Understanding Immunotherapy Part 3: CTLA-4

By Amrita Bhatt, MRA Intern

Now that you’ve read our background on immunotherapy and learned about PD-1, it’s time to focus on another protein that plays a key role in cancer development, CTLA-4.

What is CTLA-4?

In addition to displaying PD-1 on the cell surface, T cells also display CTLA-4. This protein will bind to its partner, B7, causing the T cell to be turned off. Consequently, the immune response is impaired. As with the PD-1/PD-L1 interaction, this is a normal negative control of the immune response. Unfortunately, melanoma cells can take advantage of this, allowing the cancer cells to flourish.

What anti-CTLA-4 drugs are available now?

Currently, two anti-CTLA-4 drugs have been approved by the FDA – Ipilimumab (Yervoy®) and a combination therapy, Nivolumab + Ipilimumab (Opdivo® + Yervoy®). Yervoy is a checkpoint inhibitor that boosts your immune system in order to attack cancer cells. Specifically, it promotes the function and growth of T-cells, which are part of the immune response. When used in combination, Nivolumab and Ipilimumab help build your immunological “memory,” meaning that your immune system may continue attacking melanoma cells even after treatment. A phase II clinical trial in 2015 indicated that using the two in combination showed a higher response rate than just using ipilimumab alone.

Watch Dr. Evan J. Lipson of Johns Hopkins Medicine discuss more on the benefits of combination therapy.

What type of CTLA-4 research has MRA funded?

Anti-CTLA-4 therapy is a promising agent for the treatment of cancer patients and research funded by MRA plays a crucial role in advancing the field. MRA is currently funding the melanoma supplement of the SU2C-CRI Immunology Dream Team co-led by Drs. James Allison and Antoni Ribas. Their studies aim to identify biomarkers of response in patients treated with ipilimumab, nivolumab, and a combination of the two.

In 2008, MRA funding helped Dr. Jedd Wolchok of Memorial Sloan Kettering Cancer Center and Dr. Padmanee Sharma of MD Anderson Cancer Center work on research projects focused on biomarkers for ipilimumab. Biomarkers are biological substances that can be indicative of a certain disease – in this case, melanoma. Additionally, Dr. Frank Hodi of the Dana-Farber Cancer Institute worked on two funded projects that investigated combination therapy involving ipilimumab.

What’s Next?

Immunotherapy provides hope to not only melanoma patients, but patients of all cancer types. Recent clinical trials have shown that ipilimumab allows for greater survival compared to a vaccine. Additionally, ipilimumab can be used as adjuvant therapy in cases of high-risk melanoma. In these situations, ipilimumab is given in addition to the primary treatment, which is usually surgery. High-risk patients undergoing adjuvant therapy are able to experience a longer relapse-free survival. As we continue to learn more about immunotherapy, and CTLA-4 in particular, MRA is committed to accelerating research in order to benefit even more patients.

We hope you enjoyed and learned more through mini-series on immunotherapy!

Learn more about the promise of immunotherapy:

Whither melanoma and whither cancer research? 

By Louise M. Perkins, PhD
Chief Science Officer, Melanoma Research Alliance

There is no doubt that the last few years have seen incredible progress for melanoma patients with 11 treatments approved since MRA’s founding in 2007: personalized medicine, targeted therapy, immunotherapy. What remains to be done for melanoma and other cancers? How are the successes in melanoma and other research areas converging on even greater progress for patients?

The answers to these questions were touched on at the American Association for Cancer Research (AACR) Annual Meeting in New Orleans in late April.

First – a quick comment on the AACR Annual Meeting itself. It is the largest meeting of cancer researchers from around the world and takes place during half a week.  In that time, there are many and various presentations covering basic cancer biology, translational research and clinical outcomes.

Image courtesy of AACR twitter account.

Vice President Joe Biden speaking at the 2016 AACR Annual Meeting. Image courtesy of AACR twitter account.

Starting with the opening plenary session (featuring two MRA-funded researchers) and throughout the meeting, one couldn’t help but notice how melanoma remains as the premier case study for immunotherapy – treatment that is benefiting not only melanoma patients, but also lung, kidney and blood cancer patients.  There is continuous forward progress in building beyond the status quo to expand the benefit of these new treatments to many. Meanwhile, data at the meeting revealed that 1 of 3 melanoma patients who received nivolumab were alive at 5 years. Similarly, the news was good for combination immunotherapy with early data showing that two-thirds of patients treated with the nivolumab-ipilimumab combination regimen were alive after 2 years. This is amazing!

