Bringing CARs to Market: Novel T-Cell Therapies Make Rapid Progress Despite Challenges

OncologyLive, November 2014, Volume 15, Issue 11

When Marcela V. Maus, MD, PhD, thinks of the challenge of bringing chimeric antigen receptor (CAR) therapies to market in the battle against cancer, she is reminded of the auto industry's first days.

Marcela V. Maus, MD, PhD

When Marcela V. Maus, MD, PhD, thinks of the challenge of bringing chimeric antigen receptor (CAR) therapies to market in the battle against cancer, she is reminded of the auto industry’s first days.

American industrialists managed to streamline the process of making autos from one at a time to several rolling off the assembly line every minute, and the same kind of revolution could make CARs available on a broad scale, said Maus.

“Right now we’re at the very beginning, and I think this has tremendous potential to become something that can be manufactured by different groups in different plants all over the world,” Maus, director of Translational Medicine and Early Clinical Development at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia (UPenn), said in an interview.

The CAR technologies currently in development for hematologic cancers are a form of adoptive cell therapy in which the patient’s T cells are cultured and then primed to specifically recognize CD19, a protein expressed on normal and malignant cells of B-cell lineage. Thus, CD19 presents a suitable tumor-associated antigen against which to target anticancer agents (Figure).

The experimental technology has been successfully used to combat acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma, bringing many patients who participated in clinical trials into complete remission (Table). The success of these therapies has caused much excitement, and hopes are high that the CAR approach could one day become a frontline treatment for many types of cancer, including solid tumors such as breast, ovarian, and prostate cancers.

Getting CAR therapies to market will involve the crossing of many hurdles, according to researchers, pharmaceutical executives, and industry observers, particularly in light of the manufacturing complexity and safety concerns involved. The drug industry, however, is more than willing to tackle the task of translating CAR therapies to clinical practice.

Figure. Chimeric antigen receptor (CAR) technology

Illustration courtesy of Novartis Pharmaceuticals

“It’s not without challenges,” said Usman Azam, MD, global head of the Cell and Gene Therapies Unit at Novartis Pharmaceuticals, which is working with UPenn to bring the CAR therapy CTL019 through clinical trials. “This is new for the agencies, it’s new for the hospital systems, it’s new for Novartis, but I think we have the building blocks in place. We have incredibly compelling data, and we’re going to be sharing some insights and a lot more at the upcoming ASH [American Society of Hematology] meeting. The data are showing great outcomes out to three years in the ALL population.”

Azam said his company is “doubling down” on immunotherapy, including CTL019, for which the FDA has granted breakthrough therapy status, allowing Novartis steady guidance throughout the clinical trials process to aid in bringing what could be a critical new agent to market as rapidly as possible.

Novartis Buys Former Provenge Plant

Trials of CAR therapies by different industry/ academic partnerships have been conducted among pediatric and adult patients with relapsed or refractory leukemia, often resulting in complete remission lasting upward of a year or longer. The success for patients whose cancers were resistant to multiple other treatments has spurred huge investment to bring this technology out of the laboratory and into commercialization, and to explore the breadth of ways in which this form of immunotherapy could be employed.Hoping to be the first to bring CAR therapy to market, Novartis in 2012 purchased the 173,100-sq-ft Morris Plains, New Jersey, plant that Dendreon had hoped would help make a financial success of sipuleucel-T (Provenge). The prostate cancer vaccine is similar to Novartis’ CTL019 in that both involve the removal of a patient’s T cells for modification at a manufacturing facility. In the $43 million acquisition, Novartis retained about 100 former Dendreon employees.

“That’s given us a very strong footing, both in terms of not just the facility but the talent and capability of those individuals,” said Azam. “That’s the unique edge that Novartis has. We’ve doubled down in this space by going big and bold. This is where our competitors are going to be struggling—actually getting the manufacturing knowhow. I do think we have the capabilities to get a leap start in front of the others.” But the race to market is not over yet, said Renier J. Brentjens, MD, PhD, a medical oncologist specializing in acute and chronic leukemias at Memorial Sloan Kettering Cancer Center in New York and a founding member of Juno Therapeutics, which over the past year has raised more than $300 million in startup capital to develop immunotherapies including T cells programmed to go after the CD19 antigen.

“Our early work in CD19 technology was instrumental in translating this medicine to the clinic and as such we were the first to publish significant clinical responses in relapsed B-cell ALL using these CAR T cells,” said Brentjens.

His group has been conducting research into CARs for more than a decade and reported on the first patients with ALL or CLL treated with the 19- 28z CAR therapy in 2011.

Brentjens and Azam anticipate that CAR therapy will be commercialized very soon. “I wouldn’t be surprised if by 2016 these CAR T cells are on the market,” Brentjens said. “There are now several companies that are developing this technology.”

MSK and Juno are working in conjunction with the Fred Hutchinson Cancer Research Center and the Seattle Children’s Research Institute, an example of the diversity of collaboration that has arisen.

Separately, Celgene and bluebird bio are working their own partnership on CAR therapy with Baylor College of Medicine, The National Cancer Institute is working with Kite Pharma, and MD Anderson Cancer Center is working with Johnson & Johnson. The biopharmaceutical company Cellectis has partnered with Pfizer and the French company Servier.

