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:

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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.

Research Q&A: Dr. Tim Bullock

BullockIn the latest blog post, we chatted with the University of Virginia’s Tim Bullock, Ph.D., a tumor immunologist in the Pathology Department and MRA-funded investigator. Read on to learn what he has to say about melanoma research and prevention efforts.

Can you explain a bit about your research?

I received an Academic Industry Award from MRA, which was a fantastic segue from the more basic/translational tumor immunology we were well-versed in to getting me more exposed to (and appreciative of) the challenges and opportunities that are presented in clinical tumor immunology. It really helped establish our lab in truly translational research.

The grant led us to begin to understand what goes wrong with T cells in patients with melanoma. We’re conducting research now to look at the transcriptional basis of what’s wrong with tumor infiltrating T cells, looking at the genes that control T cell function, and what signals from the tumor microenvironment influence the expression of these genes. We’re trying to understand if we can identify critical differences in genes in T cells that are failing to control tumors compared to those that either control tumors or infections, so that once we understand them, they could either be biomarkers for effective anti PD-1 therapies or provide opportunities to complement anti-PD1 therapy.

We take a collaborative approach with investigators at UVA, so I value working with clinicians and researchers from a variety of backgrounds. We work in teams to look at how targeted therapies and more traditional chemotherapies affect newer immunotherapies to understand the cumulative effects of these treatments. The hope is that this will help us identifying rational combinations of tumor-targeting therapies that will work well with immunotherapies.

Can you explain how your research is helping making a difference for patients?

Our most recent funding, as an Established Investigator, uses a fairly novel technology called focused ultrasound. It’s a way of delivering acoustic energy, as opposed to the more traditional radiation, into tumors, with the intent of causing damage to the tumor that the immune system can respond to. It’s in early stages yet, so we need to understand how innate and adaptive immunity, and the tumor, respond to this type of “insult.” This is focusing specifically on melanoma brain metastases as there is such an unmet need in this patient population. We’re trying to answer important questions, like:

  • Can we use it to treat brain metastases (similarly to how it’s being used to treat Essential Tremors and patients with Parkinson’s Disease)?
  • How does the brain’s immune components respond?
  • Can we integrate this technology with immunotherapy?

There are a lot of unanswered questions, but our goal is to get it to patients as soon as possible. We’re integrating our work with biomedical engineers and have funded this collaboratively because many people see the potential for focused ultrasound. If efficacy is the same as radiation, this technology could provide a new approach meet the challenge of these poorly served patients.

How has MRA funding helped your work?

Each stage of my career, MRA has been there. The Young Investigator Award helped get my lab up and running. And the continued support through Academic-Industry Partnership and Established Investigator awards have helped sustain my work.

The funding has been important, but I also value the collaborative network that MRA has fostered. The Scientific Retreat is a relaxed setting to chat about real challenges and new opportunities.

MRA has a real enthusiasm for thinking outside the envelope. MRA provides the building blocks and foundation to get important research moving forward. MRA is notorious for that and it’s certainly had an impact on my career.

What do you hope to see more of in the future of melanoma research?

The future is understanding how to integrate these amazing therapies we have now. We’re trying to understand each patient’s disease to select the appropriate combination of therapies to treat them.  We can almost come up with a “prescription” for each patient. We’re also talking about real-time monitoring of tumors to identify mechanisms of adaptive resistance. This could allow us to develop counter responses by figuring out how to react in near real time.

This is absolutely personalized, precision medicine, and I think melanoma researchers and the MRA are going to lead it.

Can you share a little about yourself? What do you outside of the lab?

One of the things I enjoy most is coaching soccer. Right now I’m coaching U14 girls soccer.

 

 

8th Annual Scientific Retreat Recap

The end of February was a momentous one for the MRA team and all the folks in the melanoma community. We hosted our 8th Annual Scientific Retreat in Washington, DC, and they truly just seem to get better and better.

The Retreat serves two main roles for those invited participants. First, is the centerpiece of scientific knowledge sharing, as evidenced by the more than 20 MRA-funded investigators who presented at the meeting as well as several supplementary events and sessions aimed to provide a holistic look at the state of melanoma research and treatment. Secondly, the Retreat provides an opportunity for participants from all sectors to network. We consistently hear about the new collaborations to fight melanoma that arise from networking at this meeting.

Our Melanoma Forum opened the Retreat with a session about the continuing evolution of patient participation in the research process. It was attended by 50 patients, advocates, and supporters who shared their personal experiences to help advance our work by articulating the unmet needs and burden of the disease from those who understand it personally. Special thanks to Raj Kulkarni, an MRA Young Investigator at UCLA, and Kim McCleary of FasterCures for helping to build out this event.

