By Jamie Reno, Yahoo Finance Contributor

Sometimes, a cancer patient just knows when enough is enough. Robert Legaspi, 27, was diagnosed with acute lymphoblastic leukemia (ALL) when he was 9 years old. Since then, his cancer has recurred several times. The chemotherapy regimens have been long and brutal, and it’s taken two years each time for him to get back into remission.

When Legaspi’s cancer returned for the fourth time earlier this year, his oncologist, Dr. Ted Ball at Moores Cancer Center at UC San Diego Health, asked him if he’d be interested in trying an experimental new treatment that would harness his own cells to fight the cancer.

Ball expressed to Legaspi that there were some potential serious side effects in this treatment including neurotoxicities.

Earlier this month, it was revealed that after a different trial from another company for the same kind of treatment, three patients died from cerebral edema (brain swelling), posing a potential roadblock to a very promising treatment.

But Legaspi was undaunted by the risks. He immediately enrolled as the first participant in the clinical trial at UCSD of an immunotherapy called CAR-T, which engineers the body’s T cells to recognize and kill cancer cells. The trial is sponsored by Kite Pharma (KITE), a biotechnology company in Santa Monica, Calif.

Today, Legaspi is in complete remission, just two months after taking part in the trial, which involved a very short regimen of pre-conditioning drugs followed by a one-time infusion of the CAR-T cells. While doctors don’t know just how long Legaspi will remain cancer-free, the data so far is showing durable remissions in most patients.

“I’m a homebody who likes video games, but now I’m riding my bike, taking long hikes, kayaking, and doing things I never had the energy to do,” said Legaspi in an interview with Yahoo Finance.

He had some complications from the treatment, including high fevers, some confusion and even blackouts. But that lasted only a week or so. “It wasn’t nearly as hard as my chemotherapy treatments I’ve had in the past, or as long,” he said. “I encourage others to do CAR-T. It’s the greatest thing you can do for yourself.”

Immunotherapy is the new rock star in the cancer pharmacology world. One of the fastest-growing areas of oncology research, it’s garnered lots of media attention this year, from Time to The New York Times.

While multiple immunotherapy technologies are being studied, among the most promising is chimeric antigen receptor T-cell therapy, or CAR-T, whose human clinical trial data shows a remarkably high percentage of total remissions. In these trials, Legaspi’s response is the norm, not the exception: CAR-T trials often see a 70% to 80% complete response rate — and these are in cancer patients who are gravely ill and have failed other treatments.

Dr. Januario Castro, the principal investigator of the CAR-T studies at UCSD, said Legaspi is not only leukemia-free now but “could be potentially be cured from this deadly medical condition.”

Two American biotech companies — Kite (KITE), and Juno Therapeutics (JUNO) from Seattle — along with Swiss pharmaceutical giant Novartis (NVS), are competing to reach the clinic first with their respective CAR-T cell treatments for various leukemias and lymphomas.

Despite sunny results in CAR-T trials from each of these companies, a few clouds have appeared on the horizon.

Earlier this month, after Legaspie’s trial concluded, Juno announced that three patients in its CAR-T trial for ALL died from cerebral edema (brain swelling) following the trial. That trial included a pre-conditioning regimen employing familiar chemotherapy agents fludarabine and cyclophosphamide to suppress the immune system before infusing the engineered T cells. The company later revealed that a fourth patient had died from the same cause in a separate CAR-T trial.

While Juno’s policy is not to discuss open trial numbers except at medical conferences when it releases all the data, a spokesperson for Juno, Christopher Williams, said the CAR-T trial for ALL in which three patients died had “more than 20” participants.

Juno had reported all four patient deaths properly to the Food and Drug Administration, but after notifying the FDA of the two most recent fatalities, the agency placed a clinical hold on the trial.

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News of the neurotoxicity issues with CAR-T cast a pall over the national cancer community, which has excitedly monitored the progress of CAR-T as it quickly makes its way to FDA approval.

