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The Medicine, Miracles & Masterminds Behind CAR T-Cell Therapy

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000546319.94665.c3
1250: News

The emergence of chimeric antigen receptor (CAR) T-cell therapy is like the explosive landing of an ocean wave upon the blistering beach of hematologic cancer. Could it turn the tide? At the very least, it is beginning to wash over diseases that have entangled patients in a riptide of despair for too long. Of course, it has not all been so poetic. CAR T-cell therapy has been built on decades of hypotheses, imaginative research, down-and-dirty hard work, hopes dashed/hopes realized. There have been losses (deaths), near misses (recurrent disease), and victories (complete remissions). It is the opinion of some experts that CAR T-cell therapy has limits to its utility. Yet, in the purview of blood cancers, it seems the medical science powering CARs is merging with the strength of human resilience, and every day another wave of progress takes aim at the shores of hope.

In the most simplified terms, CAR T-cell therapy involves extracting a patient's own T cells, genetically reengineering them in a lab into emboldened, Superman-like CAR T-cells which, after being reintroduced into the patient's body, are capable of seeking out and obliterating tumors and cancer cells.

In August 2017, the FDA approved tisagenlecleucel, a CAR T-cell therapy developed in collaboration with Carl June, MD, and fellow researchers Bruce Levine, PhD, Stephan Grupp, MD, PhD, and David Porter, MD, at the University of Pennsylvania, for use in pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It was a seminal event in cancer therapy. Heralded as a “new era in treatment” (JAMA 2017;318(19):1861–1862), tisagenlecleucel became the first CAR T-cell immunotherapy and first gene therapy approved by the FDA. The FDA described it online: “Tisagenlecleucel consists of autologous T cells collected in a leukapheresis procedure that are genetically modified with a new gene containing a CAR protein allowing the T cells to identify and eliminate CD19-expressing normal and malignant cells.”

In October 2017, axicabtagene ciloleucel, developed with the NIH, received FDA approval, making it the first approved CAR T-cell therapy for adult patients with certain types of large B-cell lymphoma who have not responded to or have relapsed after at least two other kinds of treatment. Thus, it became the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma.

The rising tide of progress continued in May 2018 when tisagenlecleucel was FDA-approved for a second indication: treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. This approval, which includes the treatment of diffuse large B-cell lymphoma (DLBCL) as well as high-grade B-cell lymphoma, continued the expansion of a therapy so personalized that it was once thought to be fiscally untenable. Stephen Schuster, MD, Director of the Lymphoma Program at Penn's Abramson Cancer Center, called it “a massive step forward” reflective of a heretofore immense unmet need in hematologic oncology.

“DLBCL is the single most common hematologic malignancy of all, and I am talking about everything—ALL, chronic lymphocytic leukemia (CLL), all of the myeloma variants, follicular lymphomas, etc.,” Schuster told HemOnc Times. “There are 28,000 to 30,000 cases annually in the U.S. alone. And sadly, a third of those will relapse after primary therapy. Potentially there is a large number of patients who could benefit from this therapy.”

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At the Beginning

So how did we arrive at these tsunamic events of therapeutic progress? It happened at the hands of medical Neptunes driving waves of translational research. Steven A. Rosenberg, MD, PhD, Chief, Surgery Branch, NCI, has spent most of his 78 years on Earth chasing down the potential of immunology and cell therapy. The evolution of cell therapy can be discovered through bits, pieces, and instructive chunks of his own experience.

Flashback to 1968; Rosenberg had already earned his PhD in biophysics, had graduated from medical school, and was doing an internship at Harvard. There he observed the unimaginable.

“I saw a patient who, in the absence of treatment, had a spontaneous regression of cancer—one of the rarest events in all of medicine,” he recalled. “There was no good explanation for it. It seemed to be something within the body's protective mechanism that was able to accomplish that, and it made me think about use of the immune system. It sparked my interest.”

Most of his contemporaries at the time “...thought it made no sense whatsoever. I remember there was an editorial in Cancer Research that said something to the effect that it would be as difficult to reject the right ear and leave the left ear intact as it would be to cause the rejection of a human cancer,” said Rosenberg. “Funding was difficult. Not a lot of people had much confidence in this idea. But when doing research, you develop intuitions about how biology works. I became convinced in my own mind that the immune system had led to that spontaneous rejection. And I began working on it.”

