Zeroing In on CAR T-Cell Therapy

Publication
Article
CUREHematology Special Issue (March)
Volume 1
Issue 1

CAR T-cell therapy is drastically changing the landscape of cancer treatment.

By January 2016, Jami Cameron of Fort Myers, Florida, had really been through the wringer: Beginning in 1994, she’d had lymphoma in her breast and in one eye, breast cancer, a mastectomy, multiple lashings of chemotherapy and radiation, a third recurrence of lymphoma and a bone marrow transplant. Now her lymphoma was back for the fourth time, chemo-resistant and so big she could see the tumor in her pelvis as it pushed on her nerves and caused excruciating pain. Her medical team gave her just months to live.

“There was no treatment,” says Cameron, now 53. “I didn’t qualify for anymore chemo or radiation. My bone marrow was so depressed from the previous treatments that I couldn’t tolerate a chemotherapy regimen.”

Then, a treatment counselor at the Leukemia and Lymphoma Society suggested a clinical trial of chimeric antigen receptor T-cell (CAR T) therapy, a new technique in which doctors extract some of a patient’s immune cells, alter them, and then re-infuse them into the bloodstream to jump-start the patient’s own immune system to fight their cancer. Cameron, a retired nurse practitioner, emailed the researchers immediately. Within a week, she was in Boston at Massachusetts General, signing consent forms for the study Three days after receiving her CAR-T infusion, Cameron could no longer see the tumor that had been bulging out of her pelvis. She left the hospital six weeks later, and remains in remission today.

“I thought I would not be able to see my daughter’s wedding,” Cameron says. “Now, I will be able to see it. I’m well. I’m not just existing, I’m really living.”

THE ‘FIFTH PILLAR’

For decades, the pillars of cancer treatment have been surgery, chemotherapy and radiation.

Then, beginning in the 1980s, monoclonal antibodies have been able to target specific molecular changes or markers in cancer cells. Now, despite a few false starts over the last 20 years, the oncology community is beginning to get excited about immunotherapy, training patients’ immune systems to fight their own cancer. Some are even saying this could be the “fifth pillar” of cancer treatment.

Research teams are going at immunotherapy from many different directions, but some of the best early results have been with CARs in which certain immune cells, called T cells, are genetically engineered to zero in on particular markers found on the surface of cancer cells. In small, early studies, as many as 80 to 100 percent of patients responded to CAR-T treatment, prompting the U.S. Food and Drug Administration (FDA) to award breakthrough status to CAR-T treatments for B-cell malignancies such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), as well as in B-cell lymphoma and non-Hodgkin lymphoma. Beginning in 2013 and continuing today, these early results have led to a flurry of academic-business partnerships and hundreds of new research studies seeking to refine the treatment, and to see if it might be useful in more common blood cancers and solid malignancies.

“We are at a watershed moment,” explains Renier Brentjens, M.D., of Memorial Sloan Kettering Cancer Center, the institution that published the first CAR-T study. “There is massive enthusiasm for CAR T, but also massive expectation. I think we can get there, but there are still many obstacles to overcome.”

Brentjens was part of a team that nearly 20 years ago showed that T cells with an added receptor for an antigen called CD19 could kill cancer cells in a Petri dish. That was followed by studies in mice showing that the CAR-T cells could stamp out cancer 50 to 100 percent of the time. But in the early 2000s, the researchers ran into challenges. It was difficult to find a “vector” that could insert the edited DNA into the T cell. It turned out that tumor cells could evade and suppress the edited T cells, and that it couldn’t be taken for granted that the changed T cells would multiply and thus persist in the patient’s bloodstream.

Today — thanks to advances in “gene editing” technology, as well as better understanding of the biology of both the T cells and the cancer — CAR T has begun to overcome these hurdles and show dramatic results in some blood cancers. In some leukemia patients who have relapsed, the still experimental treatment has helped 80 percent achieve complete response, whereas only 10 percent might respond using more traditional treatments.