Juno’s stock dropped more than 30% from $40 on Thursday, July 8, the day after the FDA placed the hold on the trial. The stock value at Kite — which uses the same two chemotherapy drugs as pre-conditioning agents but at a substantially lower dose — also took a hit.

Following a brief hold, the FDA allowed Juno to resume its trial after the company recommended that fludarabine be removed from the trial regimen but that cyclophosphamide remain.

The FDA would not comment to Yahoo Finance specifically on why it resumed the trial, but industry analysts say the federal agency was satisfied with Juno’s assertion that the trials are safer now that fludarabine has been removed.

After the trial resumed, Juno’s stock shot back up and has been hovering around $30, not quite at the level it was before the FDA announcement. Kite’s stock has also rebounded. Wall Street seems mollified, for now. But the publicity surrounding the trial deaths and FDA hold has brought new scrutiny to CAR-T and the potential toxicities of this vaunted new cancer treatment.

How does CAR-T work?

View photos An image of lab technicians provided by Juno Therapeutics. More

According to the National Cancer Institute, CAR-T trials for both adults and children with leukemia and lymphoma use a patient’s own T cells, which play a large role in a person’s immune response. Those cells are engineered to target the CD19 antigen — which can be found on most normal and cancerous B cells (a kind of white blood cell).

The process involves collecting white blood cells from the patient’s own blood and genetically engineering the cells to boost their potency and recognize cancer cells.

Through CAR-T therapy, receptors known as chimeric antigen receptors (CARs) are produced on the surface of a patient’s T cells. In turn, these CARS allow the T cells to identify a specific antigen located on cancer cells. The so-called CAR-T cells are then grown in the lab until there are billions of them and ultimately they are returned to the patient’s body.

At that point, the CAR-T cells ideally multiply even more and end up knocking out cancer cells that have the antigen on them, according to the National Cancer Institute’s description of the process. The T cells bind only to the cancer cells that express target proteins, such as CD19, a molecule found on cancerous B cells involved in most lymphomas and leukemias.

Like with any experimental cancer treatment, CAR-T is still being perfected. And toxicity is a concern — both from the older chemo drugs used to pre-condition the body for optimal immune suppression and from the CAR-T cells themselves.

In 2014, Juno’s CAR-T clinical trials were stopped temporarily at Memorial Sloan Kettering Cancer Center in New York due to several patient deaths as a result of cytokine-release syndrome (CRS), a potentially deadly toxicity associated with increased levels of cytokines in the body including interleukin (IL)-6 and interferon γ.

Cytokines, which according to the National Cancer Institute are “chemical messengers that help the T cells carry out their duties,” are released by the infused T cells. Cytokine-release syndrome is a common problem in patients treated with CAR-T cells.

“With cytokine-release syndrome, there’s a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure,” the National Cancer Institute notes.

In the current trials, patients with the most extensive disease prior to receiving the CAR-T cells were more likely to experience severe cases of cytokine-release syndrome. But for most patients, the side effects can be managed with standard supportive therapies, including steroids.

In the Sloan Kettering trial, the dose of cells in patients with large tumor burdens was reduced, as the degree of tumor load appeared to correlate with the severity of CRS.

Juno responds to the controversy

In separate interviews, the CEOs at Juno and Kite and a spokesperson for Novartis each spoke about the CAR-T toxicity issues, how each company is working to address them, and what they see as the still-bright future of this therapy.

Hans Bishop, Juno’s CEO, said that safety and lessening the side effects in its CAR-T trials is a “top priority,” and noted that patients who are enrolling in these trials have failed other treatments and are very ill.

“Our goal now is to educate people and share our experience,” Bishop said, adding that the removal of fludarabine from the specific trial does not mean it is a bad drug. He said Juno will continue to use it in other CAR-T trials, as will Kite and Novartis.