Rosenberg and colleagues doggedly pursued ways to stimulate the immune systems of patients—66 of them to be precise. But it was not until 1984 when “Patient 67,” a young woman with widespread melanoma, was treated that the promise of immunology became apparent. “We treated her with interleukin-2 (IL-2), a hormone with no impact on cancer cells at all; it only impacts the immune system. When we gave her this immune stimulant, all of her cancer disappeared,” he remarked, glancing at her photo on his wall. “She has remained completely disease free ever since. She was the one who taught us that remission—even cure—following immune therapy is possible.” This event was duly reported in literature (N Engl J Med 1985;313:1485–1492, J Am Med Assoc 1986;256:3117–3124, N Engl J Med 1987;316:889–897) and IL-2 became the first immunotherapy ever approved by the FDA in 1992.

“T lymphocytes are the warriors of the immune system. When this T-cell stimulator caused a complete regression of cancer, it became clear there must be T cells in that patient that caused the regression,” explained Rosenberg. “We published a series of studies showing that if you isolate lymphocytes from inside a tumor—and what better place to look for cells doing battle with a cancer than within the cancer itself—and grow them to large amounts and deliver them back to the patient, you can mediate tumor regression in a metastatic cancer. That was the start of cell therapy” (N Engl J Med 1988;319:1676–1680, J Natl Cancer Inst 1994;86:1159–1166).

Rosenberg and his team continued to take tumor-infiltrating lymphocytes from patients (with melanoma), grow them under appropriate conditions, make sure they had anti-tumor activity, give them back, and observe good cancer regressions.

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Emergence of CAR T-Cell Therapies

T cells have unique receptors that recognize invading bacterium or viruses by their protein fragments. But because cancer is a mutation that springs up from a patient's own body, it may be very weakly recognized by T cells as an outside invader. Thus, researchers began genetically modifying peripheral blood lymphocytes to make them capable of locating a cancer cell and attacking it. These emboldened warrior cells would eventually become CAR T-cells.

“The very idea of doing such a thing as genetic manipulation caused a furor,” said Rosenberg. “Biotechnology activists argued that we shouldn't tamper with the human genome. There were lawsuits filed and the program at NIH was cancelled for 9 months. But later it was reinstituted and we finally got permission to use genetically modified lymphocytes to target where they went.” Rosenberg reported on the first-ever insertion of foreign genes into humans in 1990 (N Engl J Med 1990;323:570–578).

“We were putting bacterial genes into lymphocytes so we could track where they went. Then, after a fair amount of work, in 2006 we demonstrated for the first time that normal circulating lymphocytes with no reactivity could be genetically engineered by inserting a gene that could recognize molecules on a cancer (Science 2006;314:126–129, Blood 2009;114:535–546). We showed that genetically engineered lymphocytes could cause regression of melanoma in humans,” said Rosenberg of a truly momentous assertion.

CAR T cells are indeed very different than conventional T cells, which naturally have their own receptors that can recognize molecules. “CAR T cells are laboratory creations in which the combining site of an antibody is attached to intracellular signaling chains. The ability of the T cell to recognize what it normally would recognize, based on its receptor, is changed to recognize whatever is recognized by the CAR,” noted Rosenberg.

He explained that the discovery by others of the CD19 molecule in hematologic cancers led to “an obvious application” of emerging CAR T-cell therapy. “We knew that cell transfer could work. And it became clear that the CD19 molecule appeared on almost all lymphomas and many leukemias, yet it was not present on any other cell in the body—it was an ideal target. When you do treatments with CAR T cells, you are also eliminating the normal B cells in the body.” When a massive number of CAR T cells are introduced to a human body, they enter an environment which has been prepared and proactively stripped of normal T-cell activity. For about a week, the CAR T cells do battle in the absence of the natural T cells. Shortly thereafter, the normal T cells revive. “Yet the CAR T cells remain. They are there to stay; they are part of the patient. This is a living therapy,” Rosenberg stressed.