But challenges remain. With the increased side-effects of the combination, which patients should get single-agent vs combination therapy? And what new treatments can be brought forward for those who either never benefit or whose tumors progress despite treatment whether they have melanoma or a different cancer?  Radiation therapy, new immunotherapies, different timing of treatments, new targeted therapies, biomarkers that match patients to treatments  – all of these are under study to further improve outcomes for patients.

One last note. Treating cancer is one thing, but doesn’t it sound better to never get cancer in the first place? Unfortunately, most cancers really can’t be prevented. Outcomes are improved by early diagnosis as is the case for breast and colon cancer, but we still can’t prevent most cancers (cervical cancer is a notable exception with HPV-vaccination, by the way).  But melanoma is different and this is incredibly relevant for Melanoma Awareness month. The evidence is clear: ultraviolet light causes DNA damage leading to mutations. And melanoma tumors have the most mutations of any cancer. The pattern of the melanoma mutations is clearly due to UV exposure. Further, in mouse models predisposed to melanoma, broad spectrum sunscreen profoundly decreases the number of melanomas those animals develop. And in the absence of UV light, they get very few tumors.

In practical terms, what does this mean? Basically, use UV-safe practices! Cover up, use sunscreen liberally and avoid UV light whether from the sun or tanning beds.

To paraphrase the most interesting man in the world, “Stay shady, my friends.”


About the Author

Louise M. Perkins, Ph.D., joined the Melanoma Research Alliance (MRA) as Chief Science Officer in 2013 where she is responsible for the development and implementation of MRA’s scientific strategy.

Understanding Immunotherapy Part 2: PD-1

By Amrita Bhatt, MRA Intern

Now that we’ve provided a brief background on immunotherapy, it’s time to dive more deeply into the subject. In the second installment of this blog series, we’ll be examining PD-1, a protein that plays a crucial role in cancer’s ability to hide from our immune systems.

What is PD-1?

PD-1 is a protein found on certain immune cells, including a type of white blood cell known as a T cell. When PD-1 links up with its partner protein, PD-L1, a signal is sent to the T cells to shut down. Usually, this is used as a means to prevent the development of out-of-control immune activity that could lead to auto-immune disease. Unfortunately, the same PD-1/PD-L1 signal can be used by tumors to turn off T-cells and thereby help the tumors avoid being destroyed by the immune system.

What anti-PD-1 drugs are available now?

Two anti-PD-1 drugs have been approved by the FDA – Nivolumab (Opdivo®) and Pembrolizumab (Keytruda®). These drugs block PD-1 and free up the T cells to attack the cancer. Additionally, the combination therapy of Nivolumab and Ipilimumab (Yervoy®), an anti-CTLA4 drug, was approved just this past year.  First FDA-approved in melanoma, these anti-PD-1 treatments are also available for kidney and lung cancer patients, and the data are encouraging in a number of other cancers as well.

What type of anti-PD-1 research has MRA funded?

With melanoma serving as the lead for immunotherapy across various cancer types, research funded by MRA has played a pivotal role in advancing the field. Funding from an MRA Team Science Award to Drs. Drew Pardoll, Suzanne Topalian, and Lieping Chen at Johns Hopkins University provided some of the earliest observations on the role of PD-L1 as a potential biomarker in melanoma, lung, and prostate cancer patients. Correlating the expression of PD-L1 to treatment response has contributed to understanding its best use as a biomarker for cancer therapy.

Watch this video to learn more about research on immunotherapy that blocks the PD-1/PD-L1 pathway:

MRA has funded a number of studies on biomarkers for immunotherapy.  In partnership with the Lung Cancer Research Foundation and Lungevity, MRA-funded Young Investigator Dr. Lucia Jilaveanu is conducting research to identify biomarkers that relate to pembolizumab treatment in patients with metastatic brain disease. This partnership allows for powerful insight across cancers, as brain metastasis is a common feature of both melanoma and lung cancer. MRA is also currently funding the melanoma supplement of the SU2C-CRI Immunology Dream Team co-led by Drs. James Allison and Antoni Ribas. Their studies aim to identify biomarkers of response in patients treated with ipilimumab, nivolumab, and a combination of the two.

