For a field that not too long ago was considered science fiction, CAR-T cell therapy has transitioned from the clinic to the market in remarkable speed. This year's annual meeting of the American Society of Hematology (ASH), set to kick off Saturday, will highlight that emerging clinical and commercial promise in several blood cancers.

Juno Therapeutics Inc., a Seattle-based biotech, will be among the companies unveiling new research. Once at the forefront of the field, Juno has spent the past year recovering from a clinical tragedy that led to the shuttering of a study called ROCKET and the discontinuation of the company's then-lead CAR-T candidate.

Yet Juno will enter ASH with renewed momentum, having pivoted to an experimental successor therapy known as JCAR017. Early clinical data released in November showed potentially competitive efficacy and safety in a type of non-Hodgkin lymphoma.

That Juno is even back in discussion as a potential rival to Novartis AG and Gilead Sciences Inc., which own the only two CAR-T approvals to date, speaks to the rapidly evolving science.

Perhaps out of necessity, Juno's CEO Hans Bishop believes JCAR017 could be best-in-class, suggesting the company could even leapfrog Gilead and Novartis in the market, given time.

"The history of medicine shows that what is most important is not your time to market per se, but it is your degree of differentiation," Bishop said in an interview. "Thinking about this question of time to market in a static sense is, I think, misunderstanding how much these therapies are going to continue to get better."

But Novartis' Kymriah (tisagenlecleucel) and Gilead's Yescarta (axicabtagene ciloleucel) have set the bar. This year's ASH will therefore be a good gauge of whether Juno can make up the ground it lost last year.

Room for multiple companies

In some respects, CAR-T's rapid emergence over the past several years masks the still-early nature of the field. Recent events, though, have spurred optimism in cell therapy’s potential as a treatment for cancer even higher.

Over the course of a little more than six weeks from late August to mid-October, the CAR-T field was catalyzed by three successive dominoes: Gilead's acquisition of CAR-T developer Kite Pharma for $11.9 billion; the landmark U.S. approval of Novartis' Kymriah in adult lymphoblastic leukemia (ALL); and a second regulatory OK for Kite's Yescarta in a type of non-Hodgkin lymphoma (NHL) called diffuse large B-cell.

Industry watchers were rightfully enthused by the developments. Yet, even with those successes, key questions still remain around CAR-T's safety and manufacturing feasibility in a commercial setting. Treatment cost — $475,000 for Kymriah and $373,000 for Yescarta — could pose another hurdle for patient access.

All of that is to say, the CAR-T market is far from set. That strengthens Juno's belief that, if it can advance JCAR017 to market with a superior efficacy and safety profile, it can still carve out a space for itself.

"Patients with NHL that fail R-CHOP [a standard treatment regimen] only have a 10% chance of getting into a durable remission with subsequent approved therapies. Helping that group of patients is clearly going to require multiple companies," explained Bishop. "I think that is particularly true with cell therapy, which is still in its first phases of commercialization."

That said, Juno remains a year or more behind Gilead and Novartis in NHL. Yescarta is already approved in NHL and an OK for Kymriah in the same indication looks likely for early next year. If JCAR017 is to compete in the future, Juno needs to meet or exceed the standard set by these two therapies.

Competitive profile?

Juno's position was strengthened in November by updated data it released from a study of JCAR017 called TRANSCEND of patients with relapsed/refractory DLBCL — a patient population that has largely run out of other options.

In the trial, which seeks to find an appropriate dose for a pivotal study, treatment with the CAR-T led to initial responses in 51 of the 68 patients (75%) evaluable for efficacy by a July 7 data cut-off. At six months, the response rate dropped to 40% (14/35). Importantly, all but one of those 14 patients were in a complete response.

Such findings remain early, but they hint at competitive efficacy when compared to the results which supported approval of Gilead's Yescarta. This spring, then-unacquired Kite Pharma disclosed results showing a 41% response rate and 36% complete response rate at six months.

