CAR-T Cell Therapy Means A Lot More Than One Or Two New Drug Approvals

Includes: JUNO, KITE, NVS
by: Zach Hartman

Bioengineered T cells have an end in sight, with several techs being reviewed at the FDA.

Approval of just one of these methods has the promise to usher in a new era for immunotherapy.

It's time to get ready for a wild ride in biotech.

In the world of cancer medicine, immunotherapy has taken over with a vice-like grip, offering far-reaching potential for nearly every tumor type known to man. Most prominent in the marketplace have been the immune checkpoint inhibitors, with almost every one of the big five PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab) gaining some high-profile drug approval in the last 5 years, to say nothing of the landmark approval of Yervoy in 2011 to kick all of this fervor off.

But before immune checkpoint inhibitors were approved, we had cell-based immunotherapy, notably with the introduction (and subsequent challenges) of Provenge. Cell-based immunotherapy actually goes all the way back to the late 1800s, with bacterial infection being used as a vector to stimulate an immune response in cancer patients.

Now we've gotten more sophisticated. Three companies, Kite Pharma (NASDAQ:KITE), Juno Therapeutics (NASDAQ:JUNO), and Novartis (NYSE:NVS) have been frontrunners in the race to bring so-called CAR-T cell therapy to market for hematologic malignancies.

A primer

Source for image:

The intricate details of CAR-T cell manufacture are too complex to manage in a short publication like this one. But it can be simplified in broad terms down to a few steps:

  1. Leukapheresis - a process by which immune cells are separated from the patient's blood, and the remaining blood is returned to the patient.
  2. The leukapheresed sample is further purified to yield the white blood cells and remove residual red blood cells and monocytes.
  3. T cells are incubated with a virus that encodes the chimeric antigen receptor (CAR).
  4. T cells are reintroduced into the body, where they can grow and attack cells that express the target of the CAR.

Some of the more curious among us might be asking...why go to all this trouble? We can train the body's immune system to recognize specific targets. Heck, we've been doing it for decades now with Herceptin and Rituxan. What's wrong with the body's natural defense?

The answer is that CAR-T cells present a few extra advantages to ramp up the immune response: the CAR itself - The name of the technique gives this away. "Chimeric" isn't just a cool word (which it certainly is); it signifies that we've done something special to the receptor in question. In the current line of techniques, we've fused the antigen recognition portion of an antibody to the part of the T cell receptor that tells the cell to grow and divide.

This differs from the normal method the body has to detect a foreign antigen and develop T cells against it:

Source: Srivastava, et al.

You may not recognize the names of the molecules in this figure, but you should be able to see that on the left side, there is careful coordination of a large number of molecules that is required to activate a T cell.

CARs short circuit the whole process, allowing for direct activation of the T cells by tumor cells. This MHC-independent T cell activation is the linchpin of the whole process, bypassing a number of tumor cell defenses and allowing us to develop a special subset of T cells that specifically look for and eliminate any cells in the body that express the antigen we're looking for. In the current case, this is CD19, which is a marker of B cells, hence why all of these latest studies are looking at diseases like B-cell leukemia and diffuse large B-cell lymphoma.

Bioengineered T cells have an end in sight, with several techs being reviewed at the FDA

Since the seminal publication by Maude, et al in 2014 showing incredible response rates in a small cohort of children with relapsed/refractory acute lymphoblastic leukemia (ALL), the world has been watching and waiting for the emergence of CAR-T cell therapy and its revolutionary potential.

No rides are ever smooth in biotech, it seems. For a while, the three big players- KITE, JUNO, NVS- were chasing three different patient populations.

NVS had CTL019, which was being studied in pediatric patients with ALL.

JUNO had JCAR015 for adult patients with ALL.

KITE decided to chase a different beast first, focusing on patients with diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma.

In my mind, this presented three distinct patient classes that could allow all three technologies to be marketed simultaneously. In the United States, ALL in kids and adults is not generally managed by the same hematologists; pediatric doctors handle children, specifically.

Unfortunately, fate was not kind to JUNO, who had to suspend their ROCKET trial in adults due to life-threatening toxicity risk. I wrote about this episode last year, and even though the clinical hold was lifted, JUNO eventually terminated development of its JCAR015 platform in March 2017, choosing instead to focus on JCAR017 for DLBCL.

KITE and NVS, in contrast, have achieved significant progress in moving CAR-T cells to the clinic. Both axicabtagene ciloleucel and CTL019 are now being reviewed by federal regulators, and it is likely we'll see responses by the end of 2017.

Given results like those we've seen with the ZUMA and ELIANA (the former I covered in my digest series, 3 Things You Should Learn Today in Biotech), it seems like CAR-T cell therapy presents an enormously promising treatment strategy for these intractable B cell malignancies. Aside from the risk of cytokine storm (an active area of research), these CAR-T platforms are not associated with an outsized risk of severe toxicity, either. I am going to be very surprised if these two techs do not get the nod from the FDA.

Approval of just one of these methods has the promise to usher in a new era for immunotherapy

It is difficult to overstate how reticent the FDA can be to accept a new therapeutic strategy into the fold. They are definitely conservative, and I say this is a very GOOD thing. The history of cancer medicine is peppered with charlatans who have generated excitement and clamor for new, promising cancer therapies.

The FDA needs to be the voice of reason and consider everything, from manufacturing to efficacy to every bit of safety they can uncover. As such, many are frustrated with the speed at which they move.

But the data on CAR-T cells are too compelling to ignore. I think this is going to prompt the FDA to get more familiar with cell-based immunotherapy in general and develop a different tolerance for risk of these approaches.

This represents a major, major inroad for other forms of cell therapy, including JUNO's JCAR015 and the other KITE/NVS platforms for CAR-T cell therapy. We could potentially see approvals for CAR-T cells emerge quickly in other hematologic malignancy settings.

But it also could signal an increasing tolerance for other approaches. And this is the biggest implication for those looking for diamonds in the rough with the stock market. Lots of small up-and-comers are exploring cell-based immunotherapy in various forms. To name just a few:

Company Lead product
Inovio (NYSEMKT:INO) SynCon vaccines
Advaxis, Inc (NASDAQ:ADXS) Listeria-based vaccines
Aduro Biotech (NASDAQ:ADRO) Listeria-based vaccines
Northwest Biotherapeutics (NASDAQ:OTCQB:NWBO) Dendritic cell vaccine
Sorrento Therapeutics (NASDAQ:SRNE) Solid tumor CAR-T cells
OncoSec Medical (NASDAQ:ONCS) Interleukin-12 DNA pulse
Oncolytics (OTCQX:ONCYF) Reolysin, a tumor-killing virus

It's time to get ready for a wild ride in immunotherapy

To be clear, pointing out these companies does not mean I'm suggesting you buy, buy, buy. There are still risks associated with all these nascent technologies, and many will not pan out. Hematologic malignancies have had a long history of achieving groundbreaking therapeutics results that do not translate to solid tumors, so CAR-T cell therapy for, say, pancreatic cancer sounds tantalizing, as this is a huge unmet need. But pancreatic cancer chews through "promising" technologies like nothing else. The graveyard is long and grim there.

Still, my thesis here is that the likely approval of CAR-T cells in heme malignancies is going to give the FDA more experience with "live" immunotherapies, which will help them produce better guidance for other players in the field. This will almost certainly generate substantial excitement, and intrepid investors had better get on the ball sooner rather than later, or else they'll find themselves chasing the gold. Use the experience of JUNO, KITE, and NVS to your favor, and learn what you can about these promising therapies. It will come to play a major role in your due diligence.

Disclosure: I am/we are long ADXS. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.