What’s Next?

With the potential to help combat not only melanoma, but many other types of cancers, anti-PD-1 therapy provides great promise. Melanoma is referred to as the case study for this new wave of cancer therapy, and researchers are now exploring immunotherapy across many cancer types. As MRA-funded researchers continue to study the mechanisms underlying therapy response and resistance, more and more patients will benefit from the knowledge gained.

 

Keep a look out for our next post discussing another protein integral to cancer’s ability to evade our immune systems – CTLA-4.

Understanding Immunotherapy Part 1: What is Immunotherapy?

By Amrita Bhatt, MRA Intern

If you follow science, you have probably heard about immunotherapy. In just the last year or two, immunotherapy has burst into the mainstream media, with coverage from the New York Times to Time Magazine bringing this emerging field to light beyond the scientific community. More recently, President Jimmy Carter helped put a face on immunotherapy when he announced its use in treating his metastatic melanoma.

While there is a broader understanding of immunotherapy now than there was a few years ago, there is a lot to discuss on this complex topic. We’ll be starting a blog series to help readers understand immunotherapy – and how it is being used to treat melanoma and other cancers.

Let’s start with a little background. Just 10 years ago, there were hardly any treatments available for patients diagnosed with melanoma, and a diagnosis of metastatic melanoma was an almost certain death sentence. Since MRA’s founding, the FDA has approved 11 therapies for melanoma. These have included targeted and immunotherapies – and combinations of the two. With nearly $68 million in funding to date, MRA continues to play an integral role in making revolutionary changes available for patients.

So, what is immunotherapy?

It’s a method of treatment that involves engaging the patient’s own immune system to fight cancerous cells. Four of the eleven FDA approved therapies since 2011 have been checkpoint therapies, including one combination therapy, and MRA’s funding has been vital to keeping the momentum going.

How does immunotherapy work?

Our immune system protects us by warding off foreign invaders such as bacteria and viruses. The immune system can also sometimes recognize cancer cells. However, since cancer cells arise from our normal cells, sometimes the cancer just isn’t different enough for the immune system to attack it.

In some cases, even when recognized as foreign, cancers use other strategies to evade the immune response. Immunotherapy works to boost your body’s immune response in order to attack cancer cells and prevent them from evading our defenses.

This video provides a visual explanation for how immunotherapy works.

Figuring out how to engage the immune system to fight cancer has been a goal for many years. MRA has funded a great deal of research in this area, including research on two proteins that allow cancer cells to escape attack from the immune system – PD-1 and CTLA-4.

In this continuing blog series, we’ll explain what these proteins are and how MRA funded researchers are strengthening our understanding of their role in cancer progression and treatment. Immunotherapy is broadening the scope of patient therapies and we must continue to fund vital research that keeps the momentum going.

Fast and Furious: Melanoma Research in 2015

By Louise Perkins, Ph.D.

Chief Science Officer

The world of melanoma has changed dramatically in a way one might not have envisioned in 2011. How can you tell?  From the stories of patients and their caregivers. A common story can go like this: Just diagnosed with Stage 4 melanoma. Need to select the best treatment approach sooner than later. Many options to choose from. What questions should they ask the doctor?

In 2008, when MRA’s first grants were made, no one would have imagined we’d be talking about how to choose among so many treatments for patients. The pace of change has been fast and furious since 2008, and it’s picked up steam in 2014 and 2015.

In less than 5 months, there have been 5 new treatment approaches approved by the FDA. Think about that for a minute! This pace of treatment change is beyond unprecedented and includes a number of “firsts.”  What were these changes and what does it mean for patients?

“Firsts” for Melanoma in 2015:

  • The first combination immunotherapy – ipilimumab and nivolumab – approved
  • Nivolumab is approved as a first line of treatment, marking the first anti-PD-1 immunotherapy drug for previously untreated BRAF wild-type melanoma
  • T-VEC, an oncolytic viral therapy that’s directly injected into a tumor, is the first of its kind treatment to be approved
  • Vemurafenib and cobimetinib is approved by the FDA, the first melanoma combination approval that includes a never-before-approved drug
  • Ipilimumab is approved for adjuvant treatment, the first checkpoint inhibitor drug approved in the adjuvant setting
  • Pembrolizumab is approved as a first line of treatment for metastatic melanoma regardless of a patient’s BRAF status – the first anti-PD-1 therapy to receive such designation

All of these ‘firsts’ should give you a sense of the true innovation in new treatment approvals that melanoma is spearheading with the help and support of patients, doctors, companies, and the FDA. These offer good options for patients as they pick their Plan A.