The first-ever use of CAR T cells in a cancer patient occurred under Rosenberg's watch in 2009. “The patient had pounds of tumor—a chest-full, a belly-full—and had been through multiple chemotherapies; he was just months from dying,” he recounted. “We treated him with his own CAR T cells that could recognize the CD19 molecule and all of the cancer disappeared.”

Though the patient relapsed once and required retreatment to re-induce remission, “he is cancer free today, 9 years later,” said Rosenberg. “We combined what we had done before in cell transfer and genetic engineering to treat that first patient. And he had a stunning response. Almost a year later Carl June reported a similar success, and the field took right off.”

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A Confluence of Minds & Efforts

Indeed, other great minds were at work on parallel tracks through the years. Zelig Eshhar, an Israeli scientist, developed one of the earliest, albeit crude, CARs in 1989. Michel Sadelain, MD, PhD, now Director of the Center for Cell Engineering, Memorial Sloan Kettering, New York, N.Y., demonstrated by 1992 that he could genetically engineer mouse CAR T cells. By 2003, he and his colleagues showed that these genetically engineered CAR T cells could cause regression of certain cancers in mice. Stanley Riddell, MD, and colleagues at Seattle's Fred Hutchinson Cancer Research Center were laser focused on CAR T-cell usage as well.

And at the Naval Medical Research Institute, in Bethesda, Md., June and colleague Levine, now both at the University of Pennsylvania, were also investigating T cells and developing methods for multiplying them outside of the human body, from 1986 to 1999. During that time, June began genetically modifying T cells with hopes of finding a means to kill HIV. His interest in immunotherapy took hold when he spent 2.5 years at the Fred Hutchinson Cancer Research Center at the behest of the U.S. Navy, which was interested in starting a bone marrow program. “It was there that I saw firsthand what the immune system could do,” recalled June. “I observed the active immune system of a donor's bone marrow attack the recipient's cells [graft-versus-host disease]. It was an amazing, powerful thing to see. I started to study the immune system from that point.”

June had an obligation to the Navy which had paid for his college and medical school training, so he persisted in working on HIV for 15 years. “I was an indentured servant. Even though I was a board-certified oncologist with a specialty in leukemia, I worked on HIV and malaria. The first patients treated with CAR T cells in 1997 had HIV,” said June, who noted the CAR T cells in those patients persisted for a very long time, with a half life of more than 17 years.

Upon leaving the Naval Institute, June went to the University of Pennsylvania in 1999. It was a time of immense transition, some borne of personal tragedy. “I had published several hundred papers by then, mostly on basic science things that I had done in my lab. But things changed in a huge way when my wife was diagnosed with ovarian cancer in 1996,” June revealed. “Treating patients with CAR T cells had been a back-burner effort. But when she got sick it moved to the front burner; I started in earnest. I tried to make a CAR T cell for ovarian cancer and I made cancer vaccines for her. In the process, what I learned was how hard it is to accomplish the translational part of medicine.”

The frustration for June was intense. The window of time for his wife was ticking away all too quickly. “No one believed in immunotherapy then. People laughed at us. I went to some of the biggest pharmaceutical companies because I had seen things that were really promising and there was already supporting data that checkpoint therapy could work synergistically with the cancer vaccine I was developing for my wife. But I couldn't get one pharmaceutical company to give me the antibody.” June's wife died in 2001.

A lesser man might have walked away from the research. But June took the lessons he'd learned about the power of CAR T cells, translational work, and trial initiation, and added his own persistence and belief in the power of immunology.

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A Trial Interrupted

Working together, June and Porter opened a trial in 2009 for 14 CLL patients. They were treated by Porter with CAR T cells made by June and his team, all at Penn. It would become a watershed moment in medical history. Of the first three patients with advanced disease, two survived. Now, speaking through the fullness of time, June said it appears they are “cured.”

“When they came to Penn they expected to die; they were in end-stage leukemia,” June retold. “Patient number one was Bill Ludwig, a corrections officer and a retired Marine. When we treated him, we didn't even know what cytokine release syndrome was, so he suffered through 3 weeks of it in the ICU. He had fever, organ failure, and was literally at the point where they were going to give him his last rites.”

