b'Redefining Research & CareChallenge: Dissecting the Battlefront tumorgraft from the corresponding patientsin tumors under a heavy immune attack Understanding how immune cells orches- tumor, they would be left with information(see page 46). Interestingly, these tumors trate an immune attack against cancer cellscorresponding to the noncancer cells. might be most likely to respond to exist-and what strategies cancer cells employ toUsing RNA sequencing (which scoresing immunotherapies. evade them is essential to making prog- activated genes) and a new tool Dr. WangBased on this research outcome and with ress. However, figuring out the battlefield isdeveloped called DisHet, investigatorsSPORE funding, Dr. Wang is now furthering challenging. A first approach involves tryingwere able to accomplish the task. Theirhis research to find features in cancer cells to separate cancer cells from noncancerapproach identified twice as many genes asthat make them targets for immune cells. cells in tumors. Separating cancer cellspreviously thought to be active. They also(Wang et al., Cancer Discov, 2018; Zhang et from noncancer cells is difficult, and thefound that more than 60 percent of genesal., Genes, 2019) process of picking out the different cells maypreviously thought to be activated were in disrupt them, compromising the utility offact not activated.the approach.With this powerful tool, the investiga-Larry Carlson benefited from participating in the RADVAXKevin Patterson was diagnosed with stage 4To understand how defenders mounttors were able to learn about the immune trial and now volunteers in the clinic.ccRCC just days after his wedding. He had a complete response, with all traces of the canceran immune attack, Tao Wang, Ph.D., andcell attack. Based on the intensity of the disappearing, following the combination of Dr. Brugarolas took an innovative approach,immune attack, they were able to sepa-high-dose IL-2 and SBRT in a clinical trial.which doesnt involve disruptive experimen- rate tumors into those under heavy attack tal separation, but leverages a new tool theyand those that were not. Interestingly, they SBRT Plus Latest Immunotherapies investigators have developed an innovativedid not. (Vento et al., J Immunother Cancer,developed. Patient tumors transplanted indiscovered that the intensity of the immune A clinical trial is evaluating the combina- strategy using UT Southwesterns cyclotron.2019) mice grow to form tumors (called tumor- attack correlated with particular gene tion of SBRT with checkpoint inhibitors,The team labeled a drug that binds PD-L1The FDA has now granted an INDgrafts; see page 67), but the only cells thatmutations in tumors (specifically BAP1; see nivolumab and ipilimumab (NCT03065179).(atezolizumab) with a tracer that can be seen(Investigational New Drug) to the tracergrow and expand are the cancer cells.page 40) as well as factors used by doctors Taking its name from the notion that radia- using a PET (positron emission tomography)produced by UT Southwestern, and Dr. AlexOther cells in the battlefield dont survive into predict how aggressive the tumor might tion may function as a vaccine, the studyscanner. By identifying those tumors thatBowman and Dr. Brugarolas are conduct- the mouse.be. Their data suggest that factors such is referred to as RADVAX.have PD-L1, investigators hope to bettering a clinical trial to assess its potential inThe investigators reasoned that tumor- as high platelets or low red blood cells The addition of SBRT to the combi- select patients for PD-L1-targeting drugspatients (NCT04006522).grafts may provide a venue to deconvolute(anemia) may be altered in these patients nation of nivolumab with ipilimumab maysuch as nivolumab.Representing the Simmons Cancerthe battlefield. If they could subtract theas a consequence of the inflammationUnderstanding the cancer battlefront. significantly boost response rates from 40To test this notion, investigators evalu- Center, Dr. Brugarolas, along with his percent to 60 percent, says Dr. Hammers,ated mice transplanted with kidney cancerscolleagues Xiankai Sun, Ph.D., and principal investigator. that had PD-L1 or did not. The mice wereDr. Bowman, received a $600,000 grant from Toxicities so far are in the range of whatthen injected with atezolizumab, which hadthe V Foundation in 2018 to identify patients is known when nivolumab and ipilimumabbeen labeled by Dr. Xiankai Suns team withwhose renal cancers are most vulnerable are given together without radiation. a radioactive molecule, zirconium-89 ( 89 Zr).to immunotherapies. The grant is designedTHE IMPACT OF BODYAs shown in the figure, mice with tumorsto support research from the bench toBACTERIA ON IMMUNOTHERAPYChallenge: Predicting Who Benefitsthat had PD-L1 lit up, and those withoutthe bedside. from Checkpoint Inhibitors Trillions of microorganisms liveinhibitors. With grant support One approach that cancer cells employin and on our bodies, includingfrom the Kidney Cancer Program, to avoid being killed by immune cells is toiPET may identifyin the gastrointestinal tract. TheyDr. Koh is setting out to identify hide from the immune system. They can dotumors most likely so by cloaking themselves with a proteinto respond toare referred to as the humanhow the microbiome affects immunotherapy. called PD-L1 on their surface. PD-L1 sends( 89 Zr) atezolizumabmicrobiome. They educatethe response of kidney cancer a signal to nearby immune system killerilluminates (redand modulate the immunepatients to immune checkpoint signal) a kidneysystem. Microbiome expertinhibitors. In the future, precision PD-L1cells that turns them off.tumor transplant Nivolumab fires up the killer cells againstdecorated withDr. Andrew Koh believes thatprobiotic therapy with gut PD-L1. Microscopicthere is a unique populationbacteria identified in this studyDr. Andrew Koh is partnering with Dr. Lora Hooper, Chair of the cancer by disabling the effect of PD-L1.pictures of tumor cells from the originalof gut bacteria that controlcould be used to augmentImmunology, HHMI Investigator, and member of the National However, not all cancers use this strategy.patient tumor orAcademy of Sciences, to determine how bacteria affect In fact, only 25 percent of kidney cancerstransplant in theresponses to immune checkpointcancer immunotherapy efficacy. immunotherapy treatments. respond to nivolumab.mouse shown on the side. Brown color To identify tumors that have PD-L1,indicates PD-L1.48 49'