients is on androgen deprivation therapy. What if I asked you the simple question, “Who has more disease? Is it the first guy who is hormone naïve, or is it the second guy on hormones? Do they have the same amount of disease? Do you not know?” The answer has got to be, for the most part, guy number two. His testosterone levels are already low and he’s making less PSA.

This makes perfect sense. This forms the basis of why we advocate to the urology world, and to everybody, that if you’ve got a patient on androgen deprivation therapy and their PSAs are going up, albeit small values, you better start looking for disease. This highlights that if you start these patients early on therapy, they will live longer.

Now, Schellhammer’s study was not powered, but it is pretty significant. If you understand the nuances, especially in the control group of IMPACT, it becomes even more meaningful. Again, I encourage you, be looking for these patients if they’re on ADT when they have small bumps in their PSA. Remember that with sipuleucel-T, we’re actually driving it off the epitope of prostatic acid phosphatase. We’re only targeting one antigen. We know prostate cancer cells express multiple different membrane antigens. Once you get cell kill, then you get release of these antigens, then you get antigen spread. Even though you’re only targeting one particular antigen, in this case PAP, you still get spread and uptake of other antigens which can result in an enhanced immune response. By looking at various expressions of increased antigen spread, you can see it is associated with  an increased overall survival if it was PAP only, two secondary antigens, or three secondary antigens. This concept of antigen spread, even though sipuleucel-T only targets one antigen, once you get cell kill, you also get broader antigen spread.

This was a small trial looking at sipuleucel-T, reported in 2012. They used sipuleucel-T in a neoadjuvant setting before radical prostatectomy. This was histologically confirmed adenocarcinoma of the prostate, non-metastatic. The patient was scheduled to undergo radical prostatectomy. They received sipuleucel-T as we would if you were a CRPC patient. They then underwent prostatectomy, got a booster 12 weeks post-radical prostatectomy, and then followed up.
What they found here was interesting. There was quantification of lymphocyte infiltration in the tissues due to the sipuleucel-T effect. So sipuleucel-T is an active drug. This has been questioned multiple times. A lot of our medical oncology colleagues don’t believe in sipuleucel-T, because they don’t understand how it works. The fact that there’s no drop in PSA is befuddling to many people. But, I remember James Eastham making a really good point. If you look at the data, patients on sipuleucel-T, no doubt, live longer. So I tell my patients, “Hey, you want to have a low PSA, or would you rather live longer?”

Dendreon, as you know, has just been purchased by a Chinese company. They’re involved in multiple trials looking at sipuleucel-T. They’ve also looked at some very small studies combining sipuleucel-T with some enzalutamide as well as abiraterone. Those studies were driven to make sure that if you had concomitant use with these other agents, it would not affect the upregulation of the immune system.
Immunotherapy Combination Research
This roller-coaster-slide, if you will, shows the various phases of prostate cancer:
Another immunovaccine is PROSTVAC-Tricom. You may have heard of it. It uses a viral vector. It’s a recombinant cancer vaccine using vaccinia and fowlpox.
Immunotherapy for Prostate Cancer
PROSTVAC-Tricom is PSA driven. There’s no apheresis required for this. It is a series of injections. Their original trial was a phase 2, reported in 2010. There were asymptomatic or minimally symptomatic CRPC patients. They were randomized 2:1, versus an empty vector and placebo. Again, the endpoint was survival. The trial showed a significant survival benefit of about 8.5 months. This was phase 2 trial. The company that originally did this trial ran out of money. 
Phase 3 didn’t start until a few years later. And at that point, the problem was that other drugs were already FDA approved. In any case, they did start a phase 3 trial, which was the PROSPECT trial. This was for a minimally symptomatic, or asymptomatic CRPC patient. The patients either got low-dose adjuvant PROSTVAC plus GMCSF, versus PROSTVAC, versus placebo. This is trial is fully accrued, and they will most likely report it sometime this year? So, we have another immunovaccine. It’s a true vaccine. The difference between sipuleucel-T and PROSTVAC is that sipuleucel-T requires an element of apheresis, and PROSTVAC requires subcutaneous injections.
T Cell Image
At the center of immuno-oncology is the activate T cell. I want you to think about active immunotherapy versus immune checkpoint modulation. If you’re interested, Dan Petrylak is an expert on checkpoint modulation. 