June stammered a bit at the memory, his voice halting, and choking up. It took him a few moments before continuing: “Then on day 28 after treatment he woke up. He had survived the cytokine storm. It just burned out. It was like a forest fire; when there are no more trees it just goes out. He was examined at that point and we realized that pounds of tumor were simply gone.”

The second survivor of that trial was hematologist Douglas Olsen, PhD. He too battled through a cytokine storm, and his tumor disappeared as well. “These were truly Lazarus moments—men rising from the dead,” recalled June with emotions similarly rising again in his throat. “When Bill Ludwig found out he was in remission, he and his wife went and bought an RV. You wouldn't believe the number of pictures he has of them driving around the country visiting children and grandkids. And when Doug Olsen found out the good news, he and his wife immediately went to Annapolis, Md., and bought a boat. They didn't waste any time.” Both patients continue to be well, enjoy life, and live free of cancer.

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Oh, the Irony

Despite what had been nothing short of a miracle wrapped in science, the trial was cut short. It ran out of funding. “It was all happening just following the Wall Street collapse of 2009. We had been dependent on philanthropic funding, but donations to those groups went way down when the economy tanked. We ran out of money and couldn't even pay salaries of some of our team and had to let them go,” he recalled.

Though the trial was written for 14 patients, June and Porter decided there was nothing they could do but publish results from the first three patients.

“That report came out Aug. 11, 2011, and a firestorm happened,” said June (Sci Transl Med 2011;3(95):95ra73, N Engl J Med 2011; 365:725–733). “It was the most unbelievable tipping point. We got thousands of inquiries from patients who wanted to be treated. The phones were ringing off the hook with calls from people who wanted to give us money. For example, a $1 million dollar check just showed up one day. Even the NCI, who hadn't been willing to fund our trials, called us the day after the results were published and said, ‘We would like to fund your work.’ Then we had a bunch of pharma and biotech companies—who previously had paid no attention to immunotherapy—saying they wanted in.”

So head-turning was June's report, that Swiss pharmaceutical company Novartis licensed the rights to therapies created at the University of Pennsylvania under June's direction. Clearly the funding drought was over. It started to rain money for others, too. Other companies formed alliances—Kite Pharma with the NCI, Juno Therapeutics teamed with several institutions, and many more have since joined the effort.

The next year, 2012, 6-year-old Emily Whitehead became the first relapsed ALL pediatric patient to be treated with CAR T-cell therapy, under the direction of doctors at Penn and Children's Hospital of Philadelphia (CHOP). After receiving her CAR T cells, Emily battled through a severe cytokine release syndrome response, and nearly died. Scrambling to save their young patient, the medical team noted a striking abnormality in her interleukin-6 (IL-6) count which was 1000-fold above normal. Because IL-6 is not normally made by CAR T cells in large amounts, the doctors reasoned that CAR T cells could be the cause of Emily's life-threatening reaction.

It was by some miraculous coincidence that June's daughter, having had juvenile arthritis, had been given an arthritis drug known to target Il-6. So in a last-ditch “hail Mary” effort to save Emily's life, they administered tocilizumab, an IL6R antagonist. It worked miraculously well. Emily survived, and thrived. And researchers learned that cytokine release syndrome could be successfully handled. “It is now FDA-approved for this use as a comedication for CAR T-cell therapy,” said June. Penn doctors have said that had Emily succumbed, it likely would have spelled an end to their CAR T-cell research program for pediatric patients.

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Back to Where We Started

We began this discussion with mention of the first landmark FDA approval of tisagenlecleucel, then axicabtagene ciloleucel, and finally a second approval for tisagenlecleucel for different indications. The last of that triad can largely be traced to the efforts of Schuster, one of June's colleagues between 1999 and 2001 when they both worked on multiplying T cells.

“When Carl came here to Penn, I was an instant CAR T-cell convert,” said Schuster, who fully embraced the belief that the immune system holds within it clones capable of eradicating malignant cells. “It was all a bit controversial then,” he admitted, “But checkpoint inhibitors demonstrated that tumors cause immune suppression and blocking that suppression can lead to remission. Now we've gone a step further by reengineering T cells so they are more targeted, more efficient. The chimeric antigen receptors result in a much higher morbidity to the tumor target than the endogenous T-cell therapy receptors in human reactive T-cell clones. We have proven that cellular immunotherapy, using both checkpoint inhibitors and CAR T cells, can eradicate malignancy. No one can argue with that anymore.”

