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:

Trena’s Story: An African-American Retiree’s Journey with Melanoma

“Trena, you have melanoma and you are going to lose your toe. “  WHAT?!?!

I am a Black woman in her sixties—that is crazy!!

TB and Boyfriend

Trena with her boyfriend, Maceo.

My name is Trena Brown. Retired from corporate life, I was in the process of travelling to places on my bucket list when in March 2013, I learned that the “blister” on my great right toe was not a blister. It revealed its ugly bubble near the toenail, near a spot that had previously been excised in 2011 because of severely darkened skin in an irregular pattern.  However, the biopsy results were benign and the margins were clear so “I’m good!” So how is it possible that I had melanoma?  My doctor was explaining it all to me but I was not hearing anything except my own wild sobs and screaming.

Two weeks later with a cast up to my knee I am grateful for my family, neighbors and friends who are helping me literally get back on my feet. Some people had no clue what the word melanoma meant and thought I had an amputation due to diabetes. Others thought that melanin not only beautifies skin, but protects it. So why would this happen to any of us with lots of melanin?

TB Group

Trena (center) with her family.

After the amputation, my doctor had used the same words again…”the margins were clear”….and this time surely they were, since I no longer had a big toe.  I relegated myself to visiting my reconstructive surgeon, my dermatologist, and my oncologist every three months. In six months, I was able to take a pre-scheduled trip to China, and in a year, I was back in my Zumba class, seeing my trainer at the gym, and enjoying dancing at parties again. “I’m good!”

In December of 2015, I told my PCP that sometimes when I was outside, I seemed to have labored breathing.  He suggested I stop downstairs on my way out and get a chest x-ray. In the following days, my doctor told me I needed both a CT scan and lung biopsy.

In 48 hours after the biopsy, I got a message from MyChart, saying I had “test results.”  With my brother and sister-in-law on the phone for support, I opened the results to see the entire page filled with print, but my eyes focus on the line in the center that had two words in bold print:  Metastatic Melanoma.  My brother was talking to me but all I could hear were my own wild sobs and screaming.

TB Sister

Trena (R) with her sister-in-law, Aileen.

Three years ago, there was no cure. Surely God put angels on my shoulders because now, as I started telling friends and family about my condition and my oncologist’s recommendation for immunotherapy, I found that there were quite a few people in the clinical trials who had amazing success.  A friend introduced me via e-mail to Louise Perkins who invited me to a Melanoma Research Alliance reception in Washington DC where I had the opportunity to meet several survivors.  I also talked to several doctors about their interest in melanoma and what they hoped to see in the coming years.  It was a very uplifting experience that helped me focus through the Yervoy/Opdivo drips and envision a positive outcome where “I’m going to be good.”

In May of 2016, I had CT scans to determine my progress after starting immunotherapy in February. Because I had not experienced any symptoms throughout my immunotherapy, I always considered that I was improving. If President Carter could beat this at his age then I surely should be able to.  Later that day, I finally get a call from the doctor with words I actually can hear:

“Trena, you have had outstanding results from your immunotherapy!  The nodules have shrunk to be miniscule and the swollen lymph node is a normal size”. 

YES!!!  No screaming, no sobs, just tears of joy!

So now I am in Phase Two—maintenance.  I continue to let people know that African-Americans can get melanoma I encourage people to check out any abnormalities on their skin, wear sunscreen, and see dermatologists.  I am only one person, but hopefully one person who can help educate my community on melanoma, and as well as the advances that are being made.

I truly believe my best days are yet to come.

Insider’s Tips for Melanoma Prevention: Make Every Day Don’t Fry Day

Don'tFryDay_logo_v2The Friday before Memorial Day weekend in the U.S. is Don’t Fry Day – a day to remember to keep your skin safe as we launch into the summer season here in the northern hemisphere.

Why you should care – the case for every day as Don’t Fry Day

Most people want to avoid getting cancer, right? How many people do you know who say, “Sure, I want to set myself up for costly visits to the doctor, scars from surgery and needing drugs that may or may not save my life and have uncertain side-effects.”

And even if you’re one of those folks who want to take the risk because it might not happen to you, you don’t want your kids, family, and friends to go through that.