Bishop, who previously was chief operating officer for Dendreon, another Seattle-based biotech company focused on immunotherapy, said Juno has “ongoing efforts” to better understand and mitigate neurotoxicity in CAR-T treatments.

“We have an internal team focused on this issue, including developing intervention strategies. We are also consulting with external scientific advisors in both academic and clinical settings,” he said. “We are being very careful and we will be updating our timeline in August. But the recent situation could move our expected time of FDA approval for this treatment from 2017 to 2018.”

At Kite it’s business as usual

The same week that Juno put out a press release announcing the trial deaths, Kite issued a press release announcing that it had reached full enrollment for its Zuma 1 CAR-T clinical trial for patients with diffuse large B cell lymphoma (DLCBL), the most common type of non-Hodgkin’s lymphoma. That’s just one of several CAR-T trials Kite is running for blood cancers.

Kite CEO Arie Belldegrun, who started with the National Cancer Institute and has been working in the immunotherapy field for 30 years, said that while safety is always a top priority for Kite, there have been no deaths in the company’s CAR-T trials and they’ve not seen any cerebral edema to this point.

“For us, there is no controversy. The path is clear,” said Belldegrun, a UCLA urology doctor and professor who noted that the Kite protocol uses the same two chemo drugs in the pre-conditioning phase of the regimen as Juno used, but often in significantly smaller doses.

“The field is currently talking about high-dose cyclophosphamide versus low dose,” Belldegrun said. “Five years ago, we chose to go with low-dose cyclophosphamide for pre-conditioning, together with fludarabine. Our best understanding from what I have seen in public statements is that Juno’s study that had safety issues with using the high dose. That fine point is being forgotten. The media is paying unnecessary attention to fludarabine. It’s not the regimen, it’s the dose that matters.”

Belldegrun said he and his team at Kite are so confident in this treatment that the company is already building the manufacturing facility so that, after the drug is approved in 2017, “We will be able to deliver it to patients almost immediately.”

Novartis says safety is a top priority

View photos Swiss drug giant Novartis More

None of the Novartis senior leadership was available to comment. But Eric Althoff, head of global media relations for Novartis, which is working closely with the University of Pennsylvania on CAR-T trials for patients enrolling with ALL and adult diffuse large B-cell lymphoma (DLBCL), said Novartis will continue using fludarabine as a pre-conditioning regimen in its studies.

“This is a clinical standard as a conditioning regimen,” he said. “Patient safety and well-being in these trials are of paramount importance to Novartis and the investigators with whom we work.”

Althoff said that without intervention, patients in these trials will eventually succumb to their disease.

“Although we have seen promising results in our clinical trials, serious adverse events and mortalities associated with disease, disease-related complications and treatment-related complications have occurred,” he said. “The majority of mortalities that have occurred in our clinical trials are due to underlying disease. There have only been a small number of deaths related to the treatment; most of these are associated with cytokine release syndrome (CRS).”

Althoff would not say how many patients have suffered treatment-related deaths, or why, if there have been deaths, the FDA has not scrutinized the company to the extent it has looked at Juno.

“At this time, we do not have any clear cases that are primarily due to neurotoxicity alone,” he said, “though some neurotoxicity symptoms have occurred in conjunction with underlying disease, cytokine release syndrome CRS or other confounding issues.”

FDA intervenes

Tara Goodin, a spokesperson for the FDA, would not say specifically why the agency decided to stop the Juno trial, or why it decided to resume its so quickly.

But she noted that cellular therapies, including CAR-T therapies, hold a lot of promise in the treatment of life-threatening diseases.

“We therefore do everything possible to assist sponsors in advancing clinical development programs in an effort to bring promising therapies to patients,” she said.

Goodin said the FDA recognizes that investigational products intended to treat serious diseases “also have the potential to pose risks to patients.”

To that end, Goodin said, “The FDA constantly looks at the risk-benefit profile of experimental therapies and when we have concerns about the risks, we may place the clinical trials on hold.”