Schuster led two studies examining CAR T-cell therapy in DLBCL that were, in great part, responsible for the latest approval. He launched his own single center trial (UPCC13413) at Penn in 2013. T cells modified with tisagenlecleucel resulted in CAR T cells that were infused into patients with the hope that the engineered cells would identify and kill cancerous B cells and help patients build an effective immune response to kill cancer cells.

As reported in the New England Journal of Medicine (2017;377:2545–2554), 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response. Complete remission occurred in six of 14 patients with DLBCL (43%) and 10 of 14 patients with follicular lymphoma (71%). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients.... Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86 percent of patients with DLBCL who had a response and 89 percent of patients with follicular lymphoma who had a response had maintained the response.... All patients in complete remission by 6 months remained in remission at 7.7–37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in eight of 16 patients and with improvement in levels of IgG in four of 10 patients and of IgM in six of 10 patients at 6 months or later and in levels of IgA in three of 10 patients at 18 months or later.

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CAR T Road Show

Once Shuster observed such high rates of durable remission, with recovery of B cells and immunoglobulins in some of the patients, he realized it was time to take his trial on the road to test his findings on a world stage. Enter the 2016 JULIET Trial, a large multi-center trial funded by Novartis. “It had to be done. I wanted to prove that this wasn't just ‘the Steve Schuster show at Penn.’ We wanted to prove that anybody, in any country around the world, could do this and do it safely, and get the same results. There could be no selection bias here,” said Schuster of the transition to a global study. “But, oh my God, what a learning curve. The logistical challenges were indescribable.”

JULIET, essentially a regulatory submission of his Penn protocol modified to meet the satisfaction of the FDA, stretched her arms of discovery around the world. “I'm talking about 27 centers—none of which were even doing CAR T-cell work at the time—in 10 countries on four continents. We had to work with multiple regulatory agencies; we had to make everyone happy,” said Schuster.

From as near as Canada to as far as Japan and Australia, with a good sprinkling of centers throughout Germany, France, The Netherlands, Italy, Norway, and more, CAR T-cell use took a giant geographical step, at the hands of Schuster and Novartis.

Schuster packed his bags and travelled around the world to teach the various centers about CAR T-cell therapy, and his work in particular. “None of the lymphoma centers were doing anything like this,” he reprised, noting that he and a team from Novartis “...educated them. We taught them how I had managed my patients in my Penn trial. We taught them about the cytokine release syndrome and how to manage it, and about associated neurotoxicities and how to manage them. We created treatment algorithms to build into our protocol and made sure that all of the centers were observing the protocols.” In the process, Schuster got to brush up on his foreign language skills. “My German is pretty good now; I can get around,” he joked.

The entire process was refined to the point that it could be safely exported. “We were fortunate that our standard operating procedures included cryopreservation,” said Schuster. “So, we received frozen cells collected locally all over the world. They were then reengineered into CAR T cells, frozen, and shipped back to the various sites so the investigators could treat their patients.”

Data from the JULIET trial, presented at the American Society of Hematology Annual Meeting in 2017, revealed an overall response rate of 53 percent, with 40 percent achieving a complete response among 81 infused patients with 3 or more months of follow-up. At 6-months analysis, the median duration of response was not reached.

The FDA moved quickly; the second approval for tisagenlecleucel was granted in May. A month later, Novartis released 14-month results from the pivotal clinical trial showing “... ongoing durable responses are achievable. The relapse-free probability at 12 months after a patient's first response was 65 percent. The overall response rate was 52 percent and median duration of response was not reached at a median follow-up of 14 months, signifying responses were durable.”

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Proof Is in the Numbers

Schuster is still working hard to refine these advances in DLBCL. “In my own work, I saw 43 percent with long-term remissions. I began to analyze why almost 60 percent of patients were non-responsive,” he revealed. “I have samples of blood and T-cell production from those of patients. I now believe their lack of response may be due to antigen loss. I believe these patients have tumors capable of paralyzing the immune system to the point of checkpoint inhibition.”