Fitting CARs Into Treatment Paradigms

One key issue for investment partners and others endeavoring to bring this technology out of the laboratory is where in the spectrum of cancer-fighting agents CAR therapy will fit.

Some say the jury is still out on whether modified T cells will remain a treatment of last resort, owing to safety concerns and the availability of effective chemotherapy drugs that cost less. Cytokine release syndrome (CRS), the immune system’s feverish response to retargeted T cells, is interpreted by oncologists as a sign that CAR therapy is working, but it can also greatly sicken patients and even be fatal.

Daniel W. Lee, MD, of the Pediatric Oncology Branch of the National Cancer Institute, has been working with other oncologists to understand CRS better so that it can be managed successfully with the least amount of discomfort or danger to the patient. He believes that the problems with CRS can be overcome.

“We laid out a new proposed grading system for CRS because the old system just didn’t apply. And we also used that grading system to develop a treatment algorithm for when you should intervene in CRS to prevent grade 4 (life-threatening) toxicity,” Lee said. The system defines levels of toxicity and explains how to manage CRS.

“But the bigger issue is, can you even prevent it in the first place?” Lee asked. “To some degree you can. In our clinical trial, the patients with lower disease burdens have significantly lower risk of severe side effects. This gives us a clue as how to best incorporate this therapy in newly diagnosed patients.”

With a lower risk of exacerbating a patient’s condition, CAR therapy could prove very useful as frontline medicine, Lee said.

“If you can generate CAR T cells and reinfuse them in patients with newly diagnosed ALL at a time of minimal residual disease, they might have a low grade fever for a day or two, and that’s it. And that’s exceedingly nontoxic and may be the role for CAR T cells in the future,” said Lee.

Table. Key Findings in Recent CAR Research Reports


Patient Population





30 children and adults with ALL

  • 90% CR in 27 patients
  • 67% achieved 6-month event-free survival
  • 78% overall survival rate
  • Durable remissions up to 24 months observed

University of Pennsylvania/ Novartis

Maude SL et al. N Engl J Med. 2014;371(16):1507-1517.


15 patients with indolent B-cell malignancies and DLBCLs

  • 92% objective response rate in 13 evaluable patients, including 8 CRs, 4 PRs, 1 SD
  • 4 of 7 evaluable patients with chemotherapyrefractory DLBCL achieved CR
  • 1 patient died

NCI/ Kite Pharma Inc

Kochenderfer JN et al. J Clin Oncol. Published online August 25, 2014. doi:10.1200/JCO.2014.56.2025.


21 pediatric and young adult patients with relapsed/ refractory B-ALL or NHL

  • 70% CR rate among 20 patients with B-ALL
  • 60% of patients with B-ALL achieved MRD Neg status
  • 10 patients with MRD Neg status subsequently underwent HSCT; all 10 disease free after 10 months’ median follow-up

NCI/ Kite Pharma Inc

Lee DW et al. Lancet. Published online October 13, 2014. doi:10.1016/S0140- 6736(14)61403-3

19-28z CAR

16 adults with relapsed/ refractory B-cell ALL

  • 88% overall CR rate
  • 75% MRD Neg CR
  • 7 patients successfully underwent allogenic HSCT after CAR therapy
  • Defines diagnostic criteria for severe CSR
  • Identifies serum C-reactive protein as indicator for CRS severity

MSK/Juno Therapeutics

Davila ML et al. Sci Transl Med. 2014;6(224):224ra25.

ALL indicates acute lymphoblastic leukemia; B-ALL, B-precursor acute lymphoblastic leukemia; CR, complete remission; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; HSCT, hematopoietic stem-cell transplantation; MRD Neg, no minimal residual disease; NHL, non-Hodgkin lymphoma; SD, stable disease.

Pricing Considerations Discussed

Lee and his colleagues have been testing CAR therapy on relapsed and refractory ALL pediatric patients, with positive results. “Our feasibility rate is 90%, and that’s from all comers,” he said, noting that patients were not prescreened to determine whether their T cells would multiply successfully once modified with the CD19 receptor, as was done by other groups.Risks aside, there is also the issue of paying for the medicine, which could turn out to be prohibitively expensive, said Joseph Hedden, PhD, a pharma industry analyst with Datamonitor Healthcare, a market analysis and business information company. “At the moment, I personally find it hard to see CTL019 at the front line of ALL therapy because that’s a disease where a significant portion of patients can be cured with traditional chemotherapy despite nasty side effects,” said Hedden. “CTL019 is likely going to be prohibitively expensive to be used somewhere like that, and then along with that drug there are the safety elements. Specifically for CTL019, even though they can get around these things, it is going to push it further to the back of the treatment algorithm, where patients have exhausted other options.”

That said, if oncologists could manage CRS better and improve patients’ response to CAR-adjusted cells, the treatment could be among the tools doctors turn to first when dealing with leukemia, Hedden said.