Active immunotherapy, like sipuleucel-T, is targeted activation. Remember, Sipuleucel-T targets PAP. It’s antigen spread, it has variable efficacy, and it has limited biomarkers. But the reason patients love sipuleucel-T because it is very easily tolerated. I’ve probably given, or witnessed, or been involved with over 600 doses. We do it in the office. It’s about an hour infusion. I think we’ve had two patients that have a rigor, but no hospitalization. The biggest complaint patients usually have after the second infusion is that they get some myalgias, almost like flu-like symptoms.

But what about this checkpoint modulation we keep hearing about? To answer that, first think about what the immune system does in general. The immune system has to recognize itself. It has to recognize you. So, with some autoimmune diseases, like rheumatoid arthritis, there’s disruption in that ability to recognize you as an individual. That’s where checkpoint proteins and checkpoint modulation, like CTLA-4 agents, like PD-1, PD-L1 blockers, come into the picture. These agents try to overcome immune regulation. If you think of active immunotherapy like a “foot on the gas,” checkpoint modulation is like a “foot off the brake,” because these checkpoint proteins slow down the system. They make it so our immune system cannot keep going unchecked.

Vaccination Vs Immune Checkpoint Blockade
On the left of this diagram, you see active immune therapy with sipuleucel-T or PROSTVAC. On the right, you see the process of targeting CTLA-4, PD-1, PD-L1.
So what does this all actually mean? For cell-mediated response, or for T-cell response, to happen, there has to be priming of the T cell. The cancer cells as well as the T cells have to be primed. You have to expose an antigen to the T cell. But, antigen exposure is not quite enough. You also need activation signals as co-priming, which is primarily driven by the proteins on the diagram to the left. CTLA-4 then gets upregulated on the T-cell membrane after it is primed.
The CTLA-4 expression happens during the priming phase of the immune response. Once this is primed, starting with the T-cell receptor, and the T cell is active, there is another negative regulatory effect driven by PD-1. Ligand PD-L1, which is expressed by the tumor cell, binds to PD-1. This is the tumor’s way of having a cloaking mechanism, if you will. Ipilimumab works during this priming phase. It’s blocks CTLA-4, allowing the T cells to go unregulated and unchecked. These PD-1, PD-L1 blockers are actually working after the T cell has already been active.
Immunotherapy Checkpoint Inhibitor Combination
This is the rationale for these combinations using checkpoint inhibitors and active immunotherapy. By using them in combination, you’re manipulating on both sides.
Another thing we can do is radiation immunotherapy. The fundamental mechanism of tumor control through radiotherapy is causing double-stranded breaks in DNA. But then, there is a release of all these molecules. You release a certain antigen spread, which is called the abscopal effect. If you break down this word, ‘ab’ means ‘away’, and ‘scopus’ means ‘target.’ Sometimes, after radiation therapy of a primary, antigen spread, and stimulation of the immune system, you can occasionally get this regression, or shrinkage of metastatic sites. That is what we affectionately call the abscopal effect. A lot of people are taking advantage of this.
Ipilimumab Trial
In an ipilimumab trial, which was a CTLA-4 modulator, patients who had already received docetaxel chemotherapy, received single dose, bone-directed radiotherapy. They were randomized to get either get ipilimumab or placebo with the endpoint being overall survival.
The primary endpoint was of this trial was not met. The results were 11.2 months in the ipilimumab arm versus 10 months in the placebo arm. However, it seemed to be that patients did better if they had visceral mets. Remember, these patients had already been treated, so this was advancing patients that had already been treated with docetaxel. Prespecified and post hoc analysis suggests that mCRPC patients with favorable prognostic features may more likely benefit from ipilimumab treatment. Visceral mets had an apparent interaction with treatment effect, several factors appeared to be prognostic for overall survival.

Looking at this abscopal effect, we can take into account this potential of using radiation. Also remember, we now have an approved FDA drug that’s an alpha emitter, and a radiopharmaceutical that has a survival benefit. This has the ability to deliver radiation intravenously. There are also a lot of trials receiving attention that potentially use this combination of immunotherapy with radiation.

Here are a couple studies I thought were interesting:

This is a trial looking at using atezolizumab and radium. This is the safety, or a phase 1 trial.
This trial, out of Johns Hopkins, is looking at radium as well as concomitant use with sipuleucel-T.

The rationale behind these trials is understanding the immune system, understanding the effects of radiation, and at the same time, trying to work with all these drivers, while still taking into consideration the antigen receptor.

In conclusion, sipuleucel-T is currently the only FDA approved immunotherapy for the patient with metastatic castration-resistant prostate cancer. Checkpoint inhibitors, especially in combination with other therapeutic modalities, represent new opportunities. But again, ongoing clinical trials will still be needed, especially utilizing and developing predictive markers. Thanks.