CAR-T generating hope for patients

Dr. Ezra Cohen, an oncologist and head of the immunotherapy department at the UC San Diego Moores Cancer Center, said CAR-T therapies are generating “hope and excitement” among cancer patients.

“There is clear evidence that both adults and pediatric patients who are refractory to standard therapies, including chemotherapy and stem-cell transplants, can respond to CAR-T cells and then can go into remission for a substantial amount of time,” he said.

Cohen said that current CAR-T therapies are not meant as first-line therapy.

“The first option is still usually chemotherapies,” he said. “When those fail, these offer a very promising option. The alternative is the person is going to die.”

But one day, some scientists believe, immunotherapy could replace chemotherapy, and without the need for a pre-conditioning immunosuppressant.

Juno’s Bishop said his research team, led by Dr. Hy Levitsky, is investing significantly in research that “we believe may one day allow us to safely and effectively administer CAR-T therapy without any pre-conditioning chemotherapy.”

Despite setbacks, an industry analyst is still bullish

Biren Amin, managing director and senior biotechnology analyst at Jefferies, a global securities and investment banking firm, said that while the pre-conditioning in CAR-T treatment is inherently risky, it is controllable by selecting the right dose.

He said that despite the recent tragic deaths in the clinical trials, safety and toxicity issues with CAR-T are nothing that should surprise or shake the market.

“When you look at CAR-T and compare it to BLINCYTO, a CD19 antibody for leukemia from Amgen that is FDA approved, the approved drug had more adverse events in clinical trials and also caused more fatalities,” Amin said. “One patient who was 5 years old died from cytokine release syndrome. There is precedent that FDA will look at risk/benefit profile of this drug.”

Amin said the difference between getting chemotherapy and using a chemo drug as a pre-conditioning agent is significant. “Patients take them for three days,” he said, “it’s not like chemotherapy with its multiple cycles.”

Amin added that one advantage Kite may have in this space is that its VP for research & development and chief medical officer, David Chang, came from Amgen (AMGN), which has another antibody drug targeting the CD19 like CAR-T.

“David Chang knows the CD19 target,” Amin said. “Granted, that program was acquired from another company, but he is aware of the data set, he has a certain knowledge that Juno didn’t have.”

Legaspi is getting on with his life

Robert Legaspie Credit: Erik Jepsen/UC San Diego More

Meanwhile, Robert Legaspi, who’s been fighting leukemia seemingly his entire life, is moving forward and enjoying his health and spending quality time with his wife, whom he married shortly before his recurrence earlier this year. He recently enrolled at Southwestern College near San Diego and hopes to become an oncology nurse.

“I know all the hospital departments,” he said. “I know pretty much what you need to know to be a good nurse.”

And Legaspi’s team of doctors could not be more pleased with how he is doing.

“We’re so happy to see Robert respond this quickly and positively to the CAR T-cell therapy. This was a first for us in San Diego and it was exciting to see it work,” said Legaspi’s oncologist, Ted Ball. “We are motivated to provide this therapy option to more patients, but we’re also cautious, as CAR T-cell therapies are still in early-phase clinical trials, and there have been serious side effects, though generally manageable, and we do not know the long-term effects of the treatment.”

Castro, principal investigator of all the studies using CAR-T cell technology at UCSD, said his team follows CAR-T patients closely.

He explained: “They need to stay hospitalized for a minimum of nine days after infusion of CAR-T cells and after discharge they need to be followed sometimes daily. Patient selection is critical. Early, published and unpublished data suggest that the amount of residual disease at the time of CAR-T cells infusion determine the degree of CRS.” Castro said the consent form for would-be CAR-T trial participants is comprehensive.

“Patients typically are well informed and ask those questions about side effects and what they read in the news,” he said. “However, the patients that are eligible for these trials usually do not have treatment alternatives, so any risk is minimized and justified by the serious and many times lethal outcome of their disease.”