Hedden gives a rough estimate of $100,000 to $350,000 for a complete CAR treatment, based on industry discussion and using as a baseline the $93,000 cost in 2010 for a full treatment of Provenge. If the price of CAR treatment soars too high, manufacturers could be hard pressed to recoup their investment, he said.

“Could it push out first-line drugs? I don’t think so. I don’t think insurers are going to want to pay when other treatment options are available,” said Hedden.

At the same time, he said that success with CAR strategies against solid tumors could open up vastly lucrative markets.

Azam declined to put a figure on the cost of CAR treatment for ALL. “I think it’s premature to give a price on what this would cost.” He said the value of the medicine as a potential cure for ALL merits his company’s very bullish stance on development. “You’re looking at other options for patients, which are very scant.”

Oncologists interviewed for this story agreed that chemotherapy could be cheaper in a simple comparison, but they said there are also hidden costs to be weighed. Among them are complications of chemotherapy such as blood transfusions or serious infections, lifelong follow-up care and medication often required as a result of chemotherapy, and bone marrow transplant (BMT) for patients with relapsed disease.

They said insurers could decide that a pound of cure in the form of CAR therapy could be far more cost effective. If a CAR therapy administered early can prevent those patients who would otherwise need a BMT from getting the procedure or perhaps reducing the total amount of chemotherapy needed, the cost savings over the patient’s lifetime could be significant.

“Currently, if your child is diagnosed with ALL, she’d need two years of chemotherapy if you’re a girl and three years if you’re a boy, and at the end of the day have an 85% chance of being cured. But what people don’t understand is that these kids pay a significant price for that,” said Lee.

“Upwards of 30% of childhood ALL survivors have a significant comorbidity that limits their functioning as an adult, and that’s a huge number. So any new therapy that comes along that can potentially reduce the exposure of cytotoxic agents for these kids would be a huge windfall,” said Lee. That’s a financial argument that insurance companies would likely accept, agreed Brentjens of MSK, but he said that before paying for the procedure, they would need to know that CAR therapy is an effective modality.

Manufacturing Expertise Needed

“They’re going to pay for it only if it has a truly significant antitumor benefit,” said Brentjens. “And so, if you have a drug that actually works, then the onetime cost of producing these T cells will be far, far less than the cost of taking a patient from first-line ineffective to second-line ineffective, to third-line ineffective, chemotherapies.”The manufacturing process is also an important hurdle for manufacturers to address. Brentjens said the lab work alone for the process of leukapheresis and generation of CAR T-cells currently costs around $40,000.

That process is slow and has to be done correctly, said Maus. “Our approach right now is the autologous. The patients’ own immune cells will be modified and injected back into the patient. The main issue with the autologous is that it takes time. Blood has to be sent somewhere, modified, and sent back. It’s not something like a Tylenol that can be picked up at any drugstore,” she said. The T cells have to be grown and cultured in a lab, few places are equipped to do it, and the whole process can take up to 10 days, Maus said.

Doctors would like to speed that up and have more places certified to do the work, but it’s a delicate process and rapid expansion could easily introduce variables and upset the balance that makes CAR therapy as effective as it is now, said Maus.

Azam, who said Novartis is on a timetable for FDA approval by 2016 and aims to get CAR therapy into the marketplace shortly afterward, seconded Maus’ concerns about too rapid expansion, saying the difficulty of manufacturing on a broad scale is probably the biggest challenge ahead.

“Where the bigger challenges are going to be, and not to belittle the risk on the efficacy and safety side, is actually the manufacturing process, so this is a very complex situation,” said Azam.

Similarly, the skill levels of people involved in administering the treatments will have to be high, and whether the process would be deployed in the average hospital or clinical setting has yet to be determined.

“I think it would be a very smart move to go very deliberately and slowly to ensure that any service model that we establish works,” said Azam. “We have agreements with UPenn and plans with other sites as part of multicenter studies. For us it would be a good idea to start with a very targeted approach, but clearly we are in the business of optimizing that and getting exposure to as many patients as possible.” “Eventually we would like to see this broader- based in terms of accessibility. Not just in the US but also Europe and Japan, where there is demand but also an appreciation of what a therapy like CTL019 can offer and how it complements the existing healthcare systems,” said Azam.

A Note of Caution

Asked to estimate the size of the market, Azam described it on a sliding scale based on CTL019’s movement through clinical trials. “We’re going to be doing hundreds of patients in confirmatory studies to demonstrate to regulators that we’ve got a benefit-to-risk ratio that’s very supportive of these therapies. And then you’re probably looking at thousands of patients with ALL worldwide who could really benefit from this. And then you’re probably looking at tens of thousands worldwide when you start to look at diffuse B-cell lymphoma and chronic lymphocytic lymphoma,” said Azam.Despite the enthusiasm for CAR therapies, Brentjens cautions that far more published data are needed to optimize this modality.

“The number of patients who have been treated with CAR T cells that you can read about in the literature is still only a handful,” said Brentjens. “Centers like ours and others need to share our CAR T-cell experiences so the learning curve can be steeper—as fast as possible—so that we know how best to dose the cells, how best to deal with the side effects of the cells, and how best to utilize this technology to get the best outcomes.”

Tony Hagen is a freelance biopharmaceutical writer based in New Jersey.