Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary approach to targeted immunotherapy to treat cancer, and the details can seem like the stuff of science fiction: A patient’s T cells are harvested, re-engineered to become targeted “cancer killers,” and infused back into the patient’s body to proliferate and eradicate cancer cells. In some cases, these T cells have even been shown to minimize the risk of relapse.1,2
“This is the one tool I have where I know that, even if a patient has 90 percent bone marrow blasts and has not responded to any kind of chemotherapy, I still have an 80 to 90 percent chance of putting the cancer into remission,” Stephan A. Grupp, MD, PhD, director of the Cancer Immunotherapy Frontier Program and director of Translational Research for the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia (CHOP), told ASH Clinical News. “There is nothing like that out there.”
The excitement about bringing CAR T-cell therapy into the real world, though, is hampered by unanswered questions about side effects, indications, treatment delivery, relapse, and manufacturing.
Several CAR T-cell therapies are expected to begin the process of securing U.S. Food and Drug Administration (FDA) approval this year. ASH Clinical News spoke with Dr. Grupp and others to better understand the excitement, and limitation, of using these novel therapies.
What Are CARs?
The immune system plays a pivotal role in preventing tumor initiation and progression. However, T cells have a limited repertoire against any specific tumor, and cancer cells often evade immune detection and elimination. Immunotherapy “outsmarts” tumor cells by optimizing the immune response to the malignancy; CAR-modified T cells are just one type of immunotherapy approach under investigation.
“CAR T cells are an amazing piece of biologic innovation based on the concept of harnessing T cells’ amazing killing power and broadening their ability to recognize their target,” explained Stephanie L. Goff, MD, a surgeon at the National Cancer Institute (NCI) who works with Senior Investigator Steven A. Rosenberg, MD, PhD, head of the NCI’s Tumor Immunology Section.
CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that allows the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When expressed in T cells, CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. These cells then expand and become highly focused hunters and killers of specific cells, unlike the indiscriminate destruction wrought by classic chemotherapeutics.
“By combining the killing power with the recognition of an antibody, we can engineer T cells to target cells with any antigen on their surface,” Dr. Goff said.
For hematologic malignancies, that means CAR T cells can easily attack markers like CD19 and CD22, which are highly expressed in B-cell malignancies.
A number of different CARs have been tried, using different receptor designs and viral vectors. The early CARs consisted of only the T-cell receptor complex (TCR), while newer CARs incorporate costimulatory domains, such as CD28 or CD137, that improve cell survival and proliferation.3
On the Road to the FDA
Many of the CARs in development – especially those that are furthest along clinically – are directed at CD19, a cell-surface protein expressed on B cells and B-cell precursors. CD19 is expressed on the surface of most B-cell malignancies, which include some leukemias and myelomas, and most non-Hodgkin lymphomas (NHLs).
Three pharmaceutical companies have second-generation CAR T-cell products in advanced development (TABLE); each of which has teamed with an academic center: Kite Pharma with the NCI; Novartis with the University of Pennsylvania (UPenn); and Juno Therapeutics with Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Research Center, and Seattle Children’s Hospital.
“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,’” Dr. Grupp said. Now, though, with two products expected to file FDA applications in the first half of this year, he sees CAR T-cell therapies headed to the mainstream. “One could be an accident, but with two, we might be heading toward a trend.”
CD19-directed, CAR-modified T cells have shown promise in relapsed or chemotherapy-refractory B-cell acute lymphoblastic leukemia (ALL) and, to a lesser extent, benefit in relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell NHLs, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.4,5 (Editor’s note: At the 2016 ASH Annual Meeting, Sattva S. Neelapu, MD, presented results from the phase II ZUMA-1 trial of anti-CD19 CAR T cells in patients with relapsed refractory DBLCL as a late-breaking abstract).
Ongoing investigations are attempting to expand these indications, including to ALL in children and adults. Treatment with CD19-targeted CAR T-cell therapies has produced remission rates as high as 94 percent in children and young adults with relapsed and refractory ALL.6 “This study also confirmed the high complete remission rate, including a disease-free survival rate of approximately 55 percent at one year,” Dr. Grupp noted, adding that, “beyond one year, we have not observed much disease recurrence.”
He explained that, while some research groups are investigating CAR T cells as a bridge to hematopoietic cell transplantation (HCT), at CHOP, researchers are trying to avoid transplants. “Skipping bone marrow transplant and replacing it with immunotherapy is an attractive, exciting idea.”