Comparing trials can be tricky, particularly due to differences in patient characteristics between Juno's study and Kite's. That won't stop investors, however, from doing so in an effort to gauge where the competitive balance lies. Juno will present updated data from TRANSCEND on Monday morning at the annual meeting of the American Society of Hematology.

Perhaps more important for Juno, however, is JCAR017's emerging safety profile.

While CAR-T has so far delivered remarkable responses in some patients, the therapy can pose serious risks. Neurotoxicity and a severe immune response known as cytokine release syndrome (CRS) are commonly seen in patients treated with cell therapy.

In TRANSCEND, two-thirds (29/44) of patients in the core analysis group did not experience any CRS or neurotoxicity. Among all patients evaluable for safety at time of data cut-off before ASH, only one had a Grade 3 or 4 case of CRS. Rates of neurotoxicity also looked lower at this early check-in than in studies of other CAR-Ts.

Moving CAR-T earlier

Currently, CAR-T studies have focused on heavily pretreated patients who have few other remaining options. As CAR-T develops further, the focus will increasingly shift to cell therapy’s potential in earlier lines of treatment.

Doing so, however, will pose new challenges. Currently, for patients turning to CAR-T as a last resort, the technology's dangers may be an acceptable risk.

But as companies look toward the second-line setting — where bone marrow transplant is commonly used — the balance between risk and benefit changes. Any new treatment will have to have an improved safety profile to readily replace standard of care.

Sattva Neelapu, an oncologist at The University of Texas MD Anderson Cancer Center in Houston, says increasing knowledge of how to manage CRS has lowered some of the initial concern over that particular side effect, although he acknowledges that less is known of about how neurotoxicity occurs.

Juno, for its part, thinks it might already have an answer in JCAR017, however. "I think that if the safety profile that we have shown with JCAR017 today continues to hold as we treat bigger groups of patients, we believe that will be very supportive of use in earlier lines of therapy," Bishop said.

Lessons learned

Juno attributes the safety profile of JCAR017 to improvements in the design of the CAR-T itself.

Those lessons were learned, in part, through the tragic setback in Juno's study of its previous lead candidate JCAR015, which the company eventually shut down after five patients died from severe brain swelling.

"Clearly, the JCAR015 experience was very painful for everyone concerned," Bishop said.

Aimed at ALL rather than DLBCL, JCAR015 utilized a variable composition of modified T-cells for each completed therapy. Juno now thinks that such differences in product can lead to more severe reactions when the cells multiply too quickly once infused back into the body.

A post-hoc analysis of the JCAR015 study, presented in November, suggested that slower expansion of T-cells could improve safety.

See Also: Juno analysis of shuttered study offers clues for CAR-T»

"One of the conclusions that we came to in the study is the way CAR-T cells are conventionally made leads to products that are quite variable in terms of their cell composition," explained Bishop. "That can impact their potency."

JCAR017, on the other hand, uses a fixed ratio of CD4 and CD8 T cells that the biotech claims helps temper expansion of the modified T cells in the body and allows for more precise dosing.

"I think Juno has learned very quickly and tried to optimize not just the construct of the therapy, but also the manufacturing of it as well," said Aiman Shalabi, chief medical officer at the Cancer Research Institute. "I have to give them credit."

These product improvements have become a key feature of Juno's push to catch Gilead and Novartis, which use other constructs for their approved CAR-Ts. Not only would a safer product appeal to physicians and patients, it could also give Juno more flexibility in how it offers treatment with CAR-T.

Currently, patients receiving CAR-T therapy are treated in a hospital under close management. Juno proposes that JCAR017 could possibly be administered in an outpatient setting. That could be a competitive edge, allowing more flexible and convenient treatment, if it ever comes to fruition.

CRI's Shalabi calls JCAR017 Juno's "Seabiscuit" horse, referring to the possibility for Juno to upend the early CAR-T standings with a differentiated safety profile. But Novartis and Gilead won't be standing still, either. Both are advancing studies designed to broaden the current approvals for their two drugs, as well as prove the efficacy and safety of new CAR-Ts.