Looking forward, Schuster believes that CAR T-cell therapy can be improved by moving it to second-line therapy, in relapsed patients. His words are bold: “I am a bone marrow physician and I tell patients this is less toxic than autologous transplant, has a higher success rate and a longer durable remission. I have no doubt that when patients are less sick and have healthier T cells to collect due to fewer prior therapies we will see higher response rates and longer durations.”

Asked who, among a patient pool, is most likely to benefit from CAR T-cell therapy, Schuster minced no words. “Anyone who is not cured. Anyone who does not respond to primary therapy or has relapsed is potentially able to receive CAR T-cell therapy,” he stated. “I have treated patients as old as 79 years. This is a lot less toxic than the things we have done to patients in the past.”

Schuster, who presented information about the potential case for CAR T cells at Duke University and Memorial Sloan Kettering, said, “I did the math. And it is impressive.”

He detailed: “If you have 100 patients who either fail to respond or relapse after current standard therapies for DLBCL, only half of them will be eligible for transplant anyway. Fifty will not be eligible for transplant because they are too old, or have impaired function, or other medical co-morbidities, or they won't have the proper insurance, etc. But they could potentially get CAR T-cell therapy.

“So we start with 100 relapsed or refractory patients, 50 percent eligible for transplant. But half of those patients will respond to our second line so-called ‘salvage’ chemotherapy regimens. And only responding patients should go to transplant. So now 25 of the 50 eligible transplant patients can be added to the 50 transplant ineligible patients. Now we are up to 75 of 100 patients who are potentially CAR T-cell patients. And of the 25 patients who actually go to transplant, only about 10 percent are cured; 15 percent will relapse and then be CAR T-eligible. We are talking, without exaggeration, about potentially 90 percent of patients being eligible for CAR T-cell therapy in the relapsed refractory DLBCL setting of a theoretical 100 patients. The numbers don't lie. Clearly we should move this to second-line treatment.”

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What's Next?

Stephen J. Forman, MD, is the Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation and leader of Hematologic Malignancies and Stem Cell Transplantation Institute at City of Hope, Duarte, Calif. He proudly noted that City of Hope “... was one of the original institutions that had hopes for what this therapy could become, and now our dreams are being realized.” Appropriately, City of Hope became one of the only institutions in the U.S. to offer both FDA-approved commercial products, axicabtagene ciloleucel and tisagenlecleucel.

“We are hungry to extend this therapy to other situations besides the ones that have been so successful so far,” commented Forman, “and are committed to improving the overall results. While the target (CD19) in both lymphomas and ALL is the same, the results are not as dramatic in lymphoma as they are in ALL. The work we've seen in ALL has set a high bar of optimism that we'd like to see in all these uses.”

Forman believes it is because lymphoma has characteristics of both liquid and solid tumors that there is some response, as well as some limitations to how effective those CAR T cells can be in that setting.

“The cancers of solid tumors, once they establish themselves in a person's body, begin to elaborate an immune oppressive environment in which to live,” he explained. “So while they are thriving they are also putting up roadblocks, barriers, and walls against the natural immune system and even the CAR T cells from getting there and doing their work. As dramatic as CAR T-cell therapy has been, it is breathtaking to realize that some cancers can figure out ways around it or adapt themselves from being subjected to a natural immune response or one that we create in the laboratory and put back in the body. A lot of our work is to be tougher than the tumor is.”

And yet it is exactly the challenge presented by lymphoma's solid-tumor characteristics that makes Schuster believe that solid tumors will be the next frontier of CAR T-cell therapy. “Absolutely, absolutely,” he assured. “The mechanisms of resistance for the 60 percent of large cell lymphoma patients in whom it doesn't work are most often the same mechanisms that solid tumors use to resist this form of therapy. The things we are working on in those resistant lymphoma patients are going to become the keys to what eventually will be used in solid tumor patients.”