So, patients should always be thinking about Plan B in discussion with their doctors. Why? Because cancer is tricky, and it sometimes roars back just when it seems like it’s been beaten. In addition to that, not all patients respond to immunotherapy or targeted therapy. Others simply can’t tolerate the treatments and have to be taken off for their own safety.  This means we still need different options to battle this awful disease.

What’s Needed for Melanoma Research?

New studies are underway that address two main needs:

  1. How to use the drugs we have now in better ways, either alone or in combination
  2. Defining the biology of difficult-to-treat disease and figuring how that knowledge can be used to find new targets and treatments

Fine-tuning the drugs we have

Finding the optimal order by which to give treatments (e.g. Drug A then Drug B or Drug B then Drug A or Drug A and B at the same time) remains key if we are going to maximize the utility of these existing miraculous treatments. The field needs to think broadly about cause and effect of using various drugs, their impact on cancer cells, the immune system and the body as a whole especially as it relates to having drugs work in otherwise resistant melanomas.

Tackling difficult-to-treat melanoma

It is becoming increasingly clear that altered signals inside the cell that flow through a node called ERK are important in the vast majority of melanomas. The presence in half of melanomas of BRAF mutations that ultimately activate ERK provided the first clue that this was important. Further studies are showing that a panoply of alterations turn ERK signaling on even in the absence of activated BRAF. This highlights the need to more effectively target ERK signaling and resistance to such inhibition.  And new ways to stimulate the immune system would be a plus, too. All of this is the sort of research that MRA has supported and continues to as much as possible.

Making a long story short, there is an overriding need for continued innovation. Too many patients are not benefiting from these new therapies, and we have to ensure that new targeted and immunotherapy approaches are invented and tried – based on sound science.  What are the next new immune therapies? New signaling inhibitors?  Is there a critical mass of info that can form the basis of the next leap in progress?  This is where we need to push.

11Therapies Approved

Is a Clinical Trial Right for You?

Before the U.S. Food and Drug Administration (FDA) approves a medication or treatment for public use, it first must go through several phases of study which is known as a clinical trial. During each phase, researchers evaluate how well the treatment works and take note of any side effects.

Clinical trials are key to bringing new treatments to patients, as we have seen with melanoma. Through the efforts and commitment of many patients, as well as companies, doctors and researchers, there are 11 new melanoma treatments approved by the FDA since MRA’s founding in 2007.

The pharmaceutical or biotechnology companies developing the drug provide funding for the studies. However, their research teams rely on medical organizations, such as cancer centers and patient groups, to find people who are willing to participate in the clinical trials.

Deciding whether or not to join a clinical trial is a complex decision. If you or someone you love is considering a clinical trial, you might consider the following.

Things to Consider About Participating in a Clinical Trial

  • Early access to new, and possibly improved, treatment: One of the goals of a clinical trial is to see if a new treatment, or a combination of existing treatments, works against the disease and what side effects it may have relative to the standard of care that’s currently given. It’s possible that the treatment you receive in a clinical trial will be an improvement over existing treatments. However, there’s no guarantee; just because results look promising in a lab does not mean that a treatment will work well in humans. And sometimes something looks promising in early trials but does not end up being effective once tested in late phase trials. It’s possible that the new treatment will help others, but it won’t help you. (By the way, participants in cancer treatment studies never receive a placebo, or “fake,” treatment. Instead, the new treatment is usually studied in comparison to the current standard therapy.)
  • Side effects: One of the goals of a clinical trial is to figure out a treatment’s side effects and their severity. Medications affect everyone differently. However, it is possible that you may experience mild to severe side effects.
  • Frequent, expert medical attention: Doctors and care teams must closely monitor health-related changes in clinical trial participants and record the effects of a treatment, its side effects, and to gauge how well it’s working. That could mean extra trips to the doctor’s for checkups, blood tests, and biopsies. But that means you will have more one-on-one care.
  • Free or low-cost treatment: The research company may offer the new treatment at no or low cost to you. But even if a research company covers medication costs, you could still be responsible for copays for extra office visits and tests. Check with your insurance provider before you agree to a clinical trial and find out what expenses you have to cover.
  • Help save lives: The melanoma treatments available today exist because other people agreed to try them out. What researchers learn from your participation in a clinical trial could benefit the health of other patients. In general, cancer patients seem highly willing to be part of the movement to improve the nature of treatment for others with this terrible disease. But new treatments could be made available even faster if even more patients participated in the clinical trial process.