Stay Shady My Friends

Melanoma is one of the most preventable cancers under the sun – pun intended. Why? Because in the vast majority of melanomas from many different patients, scientists can see that ultraviolet (UV) light caused DNA damage, and DNA damage is the number one pre-disposing factor behind cancer. Very rarely, melanomas occur without an obvious amount of UV-caused DNA damage. But that doesn’t mean that UV isn’t a major culprit in causing most melanomas. It is. And, UV rays come from two major sources in our world – sunlight and tanning beds.

In a recent article in Chicago Health magazine, Jason J Luke, MD, who treats melanoma talks about the benefits of new therapies, which while good are by no means perfect. Still an ounce of prevention is worth a pound of cure. And for skin cancer and melanoma in particular, a little effort may mean you never get a bad melanoma in the first place.

Here are some tips for protecting your skin and preventing melanoma:
• Stay in the shade whenever possible
• Avoid the sun in the middle of the day when rays are strongest
• Wear a wide-brimmed hat and other protective clothing
• Use and reapply a broad-spectrum SPF 30+ sunscreen every 2 hours, and/or after swimming or excessive sweating
• Avoid tanning beds

Protect your skin – make every day Don’t Fry Day – and share with your friends and family. You could literally save a life!


Learn more about Don’t Fry Day here.

MRA Partner Feature: Neiman Marcus

By Regina Campbell

This week, we’re featuring a guest post from Regina Campbell, who is Director of Social Media for Neiman Marcus. Read more.

For some, skincare can be an afterthought. Of all the items on our to-do lists, applying SPF may not be at the top. The chaos of life often distracts us from the one thing we at Neiman Marcus consider most important—our personal health. Cancer has affected many of us in one way or another, and it’s up to us to protect ourselves as best we can.

Recently there have been tremendous advances in melanoma research, from increased attention to the disease to improved treatment options. Neiman Marcus is honored to be a part of this process, having partnered with the Melanoma Research Alliance (MRA) to increase awareness and fund research to help reduce the risk of melanoma.

Although genetics and increasing age can be risk factors for melanoma, exposure to ultraviolet (UV) rays is a major risk factor for the disease. According to the MRA, melanoma is the most common cancer diagnosis in women ages 25-29 years old.

Neiman Marcus’ wide assortment of products includes many brands that strive to incorporate agents that help protect the skin from the sun for women of all ages. In fact, during June we are partnering with companies that are generously donating 10% of net proceeds of select suncare product sales to support the MRA.

But it’s not just beauty products that help shield the sun. Swimwear brand Cover addresses the need for fashionable and protective T-shirts and cover-ups for women to wear in the sun. Founder Lisa Moore launched Cover in 2008, just two years before her 22-year-old sister was diagnosed with melanoma. Since then, the line has made health a priority.

It’s increasingly important for women of all ages to understand their family history with cancer, be persistent with regular health exams, and help protect one’s skin from external harm such as the sun.

Despite the advancements made in fighting melanoma, we must still acknowledge the long road ahead. Many still downplay the seriousness of the disease with the assumption that it’s easy to treat. As someone who has a family history of skin cancer, I’m vigilant about making frequent visits to the dermatologist. Considering my personal experience with the disease, I urge all women to do the same.

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.

Guest Post from the Polka Dot Mama

This week, we’re featuring a guest post from Tracy Callahan, who founded and leads the Polka Dot Mama Melanoma Foundation

T CallahanMy name is Tracy Callahan and I am the Founder and CEO of the Polka Dot Mama Melanoma Foundation established in 2015.

I was first diagnosed with early stage melanoma at the age of 38, and by age 40, I had been diagnosed two more times. I am the Mom of two amazing boys ages 8 and 10 and they nicknamed me the “Polka Dot Mama” because of my many moles. I consider myself fortunate that my melanomas were caught early. I know that this is not the case for many.

As a former research nurse, I knew and understood the importance of supporting and funding research. After my third diagnosis I decided to start blogging. I knew that I wanted to use my voice to raise awareness for this often unspoken about cancer. Soon after starting my blog, I reached out to the Melanoma Research Alliance (MRA).  I knew right away that I wanted to align myself with them and work towards raising money for much needed melanoma research.

In March of 2015, I began planning a Gala. I knew that I wanted it to not only benefit melanoma research, but I also wanted to stay committed to keeping it locally sourced. In addition to being a melanoma advocate, I am also a foodie!