In the studies done to date, CAR T primarily has been used in patients who have not responded to several lines of treatment. Many are just months, even weeks, from death. “How is CAR T better?” That’s an easy one,” says Ira Braunschweig, M.D., clinical program director, Hematologic Malignancies at the Montefiore Einstein Center for Cancer Care in the Bronx. “In patients with relapsed, refractory leukemia — both sexes, adults and children — who went into complete remission with CAR-T cells, there’s no other therapy that can offer that [kind of prognosis] to that kind of patient.”

Researchers often call CAR T “a living therapy.” That’s because the technique uses a patient’s own T cells, a type of white blood cell. These lymphocytes recognize and remember invading bacteria and viruses by analyzing various markers on the surface of infectious or malignant cells.

First, the doctors take a sample of the patient’s blood and isolate the T cell. In the lab, they insert a new gene that makes the patient’s T cells very sensitive to CD19, a particular marker on the surface of B cells, also expressed malignant B cells. Then, they enlist the help of a disabled version of the virus that causes HIV, which is efficient at getting the modified gene back into the T cells.

Meanwhile, the patient usually goes through some chemo to make room for the new cells. Then, the edited T cells are dripped back into the patient’s circulatory system. If all goes well, then these chimeric T cells multiply into an advancing army that takes out all the cancerous B cells by bursting their cell membranes, putting the patient into remission.

THE GOOD, THE BAD AND THE UGLY

In a sense, CAR-T therapy is cell therapy, gene therapy and immunotherapy all rolled into one. Experts say it represents a radical departure from all medicines to date.

“A cell, as a drug, is a whole lot more complicated than an antibody or a vaccine,” explains Bruce Levine, Ph.D., who directs the lab for the University of Pennsylvania CAR-T team. “It’s all very labor intensive.”

Taking place in the context of academic studies, this complex process has proved quite expensive. The procedure may be similar in cost to a stem cell transplant. Estimates for CAR-T therapy vary, but could run anywhere from $300,000 to $750,000. Experts say that as the process becomes more efficient, and available to more patients, those costs will come down. But because all of these techniques are waiting for FDA approval, the costs haven’t dropped as of yet.

Not only this, but severe side effects from CAR-T therapy can emerge suddenly, requiring teams of specialists to keep patients alive while their immune system ratchets up to fight their cancer. Adding juiced up T cells to the immune system can make things go haywire.

Douglas Olson, 70, a retired biochemist in Pipersville, Pennsylvania, was the third patient to receive CAR-T therapy at the University of Pennsylvania. His CLL had gone into remission twice, but then the cancer mutated, making it more difficult to treat. About two weeks after his CAR-T infusion in 2010, Olson began to feel very sick.

“I got all excited that I felt terrible, I felt that it had to be working,” Olson says. “I was in the hospital for three days. Then a week after that, my doctor told me they couldn’t find a cancer cell anywhere.”

Olson experienced one of the dangerous side effects of CAR-T treatment, tumor lysis syndrome, in which the T cells destroy so many cancer cells that the massive release of all those cell fragments into the bloodstream causes a variety of metabolic problems, straining the kidneys, causing heart rhythm problems and seizures.

In various studies, patients receiving CAR-T treatment have developed neurotoxicities that caused problems speaking, delirium and hallucinations.

CAR-T patients may also suffer a “cytokine storm,” when the immune system ramps up so much, that it releases too many cytokines, such as interleukin (IL), the proteins that signal the immune system to react.

This can result in labored breathing, rapid pulse, high fevers and decreased blood flow to internal organs. It can be treated with supportive care like hydration and respiratory support, as well as specialized medical therapies such as corticosteroids or through targeting IL-6, a cytokine that drives some of the major toxicities, by using the IL-6 receptor antagonist Actemra (tocilizumab).

Just after she became the first pediatric patient to receive CAR-T therapy, Emily Whitehead, now 11, had a cytokine storm so severe that her medical team put her into an induced coma for 14 days.

“When Emily got her treatment, things went out of control,” says Tom Whitehead, Emily’s father.

“One night, the head of the ICU said, ‘She’s not going to be here tomorrow.’ I said, ‘She will.’” She’ll be five years’ cancer-free in May 2017.

“Now parents call us from all over the world. We tell them, ‘We can’t tell you that it will definitely work, but when it does, it’s amazing.’”

