TMC PULSE

t m c » p u l s e | j u n e 2 0 1 5 19 "Once you get a big T-cell response, a certain population of those cells acquire stem cell-like capabilities," said Allison. "They're with you for the rest of your life. If the tumor comes back, they get turned on again and kill it." Despite its recent progress, the field of immunotherapy still has obstacles to over- come in order to reach its full potential. Federal funding is currently "overwhelmingly directed toward genomically targeted therapies as compared to immune checkpoint therapies," as Allison and Sharma wrote in their Cell article. They suggest more funds be allocated toward immunotherapy research, given its potential and recent successes. One of the reasons for this imbalance in funding is the fact that immunotherapy experi- enced years of failures before Allison's discover- ies helped revitalize the field. "Immunotherapy lost credibility as being something that was really going to make a differ- ence in cancer," said Sharma. "The genomically targeted therapies came along more recently, but showed benefit so quickly. Immunotherapy couldn't say that. But this is a different kind of immunotherapy." Though it may take time to convince everyone of the new potential in these immune checkpoint therapies, the message appears to be spreading. Allison and Sharma both noted one significant measurement of how far immuno- therapy has come over the last decade is evident at the conferences they both attend, such as recent annual meetings of the American Society of Clinical Oncology. "When I started going to these meetings in 2004, 2005, the immunology sessions would be in a small room. You'd be lucky if there were 50 people there," said Allison. "Two years ago, when the combination of ipilimumab and anti-PD1 was presented, it was in this huge theater where there were over 3,000 people." The most important change in this new era of immunotherapy research, however, can be seen in the clinic and the lab. Even as recently as five years ago, finding clinicians to provide tissue for research was more difficult. These days, many are eager to participate. "Right now there is so much enthusiasm," said Allison. "That's one thing I've sensed since coming here. Everybody wants to help—they all see what it's doing for their patients." The search for effective combinations not only includes pairing multiple immunotherapy treatments, like the anti-CTLA-4 and anti-PD-1 drugs, but also combining immunotherapy with other types of treatment. Allison and Sharma recently published papers in the journals Cell and Science to discuss the potential of com- bining genomically targeted therapy with immunotherapy. "Don't even try to make those targeted genomic therapies curative, because they're not," said Allison. "There are too many resis- tance factors. Let's start making rational combinations." For several years, genomically targeted ther- apies have been touted as the next big thing in cancer treatment, because they garner remark- able responses in a majority of patients. The downside? Those responses don't last. "The genome of cancer cells is really unstable," said Allison. "By the time you find one you can attack, there are probably other mutations that will take over. You're always following behind." If combined with immunotherapy, however, Sharma and Allison suggest it would be possible to get a durable response from a high percent- age of patients. "Because immunotherapy works not by targeting the cancer cell but by targeting the immune system, we thought the combination of these two things would be very powerful," said Sharma. A patient could begin with a genomically targeted therapy to kill tumor cells, which would release antigens for the T-cells to attack and associate with tumors. "While the tumor cells are dying, you can bring in immunotherapy and start the whole immune process," said Sharma. "You would have a durable response, because immunotherapy allows for the development of memory cells." Sharma used the polio vaccine as an exam- ple. If you received the polio vaccine as a child, you will still have an immune response as an adult. If you encounter polio, your immune sys- tem would remember it and kick in to get rid of it, preventing you from contracting the disease. "If we can get that to happen with cancer and form memory T-cells, you would have that durable response and you wouldn't have patients relapsing with their disease," said Sharma. In fact, memory is one of the biggest perks of immunotherapy. RIGHT: A T-cell connects with a larger antigen- presenting cell, which causes the T-cell to activate against the tumor. After they connect, the red CTLA-4 checkpoint molecule migrates to the connection spot to dial down the immune response. BELOW: This image shows a T-cell, and to the right is a T-cell connected to an antigen-presenting cell. (Credit: MD Anderson) B E T W E E N C L I N I C A L W O R K , O B TA I N I N G T I S S U E A N D T U M O R S A M P L E S , A N D R E S E A R C H , T E A M W O R K P L AY S A V I TA L R O L E I N M D A N D E R S O N ' S T R I A L S .

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