In CLL and NHL, response rates are approximately 40 to 50 percent, with similar durability. In the most recent trial at NCI, Dr. Goff administered CAR T cells to 19 patients with DLBCL who were refractory to standard therapies or had undergone autologous HCT. Nine of those patients achieved complete remission, and all nine remain in remission past one year of follow-up.4 “This is a population of patients who was looking for salvage therapy, and nine of them don’t have active lymphoma anymore,” Dr. Goff said.
A Complicated and Individualized Process
CAR T-cell therapy is a multistep process that can take anywhere from a few days to several weeks. After leukapheresis is completed, the T cells are activated and expanded ex vivo, then genetically modified for stable CAR expression, typically with the use of retroviral or lentiviral transduction. These reprogrammed cells are expanded to obtain a therapeutic dose of CAR T cells to be infused into the patient.
Before that happens, the patient undergoes chemotherapy to deplete his or her own remaining T cells. “The chemotherapy creates an environment within the body that is ‘hungry’ for T cells,” Dr. Goff explained. “The immune system is then generating the right kind of cytokines to help the CAR T cells proliferate and expand.”
Figuring out the right combination (i.e., which chemotherapy to use and what dose and what amount of re-engineered T cells to reintroduce), though, is difficult, she said. For most candidate CARs, this has been a long process of trial and error, sometimes with fatal results.
In the summer of 2016, the FDA placed the phase II ROCKET trial of JCAR015 in adults with ALL on hold after two patients died of cerebral edema. The drug’s manufacturer (Juno Therapeutics, Inc.) reported that the deaths were related to the addition of fludarabine to the pre-conditioning regimen, and the trial was allowed to continue after cyclophosphamide was used as a substitution. However, in November, Juno Therapeutics placed the trial on voluntary hold following two additional patient deaths from cerebral edema. These deaths, Juno Therapeutics reported, appeared to be correlated with the rapid proliferation of CAR T cells injected back into the body, and it is working with the FDA to determine next steps.
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 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 self-limiting, but in others it requires anti-cytokine-directed 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 found that other patients with CRS also have sky-high levels of IL-6.”
Once Emily was treated with tocilizumab (an antibody against the IL-6 receptor used primarily to treat rheumatoid arthritis), her symptoms rapidly reversed.
“It was incredibly fortuitous for her, and for the whole field, that tocilizumab was utterly transformative for treating severe CRS,” said Dr. Grupp. “Without the ability to block IL-6, I don’t think we could safely give these cells to patients.”
The drug is now part of the standard toxicity management protocol, and it works with all three available CAR T-cell therapies. Dr. Grupp stressed, however, that the side effects of CAR T cells shouldn’t be minimized; they require sophisticated ICU-level care and an experienced team to manage them, which may limit the number of centers able to administer the treatment.
While cytokine blockade with tocilizumab is effective in reversing CRS, it does not prevent expansion of CAR T cells or reduce their anti-leukemic efficacy.
Dr. Goff has found neurotoxicity to be a bigger issue than CRS, maybe, she speculated, because, “in leukemia, the cell being targeted is freely circulating in the blood and marrow, which may make CRS more evident. In lymphoma, the targets are solid masses, rather than cells floating around in the blood.”
In the latest trial of CAR T-cell therapy conducted at NCI, only three patients (of 19) required any sort of vasoactive medication to counteract CRS, while about half experienced grade 3 or 4 neurotoxicity.4 “We’ve seen a range of neurotoxicity, varying from mild confusion and word-finding issues to frank encephalopathy, hallucinations, seizures, and extreme agitation,” she said.
Some patients will experience both CRS and neurotoxicity – together or in sequential order – but, despite these side effects, most patients recover after careful monitoring and supportive care, Dr. Goff said. “Two patients required intubation because they were unable to maintain their mental status enough to protect their airways,” she noted, “but even without additional treatment to stop the T cells with steroids, these patients recovered.”
Ready for Prime Time?
Despite the promise seen in B-cell cancers, CAR T-cell therapy is only in its infancy. There are still many unanswered questions and ways in which the therapies might be improved or their use extended to other cancers.
“We don’t even know yet if the response rates we have seen will be replicated once the therapy starts being used more widely,” said Dr. Goff.
Assuming these therapies receive regulatory approval, myriad issues surround the implementation of such a groundbreaking therapy. Who will deliver the therapy? Where will the cell processing be done? How does one mass produce a time-, labor-, and technology-intensive personalized therapy? How can efficacy and safety be ensured throughout the process? What will it cost?
