b'Redefining Research & CareA New Strategy WhenTumors Are Mostly ControlledSwitching patient treatments might not Next-Generation Immunotherapy to harness the full potential of the immunebe the best choice if metastatic cancer is Discoveries made by UT Southwestern sci- system, both arms need to be activatedmostly controlled. entists have led to new treatments in clinicalsimultaneously, as normally occurs, forIn 2013, Drs. Timmerman and Brugarolas trials.instance, during an infection. This requirespublished the first report in the literature Immunologist Dr. Bruce Beutler receivedactivation of the innate arm. Whileof a patient with metastatic kidney cancer a Nobel Prize for the discovery of TLRs (Toll- less focused, the innate arm deploys awhose metastases were mostly controlled, like receptors). Made at UT Southwestern,rapid-response defense system. By trigger- Courtesy of Dr. James Chen, the figure shows thebut who had progression at one site, which this discovery laid the foundation for the nexting inflammation, it provides an improvedatomic blueprint of STING (two molecules shownwas treated with SBRT. The patient, an generation of immunotherapies.foundation for the activation of the adap- in gray and cyan) bound to the small molecule83-year-old man, was on sunitinib, and by Most therapies enhancing the immunetive arm.compound cGAMP (shown in orange and blue).radiating the isolated progressive metasta-system have focused on one arm of theA major portal of innate immune systemsis, sunitinib treatment could be extended immune system, the so-called adaptiveactivation comes via TLRs. Because of this,from 14 to 22 months. The late Dr. Eugene P. Frenkel (left), an internationally recognized cancer researcher, clinician, and educator, arm. This is fitting, as the adaptive arm is thepharmaceutical companies have developedNKTR-262, which activates TLR 7/8. ThisThe situation is referred to as oligopro- pioneered UT Southwestern Medical Centers Hematology and Oncology Division. He is pictured here more sophisticated of the two arms, and isdrugs that activate TLRs, to be administereddrug is being studied in a clinical trial atgression, from the Greek oligos, meaningconferring with his colleagues Drs. Yull Arriaga, Arthur Sagalowsky, and Hans Hammers. able to develop a focused attack. in conjunction with immunotherapies thatUT Southwestern. The trial (NCT03435640)few, and from the English word progres-However, recent findings suggest thatboost the adaptive arm. One such drug isevaluates NKTR-262 in combination withsion. Today, more than 30 UT Southwesterntrial is founded on the notion that while apatients are not adversely affected by a modified version of IL-2 and nivolumab.patients have been offered this option.few tumors in a patient may have developedthe treatment. UT Southwestern is one of 10 sites that arePreliminary analyses show that treatmentresistance to a particular therapy, perhapsInvestigators hope that by prolonging testing the TLR-activating drug.duration can be extended by more than sixthrough the acquisition of a mutation, theseeach therapy before the next is started, Molecular biologist Zhijian Jamesmonths in many patients. events tend to be isolated. By incorporatingpatient life span will be extended, as ulti-Chen, Ph.D., recipient of the 2019To systematically explore the benefitSBRT treatment of progressive tumors (upmately the number of available therapies is Breakthrough Prize in Life Sciences, isof SBRT in patients with oligoprogression,to three), investigators hope to maximizelimited. (Straka et al., J Clin Oncol, 2013; shedding light on a second pathwayDrs. Hannan and Brugarolas have openedthe efficacy of each cancer medication.Zhang et al., Int J Radiat Oncol Biol Phys, implicated in the innate immune systema clinical trial (NCT03696277). The clinicalThis prolongs quality of life in cases where2019)response. While TLRs largely sense the environment outside the cell, Dr. Chen discovered a mechanism whereby cells can sense if they have been penetrated by anMEET RENE MCKAY, PH.D., infectious organism. Dr. Chen discoveredDIRECTOR OF RESEARCH ADMINISTRATION a critical sensor of this process, a protein called cGAS (cyclic GMP-AMP synthase).Rene McKay, Ph.D., has been withBoard meetings; and manages the cGAS recognizes penetration by foreignthe Kidney Cancer Program fromlab and Kidney Cancer Program organisms in the form of DNA in thethe beginning, joining the programwebsites, and even the Facebook cytosol. In human cells, DNA is found onlyin September of 2013, three monthspage. Rene is the mainstay of our within the nucleus and inside mitochondria.before its inauguration by Dallasprogramshe keeps the program Outside of these structures, DNA triggersMayor Mike Rawlings. Her firstrunning, says Dr. Brugarolas. I love the activation of cGAS. Upon activation,major task: assisting with the Kidneybeing part of such a great team of cGAS sends an alert molecule calledSPORE grant application. Thesmart and committed people, says cGAMP to activate a manager of theSPORE was the culmination of manyDr. McKay. It has been very reward-immune response called STING. Much likemonths of work and the combineding to see the program grow, and TLR activation, STING activation triggerseffort of many investigators. Asidethe progress made toward finding an inflammatory response. Thus, STINGfrom helping to oversee and coor- better treatments for kidney cancer is an attractive drug target to activate thedinate the SPORE grant, Dr. McKaypatients. One highlight has been get-immune system. Dr. Chen has licensed hisdoes many other things. As theting to know our Patient Advocates, discoveries to a company, Immune Sensor,Director of Research Administration,some of whom are dealing with the LLC, which is evaluating IMSA101 in aDr. McKay assists Dr. Brugarolasdisease themselves. Their selfless phase 1 clinical trial at UT Southwesternwith manuscripts; coordinates anddedication to helping other patients (NCT04020185). helps review applications for funding;as they deal with their own difficult This research is being further expandedorganizes conferences and Advisoryjourney is so inspiring. on by chemical biologist Chuo Chen, Ph.D., who, with funding from the Kidney Cancereat team of smart I love being part of such a grProgram SPORE, is developing drugs thatand committed people.Dr. James Brugarolas (left) conversing with Nobel Prize winner Dr. Bruce Beutler, whose discoveries setactivate the innate and adaptive immune the foundation for a new medication being tested in a clinical trial, sponsored by Nektar Therapeutics, that he oversees at UT Southwestern. system simultaneously.50 51'