Forman agreed that solid tumors may eventually fall prey to CAR T cells, and certainly to some form of immunocellular therapy. “People always talked about there being three ways to treat cancer: surgery, radiation, and chemotherapy. But now we've seen that there is a fourth arm—immune therapy. I hope that in 10 years there will be immune therapies for all the cancers that afflict humans and that they are efficacious in putting them into remission. That is my hope, and based on what we've seen so far, with hard work and research and trials, we will figure that out. In the meantime, I challenge the medical community to ask, ‘Do we need to wait until someone is so desperately ill and until we've exhausted all other options to use the emerging therapies we have? Or should we be thinking about moving these therapies up to the first line?”

So much shared determination and vision is lending optimism to a field still in its infancy of recognition and development. It is also attracting funding to an area once bereft of research dollars. Kite Pharma was just a start-up company in 2012 when it entered into a cooperative research agreement with NCI to develop immunocellular therapies. “Since the approval of [axicabtagene ciloleucel] for multiple indications, Kite has soared. It was sold to Gilead Sciences in October 2017 for $11.9 billion—yes, that is with a ‘b’—billions,” said Rosenberg almost incredulously. “There is no looking back now. The field is exploding.”

While Rosenberg thinks there will be inroads that point to cures for solid tumors, he does not necessarily think they will be forged through CAR T cells. He believes it will be more of a back-to-the-future situation, via a new understanding of the potential of natural T cells. (Some of Rosenberg's insights on exciting developments in T-cell therapy will be featured in an upcoming issue of Oncology Times.) In the meantime, he expects CAR T-cell therapy will continue to thrive in the hematologic oncology space. And while it may be a costly therapy (in the realm of $275,000 per treatment), Rosenberg added that because it is a single-dose, once-and-done curative approach, it may actually be cost-effective for patients, insurers, and the entire health care system in the long run.

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Targeting Myeloma

June said there is cause for tremendous optimism, as another CAR T-cell therapy will be approved by the FDA next year, “without a doubt.” Three companies—Novartis, Celgene, and Johnson & Johnson—are actively developing CARs for use in multiple myeloma. “This is a huge thing,” he said excitedly. “CAR T-cell therapy is not just a ‘one-off’ thing with CD19, because we have a different target, BCMA, for myeloma. Our first patient in a myeloma trial at Penn was treated by Edward Stadtmauer, MD, Adam Cohen, MD, and Michael Milone, MD, PhD, about 3 years ago. He had had myeloma for 11 years; his spine had fractured and he had to wear a neck brace. He came to us literally at death's door. He had the same kind of response as Olsen and Ludwig. Now he is without myeloma. This treatment is equally life-changing.”

June added, “For so long, oncologists only got to see their patients die. At best, we could try to help patients control the disease. But now we actually get to think about cure. Cure is the goal. CAR T-cell therapy is having the same impact on the field as bone marrow transplants had in the 1980s. We live in an exciting time; we are revolutionizing hematology.”

There is an undeniable science-meets-art element running through this groundbreaking territory that is immunocellular therapy. “The science of it is equivalent to looking at a beautiful work of art,” said Shuster, reflectively. “When you see the pathways and mechanisms and then realize that you can translate them into clinical medicine, it is like looking at a masterpiece. You can't quite put your feelings into words, but there is a sense of awe, excitement, and fulfillment. And when you are the ‘artist’ involved in it, and know that you have helped create the masterpiece you are looking at, you get high on it.”

Valerie Newitt is a contributing writer.

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CAR T-Cell Studies to Watch

Phase IIa Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRz and 4-Signaling Domains in Patients With Chemotherapy Relapsed or Refractory CD19+ Lymphomas


Phase II

Status: Active, but not recruiting

Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET)


Phase II

Status: Active, but not recruiting

A Study Evaluating KTE-C19 in Adult Subjects With Relapsed/ Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL) (ZUMA-3)


Phase I/II

Status: Recruiting

Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma (KarMMa)


Phase II

Status: Recruiting

Multi-CAR T Cell Therapy for Acute Myeloid Leukemia


Phase I/II

Status: Recruiting

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CAR T-Cell Therapy: The New Frontier of Hope

Emily Whitehead became the first pediatric patient with refractory/relapsed acute lymphoblastic leukemia to be treated with her own re-engineered immune cells using CAR T-cell therapy. Her heroic fight against staggering odds, the insights and devotion of her parents, and the Herculean efforts of her medical team have resulted in many more years for Emily. Read her amazing story:

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