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.