MRARetreat_Selects-16Our lunchtime panel discussion (left), moderated by Mike Milken, featured four amazing thought leaders in melanoma. Drs. Boris Bastian of UCSF, Levi Garraway of Dana-Farber Cancer Institute, Lynn Schuchter of U Pennsylvania and Suzanne Topalian of Johns Hopkins University wo provided a look forward for the future of melanoma research.

In addition, we convened the growing group of MRA-funded Young Investigators to explore several key issues in clinical translation, while our Industry Roundtable meeting brought together representatives from the NCI, FDA, academia and industry to thoughtfully address challenges and opportunities for future collaboration on behalf of patients.

MRARetreat_Selects-19A highlight of the meeting was welcoming newly appointed FDA Commissioner Robert Califf (left), who came straight from his confirmation at the White House to deliver remarks to the MRA community.

It was truly a convergence of the brightest stars in the field and a community dedicated to achieving MRA’s mission of defeating melanoma. You can read more about in blog posts from Dr. Len, of the American Cancer Society, and T.J. Sharpe, a melanoma survivor who blogs for Philly.com.

We thank everyone who came to participate in the meeting, as well as our sponsors, who all helped make our 8th Annual Scientific Retreat a success!

 

 

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.

Gearing up for our Annual Scientific Retreat

The Melanoma Research Alliance’s (MRA) annual Scientific Retreat brings together hundreds of scientists, industry professionals, and patients from around the globe to foster collaboration in the field of melanoma research. This year, MRA will host its eighth retreat from February 24-26 in Washington, DC.

This year’s scientific sessions begin with a discussion on potential new therapy targets. Scientists from a variety of institutions, including Duke University and Sheba Medical Center in Israel, will discuss advances in the fields of targeted therapy and immunotherapy. In addition to discussing therapies, a prevention-focused afternoon session will address the pros and cons of mandatory skin screening and the self-screening process.

In efforts to include the expanding role of patients in the research process, this year’s Retreat will include a Melanoma Forum geared toward patients, caregivers, advocates and supporters. Moderated by FasterCuresKim McCleary, patients will be invited to an interactive discussion on their active involvement in research. The forum will provide an excellent venue for patients to engage in discussion and meet other individuals who share a common goal for the future of melanoma research.

flaherty, sigal, topalian

Participants at the 2015 MRA Scientific Retreat

The MRA team is excited to host this extraordinary group of individuals under one roof. Our Chief Science Officer, Louise M. Perkins, Ph.D., is looking forward to seeing so many close colleagues and friends from the melanoma research sphere. “There’s no event quite like this to share the latest in research and to build new collaborations.”

Tasheema Prince, Scientific Program Manager, joined MRA in 2015, and is anticipating her first retreat. “It’s essentially a glimpse into the collective fight to end melanoma and I’m very excited to witness a convening of bright scientific minds in the field,” explains Prince.

We hope the retreat allows individuals to build valuable relationships and accelerate momentum in the field of melanoma research, and ultimately help more patients overcome this disease.

To get more details on the Scientific Retreat visit our website to see a draft agenda and learn more about the event.

Identifying Melanoma as a Single Cell

A recent study published in the journal Science could provide important clues for melanoma diagnosis.  Led by Leonard Zon, M.D., of Boston Children’s Hospital, the study looked at cancer in zebrafish from the very beginning – when it starts as just a single cell.

Funded in part by MRA, the study is the first to see melanoma – or any other cancer – begin this early. The researchers found that the cancer developed from an interesting process: the cells reprogrammed back to an embryonic state.

“The process was surprising to us,” noted Dr. Zon. “The melanoma essentially reprogrammed melanocytes to a stem cell, similar to an embryo’s neural crest.”

While the study looked at melanoma in zebrafish, Dr. Zon said human melanomas work similarly. Moles contain melanocytes, the pigment-producing cells. Most moles have a common genetic alteration in a gene called BRAF, but very few moles turn deadly. Understanding the early process of how and why cancers develop could help target treatments, or perhaps reveal prevention strategies.

Dr. Zon’s team used fish that had the BRAF mutation. They created a way to make the fish cells light up in bright green if the embryonic gene called crestin was turned on. The fish that lit up with the bright green signal were the same fish that developed melanomas.

“There are important implications of this work for cancer diagnosis with a newly found tumor, and potential opportunities to stop cancer before it ever begins,” explained Dr. Zon.

The new published research builds off of earlier work by Memorial Sloan Kettering Cancer Center’s Richard White, MD, PhD, recipient of the Maria and Bill Bell – MRA Young Investigator Award, who observed that the melanomas in zebrafish were derived from crestin-expressing cells. Dr. White is a co-author in this new paper.

Dr. Zon told the Harvard Gazette that these findings could not only lead to genetic tests for suspicious moles to see if the embryonic cells have been activated, but also help researchers develop treatments that could prevent a mole from becoming cancerous.

You can read more about Dr. Zon’s research in the New York Times.