On May 1, 2016, we will host our first annual “Taste For a Cure: Chef’s Gala Benefiting Melanoma Research.” This unique farm-to-table gala will raise money to be donated to the MRA. We have been overwhelmed with the support of our local community. It has been incredible to see local chefs, businesses and sponsors donating their time, talent and services to help us raise as much money as possible.  As of February 4 (World Cancer Day) our event is officially SOLD OUT!

In addition to the Gala, the Polka Dot Mama Melanoma Foundation has been working with a local media company and has begun production on public service announcements as well as an awareness video that will debut at the Gala. We have been collaborating with multiple grass roots melanoma moundations across the country in hopes that together we can have a larger impact.

So many advancements have been made with the treatment options for melanoma in the last few years. It is my strong belief that we are on the cusp of not only finding more effective treatments, but also a cure.  The MRA is the largest private funder of melanoma research and I am truly honored to be a charitable ally of theirs.

A Daughter Reflects on Her Father’s Battle with Melanoma

By Samantha Stinchcomb

This week, we feature a guest post by Samantha Stinchcomb, a student at the University of Delaware. When her father succumbed to melanoma, Samantha and her family and friends founded the Wayne Stinchcomb Big Orange Foundation to raise money for melanoma research and to educate her local community about the disease and the importance of early detection.

Big Orange photo

Samantha with her dad, Wayne

At 13, while most girls were picking out a dress to wear to the 8th grade dance, I was busy picking out a quote for my dad’s tombstone. After 3 years full of long doctor appointments, harsh experimental treatments, extended hospital stays, little good news, lots of bad news, and hours of prayer, my father had lost his battle to melanoma.

It began in 2007 when my mom noticed a suspicious mole on my dad’s back. Starting with the initial dermatologist visit, my parents were always open and honest with my brother and me about what was happening. I can remember every single conversation we had after each doctor appointment or hospital visit. They tried to explain things as clearly as they could, but being only 13, I had a hard time understanding everything. In the beginning, it all seemed so simple: remove the mole and the cancer would be gone. I never expected we’d still be having those conversations three years later.

I specifically remember talking with my parents after they learned about immunotherapy. Considering I was struggling in my 8th grade science class, I didn’t really understand the concept. My mom tried to explain by comparing it to Pac-Man. She said the cells made in the lab would “eat away” at my dad’s tumors. It was our final option and, even though it was another experimental treatment, we had to have faith and pray it would work.

Initially, the treatment was going well. My once bed-ridden father, so weak he was only recognizable by his beaming smile, was becoming himself again. He was eating regularly, laughing a lot, and even leading my basketball team all the way to the championships as our coach. Christmas of 2009, my father had been declared three months No Evidence of Disease (NED) and my family couldn’t be happier.

However, just 10 short days later, our life got flipped upside down once more. My parents came home from a check-up completely silent. No one spoke but no one needed to; it was understood. The immunotherapy had been unsuccessful and the melanoma was beginning to attack other organs in my dad’s body. We were out of options and there was nothing else we could do. Three months later, at 12:37 am on April 27, 2010, I lost my father to melanoma.

Although not a day goes by where I don’t miss him, I now smile instead of cry because I know God chose my father for a reason. God knew who my father was, how many lives he touched in his short time here, and what those people were capable of. My parents’ friends founded the Wayne Stinchcomb Big Orange Foundation and has turned our tragedy into something amazing. Since Big Orange’s founding in 2010, there have been 11 new approved treatment options for melanoma, which we like to attribute in part to the $85,000 we’ve raised and donated to Melanoma Research Alliance. In addition to the funds we’ve raised, our advocacy and my father’s story has influenced many to get their skin checked and catch precancerous cells early.

People always say to me, “If only your father was diagnosed just one year later, he would’ve had treatment options,” but I don’t think about it like that. My dad was always the first one to try something new and the last one to give up. Whatever he did in life, he had to do it big and this rings true even for his battle with melanoma. The way I see it, my dad is one of the reasons all of these treatment options exist in the first place. Because of his journey and experiences with novel treatments, someone, somewhere is singing their daughter to sleep, kissing their wife goodnight, and waking up to a new day because they now have options when facing the monster that is melanoma.