ASH Clinical News January 2017 Annual Meeting Edition | Page 33

FEATURE
Immunotherapy : Science Fiction 50 Years in the Making
CAR T-cell immunotherapy appears to be an overnight success story , but the beginnings of this pioneering technique date back to the 1980s , when cancer immunotherapy researchers were searching for ways to “ trick ” the body ’ s immune system to attack tumor cells .
In Israel , chemist and immunologist Zelig Eshhar , PhD , was studying CAR T cells at the Weizmann Institute of Science , before taking a year-long sabbatical in 1990 to join Steven Rosenberg , MD , PhD , at the National Institutes of Health . There , they prepared CARs that targeted human melanoma and overcame a tumor ’ s ability to escape immune recognition .
Around the same time , Carl June , MD , was working with T cells at the Naval Medical Research Institute , where he was head of the Department of Immunology from 1990 to 1995 . He and a colleague , Bruce Levine , PhD , developed the tissue-culture technique used for multiplying T cells
outside the body – a method that is still used today .
Dr . June is now the Richard W . Vague Professor in Immunotherapy at the Perelman School of Medicine and director of the Center for Cellular Immunotherapies at UPenn . Dr . June ’ s work turned personal in 1996 when his wife was diagnosed with ovarian cancer , and he stopped seeing patients to devote his career to creating cell therapies for cancer .
Dr . Rosenberg became the chief of surgery at the National Cancer Institute in Bethesda , Maryland , the day after completing a PhD in biophysics at Harvard University and a surgical residency at Brigham and Women ’ s Hospital ( then known as the Peter Bent Brigham Hospital ).
In 1968 , as a resident , Dr . Rosenberg removed the gallbladder of a man who , 12 years earlier , had a spontaneous regression of his gastric cancer without any treatment . “ Somehow his body had figured out
how to eliminate the cancer ,” said Dr . Rosenberg in a recent podcast interview with the American Academy of Achievement in Washington , DC . “ I ’ ve only seen it one other time in my entire career , after treating well over 5,000 cases of cancer .”
His realization that the man ’ s immune system must have eliminated his cancer , just as it would eliminate a flu virus , set him on a lifelong journey to find out how he might be able to replicate this feat for patients with cancer .
In 1984 , he successfully treated a woman with advanced melanoma with interleukin-2 , a protein that affects T-cell differentiation and expansion . He had found the first effective immunotherapy for human cancer . “ We knew then it was possible ,” he said . “ Once you know something is possible , everything changes .”
Fast forward to today , when numerous other cancer researchers – including James Allison , PhD , from MD
Anderson Cancer Center in Houston , who laid the groundwork for immune checkpoint inhibitors , and Michel Sadelain , MD , PhD , at Memorial Sloan Kettering Cancer Center in New York , who devised the means to genetically engineer T cells – have taken several immunotherapies through the FDAapproval process . These include the immune checkpoint inhibitors , such as pembrolizumab and ipilimumab ; the interferons and interleukins ; several cancer vaccines ; and an oncolytic virus therapy .
But the CAR T-cell therapies – none of which are approved , but three of which are in advanced development – may just be the most exciting immunotherapy yet .
sources
• The New York Times , “ Setting the body ’ s ‘ serial killers ’ loose on cancer ,” August 1 , 2016 .
• The Scientist , “ The CAR T-cell race ,” April 2015 .
• The American Academy of Achievement , “ What It Takes : Steven Rosenberg ,” August 29 , 2016 .
Dr . Goff added that the DLBCL trial also required a modification due to issues with the chemotherapy preconditioning regimen . In a previous trial of the same agent and the same patient group , there was some concern that the high response rate observed might have been a result of the chemotherapy regimen used , as opposed to the CAR T-cell therapy . 7 They re-did the trial with low-dose chemotherapy , and these findings were similar and “ maybe even a little better ,” she said .
Determining the correct amount of T cells infused also requires precision . In one patient in the NCI trial , the investigators opted to infuse three times the normal amount of cells to see if more is better . “ It may have been coincidence , but one patient experienced some of the most severe neurotoxicity we have seen , so we immediately backed away from that higher dose of cells ,” said Dr . Goff .
High Risk , High Reward
The experiences with the ROCKET trial illustrate why some researchers are reserving judgment about the game-changing potential of CAR T-cell therapies : The potential benefits of CAR T cells come with real risks .
“ To safely manage the toxicities of the investigational therapies , it is best for patients to be treated in a large medical center with a transplant program and with a good intensive care unit ( ICU ),” said Dr . Grupp . “ The toxicities are manageable – even in the sickest patients – but it is challenging to take a patient whose bone marrow has been replaced by , literally , pounds of leukemia through cytokine release syndrome ( CRS ).”
CAR T-cell therapy holds the distinction of being one of the first cancer therapeutics wherein the best sign that it is working is how terribly ill the patient gets , Dr . Grupp noted . And , the greater the tumor burden , the more

“ Four or five years ago , people would have looked at the idea of immunotherapy as complete science fiction . They might say , ‘ It ’ s too hard , complicated , boutique , [ and ] academic .”

— STEPHAN A . GRUPP , MD , PhD the engineered T cells will work to eradicate it . The development of CRS – an inflammatory response that directly correlates with in vivo CAR T-cell expansion and proliferation – is the “ flipside ” of engineered T cells working effectively . CRS often presents first as a fever , followed by myalgia , nausea , extreme fatigue , encephalopathy , and transient hypotension . In some patients , it progresses to life-threatening vasodilatory shock . In most cases , it is selflimiting , but in others it requires anti-cytokinedirected therapy .
Researchers at UPenn have developed predictive models of CRS to learn if it is possible to intervene early enough to reduce morbidity and mortality . 8 They also have published data indicating that , while there seems to be a correlation between the development of CRS and response to the CAR T-cell therapy , there does not appear to be a strong association between the degree of CRS and outcome . 8
The first child with ALL that Dr . Grupp treated at CHOP was a young girl named Emily Whitehead . 9 , 10 “ Most of her bone marrow was replaced by leukemia ,” Dr . Grupp recounted . Emily ’ s case became public shortly after she recovered and her treatment was deemed a success . She remains in remission nearly five years later .
“ Emily got terribly , critically ill with CRS , but we found that one of the inflammatory proteins that was markedly elevated in her blood was interleukin-6 ( IL-6 ), which we weren ’ t expecting ,” he explained . “ We subsequently
ASHClinicalNews . org ASH Clinical News
31