WHAT LIES AHEAD

It may still be a year or two before any of these treatments becomes widely available. At the front of the race is Kite Pharma, which has already submitted the agent KTE-C19 to the FDA. In an interim analysis of the ZUMA-1 trial, KTE-C19 demonstrated positive results for patients with chemorefractory aggressive non-Hodgkin lymphoma. In December, the Swiss pharma company Novartis reported that 82 percent of the patients in its worldwide, phase 2 CTL019 study (41 of 50) achieved remission, and said that based on those results it would apply for FDA approval in early 2017.

Hundreds of CAR-T clinical trials are ongoing, or recruiting patients. Large pharma companies are partnering with academic teams or startups: Novartis with University of Pennsylvania, Celgene with Baylor College of Medicine, Amgen with Kite Pharma, Intrexon with MD Anderson. They are trying to make the process of culturing CARs more efficient, to manage side effects, and make the treatment applicable to more kinds of cancer. They are also looking for new antigen targets, particularly ones that occur only on tumor cells, not on healthy ones.

All CARs include a piece that recognizes the tumor marker and a piece that signals the immune system to act. Juno Therapeutics and others are working on a second generation of so-called armored CARs that incorporate an additional signaling protein that puts out an even stronger all-points bulletin for T cells to activate and recruit each other. Others are trying to optimize accuracy by incorporating genes that urge the cell to look for two targets on the surface of malignant cells, not just one. Or the CARs may require the presence of both an antigen target and a drug in order to activate the immune response. The hope is that one or more of these strategies will make CARs more accurate: targeting only cancer cells and not healthy ones.

A third generation of CARs may include three immune-stimulating factors. Meanwhile, Bellicum Pharmaceuticals in Houston, Texas, is splitting the antigen-recognition piece from the stimulating piece, creating a molecular suicide switch that can modulate T-cell activity, in case of bad side effects. Ziopharm Oncology, a Boston startup, is exploring ways to mute the T cells without killing them.

Other researchers are exploring using non-viral methods of getting the edited DNA into the T cells in the first place. And some teams are trying CAR T-cell therapy with other immunotherapies such as checkpoint inhibitors that could act as “on-off” switches for T-cells.

At least one company is exploring if they can develop off-the-shelf CARs, agents that would not have to be isolated from a patient’s cells, but could be a ready-made template that could be altered to order, even if a patient doesn’t have enough healthy B cells to culture.

“In our early studies, we find that these off-the-shelf CARs are very potent,” says André Choulika, Ph.D., chairman and CEO of Cellectis, the company exploring this approach. “We think that may be because we start with healthy cells, not ones battered by chemo.”

Many experts hope that the CAR approach may someday be used against new targets in solid cancers, such as EGFR in glioblastoma or CMET in other solid tumors. Various current studies are exploring CARs to fight sarcoma, a cancer of soft tissue, advanced prostate cancers, multiple myeloma, tumors of the chest cavity, mesothelioma, lung, breast and ovarian cancer. In a December 2016 case study, a report of just one patient, a patient close to death because of glioblastoma, a brain cancer, had CARs transfused into both his tumor cavity and his cerebrospinal fluid. The patient, a urologist with a busy practice, made such a full recovery that he was able to return to work.

“Really applying CARs in solid tumors is our next frontier, our next challenge,” says Christine Brown, Ph.D., associate director of the T Cell Therapeutics Research Laboratory at City of Hope, in Los Angeles, and the scientist who oversaw the glioblastoma case. "Our goal is to show that this therapy can have promise against many other tumors not just those that have the CD19 antigen.”

The application to solid tumors remains challenging, experts say. Blood cancers are essentially the excessive multiplication of single cancerous cells. That’s a more straightforward target than a solid tumor, which is a bit like an organ gone rogue, with its own microenvironment and vascular system. Solid tumors also create various cell messengers that can dampen the immune response. And then there’s the question of delivery: tumors may occur deep within healthy tissues. “We have really opened the door to use the human immune system to cure cancer in the last two or three years,” says Andrew Pecora, M.D., vice president of Cancer Services at John Theurer Cancer Center in New Jersey. “We’re in the first room of this house, so to speak. It’s so exciting and profound. There are lots of reasons to be hopeful. That’s not hype. That’s real.”

Related Videos
Dr. Lauren Pinter-Brown