Since its founding in 2007, the Melanoma Research Alliance has committed nearly $68 million to fund melanoma research, and has supported 21 clinical trials. With our help – and the help of patients – researchers will continue to explore new ways to fight melanoma and other cancers.

Read more about research funded by the Melanoma Research Alliance and what it takes to develop a new cancer treatment.

 

 

Research Q & A: Dr. Michael Atkins

In the latest blog series, we talked with Dr. Michael Atkins, Deputy Director of the Georgetown-Lombardi Cancer Center at Georgetown University, and a member of the MRA Medical Advisory Panel.

Michael Atkins

How did you get interested in melanoma and your field of research?

I had a couple of high school friends who developed melanoma, including someone who died during high school, so I was aware of the disease. In college, I developed an interest in cell biology and immunology. We knew at that time that soluble/diffusable factors could stimulate the immune system at a distance, but no one understood how it worked. I knew that I was interested in oncology because of my interest in cell biology and immunology and I wanted to be involved with patient care. As an oncologist, you’re always an important part of any patient with cancer’s medical team.

My fellowship in hematology/oncology was right around the time that Interleukin-2 (IL-2) was being investigated at the National Cancer Institute, and I got involved in a laboratory researching immunotherapy. The immunotherapy tended to work best in patients with melanoma. So, I was in the right place at the right time and things just came together.  My research interest in immunotherapy and my clinical and personal interest in melanoma intersected and led me to focus on this area.

Explain how your research is making a difference for people with melanoma.

One of the most surprising and gratifying aspects of my work has been seeing how many patients with melanoma can actually respond to immunotherapy. The identification of the immune checkpoints that dampen the immune response and subsequent successful efforts to block them and restore anti-tumor immunity with checkpoint inhibitors has revolutionized the way we treat advanced melanoma and some other cancers. I am continually impressed at how many patients have immune cells that can recognize and destroy their tumors once re-activated.

Further, our advances in melanoma immunotherapy have paved the way for similar advances in patients with all kinds of cancers, many of which we never dreamed of being responsive to the immune system.

Have there been any recent advances in treatment/your research that are particularly encouraging?

In my mind there are three important areas that the melanoma community is actively researching:

  1. Integrating immune therapy with molecularly targeted therapy. We’re looking at the impact of one treatment on the potential responsiveness of other treatments. What’s the appropriate sequence in patients with tumors bearing a BRAF mutation? Does the sequence make a difference? It’s an important practical question that physicians face every day.
  2. Recent work on checkpoint inhibitors suggests combination checkpoint inhibitors have an advantage over single agents. Studies are showing that patients are experiencing better outcomes if we target the multiple immune checkpoints simultaneously, so combination therapy has to be explored and we have to look at which combinations are most active in particular patients.
  3. Using biomarkers to make treatment recommendations. We’re trying to answer important questions, like who can respond best to combination or single agent therapy, and can you “rescue” patients given single agent after they have been given it if it doesn’t respond?

How has MRA funding helped your work?

We’re trying to better understand how other therapies, like molecularly targeted therapies, affect immune responses in the tumor microenvironment. MRA supports my research related to a clinical trial where we perform serial biopsies on patients’ tumors who are receiving BRAF inhibitor therapy. Our goal is to determine if there is an optimal time to start immune therapy after BRAF inhibitor therapy, and if giving it even makes sense.

Five years ago, median survival for patients with advanced melanoma was still 6-9 months and had remained constant for decades. When MRA stepped on the scene, there were new potential targets – like BRAF, CTLA4 and PD1– that had recently been identified. Funding from the MRA has been critical to expediting our understanding of how to optimally exploit these various targets. As a consequence, there is essentially no median survival for patients with advanced melanoma. We may have been able to get to this position eventually without the MRA, but the MRA support has enabled us to do so at practically light speed.