Clinically, Dr. Goff does not see CAR T-cell therapy as being more complicated than hematopoietic cell transplantation, and, in some ways, it may be less complicated. Both are highly individualized and require complex chemotherapy regimens, and they need to be performed at centers used to dealing with life-threatening side effects.
“I don’t know if CAR T-cell therapy will ever become a firstline option because there are many patients who go into remission with standard chemotherapy,” Dr. Goff said, “but I think, in a world where transplant is a feasible option, CAR T-cell therapy is no more difficult.”
CAR T cells might not yet be poised to overtake chemotherapy as the standard of care, but they are looking promising as treatment for certain patients with no other feasible options.
“The success seen in lymphoma and leukemia is not necessarily going to translate to more common cancers, even though we are still actively investigating its use in those settings,” Dr. Goff said. “The durability of the responses we’ve seen thus far is very good, so we now have something that is very effective for a population of patients in search of salvage therapy.” —By Debra L. Beck
- Maude SL, Teachey DT, Porter DL, et al.. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125:4017-23.
- Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8:355ra116.
- Maus MV, Levine BL. Chimeric antigen receptor T-cell therapy for the community oncologist. Oncologist. 2016;21:608-17.
- Kochenderfer J, Somerville R, Lu T, et al. Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma. Abstract #LBA3010. Presented at the 2016 ASCO Annual Meeting, June 7, 2016; Chicago, Illinois.
- Neelapu SS, Locke FL, Bartlett N, et al. Kte-C19 (anti-CD19 CAR T cells) induces complete remissions in patients with refractory diffuse large B-cell lymphoma (DLBCL): results from the pivotal phase 2 ZUMA-1. Abstract #LBA-6. Presented at the 2016 ASH Annual Meeting, December 6, 2016; San Diego, California.
- Grupp SA, Maude SL, Shaw PA, et al. Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Abstract #681. Presented at the 2015 ASH Annual Meeting, December7, 2015; Orlando, Florida.
- Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33:540-9.
- Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664-79.
- Children’s Hospital of Philadelphia. Relapsed leukemia: Emily’s story. Accessed December 4, 2016 from http://www.chop.edu/stories/relapsed-leukemia-emilys-story.
- Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509-18.
|TABLE. CD19-Directed CAR T-Cell Therapies in Advanced Development for B-Cell Malignancies|
|CAR T-Cell Product||Gene Transfer Method||Academic Partner||Commercial Partner|
|JCAR015, JCAR014, JCAR017||Gamma-retrovirus, Lentivirus, Lentivirus||MSKCC, Fred Hutchinson, Seattle Children’s Hospital||Juno Therapeutics|
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 FDA-approval 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.
- 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.
Expanding CAR T-Cell Therapy to Myeloma
At the 2016 ASH Annual Meeting, Adam D. Cohen, MD, from the University of Pennsylvania in Philadelphia, and colleagues presented preliminary safety and efficacy results from an ongoing, phase I study of CAR T cells engineered to target B-cell maturation antigen (a protein expressed on myeloma cells) in nine patients with relapsed/refractory myeloma.
“These patients had few other options – having received a median of nine prior lines of therapy for their myeloma,” Dr. Cohen told ASH Clinical News.
The complete remission rate was 44 percent, including one patient who has been in stringent complete remission for 12 months. “This patient was heavily pretreated, having received 11 prior lines of treatment,” Dr. Cohen noted.
Eight of nine patients developed cytokine release syndrome (CRS), which is a well-known toxicity of CAR T-cell therapies. Though most cases were mild (grade 1 or grade 2), three patients developed severe CRS. However, CRS in these patients was successfully managed with the IL-6 receptor tocilizumab, the authors wrote.
Two patients experienced neurotoxicity, which also has been described in other studies of CAR T-cell therapy. “One of the patients developed severe encephalopathy with edema of the brain,” Dr. Cohen explained. “Fortunately, this patient recovered after treatment with steroids and cyclophosphamide. Still, this is a significant toxicity, and we need a better understanding of how it develops and how to prevent it.”
“Accrual for the first cohort is complete, and we are now enrolling patients in the next cohorts, in which patients will undergo lymphodepletion with cyclophosphamide before being given the CAR T-cell infusion,” Dr. Cohen said. “We are hoping this will enhance the expansion and persistence of these cells and improve the overall response rate.”
To watch the full interview with Dr. Cohen, visit ashclinicalnews.org/multimedia.
Read more coverage of the 2016 ASH Annual Meeting.