Everyone’s talking about “CAR-T” and Cancer at the moment. But what is CAR-T? Why is it so hyped, and what could limit the adoption of such a revolutionary technology?

CAR-T is a type of engineered T-cell which is transformed in vitro to recognize cancer cells. This small tinkering with the T-cells has initiated development of a whole new range of cancer treatments, and could potentially even one day lead to a cure.

It exploits all the developments in immuno-oncology to make a super T-Cell therapy to attack tumors and cancer cells (and you can read more about how Biotech changed the field in my review from last month). In short though, CAR-T is using our body’s own immune system to fight cancer.

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How Does CAR-T Work Exactly?

CAR-T works by triggering the immune system to recognize tumors and thus activates cancer cell lysis. In brief, you take the patient/donor T-cell, and then you modify it genetically in vitro to express a Chimeric Antigen Receptor (CAR) which can recognize a specific tumor’s antigen.

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The essential part of CAR-T is the Chimeric Antigen Receptor (Source: Juno Therapeutics)

Here’s an explanation of the role of the main components of this receptor:

  • scFv, an antibody fragment replacing the TCR which will recognize the tumor associate antigen (TAA)
  • CD3 is the signaling domain that will activate the immune response once the antigen bind to the scFv
  • A Co-stimulatory domain, which improves the immune response and the survival of the cells. Interestingly, there are now three generation of CAR-T and the main differences resides in the number of those co-domains.

The T-lymphocytes of the patients or donors are then re-injected, allowing the receptor modifications to recognise certain cancer antigens (e.g. CD-19), hone in and lead to an immunoregulatory response against the cancer cells.

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How CAR-T is used, often in conjunction with other chemotherapies (Source: Klebanoff et al. (2014) Nature Reviews Clinical Oncology 11, 685–686 doi:10.1038/nrclinonc.2014.190)


So technically, CAR-T is very exciting, but how do we make it a product?

One main issue of the CAR-T production process is the expense and time taken to make each dose of the therapy. For example, the Autologous nature of these treatments (i.e. specificity of each dose to each patient) comes with cost and time constraints when compared to Allogenic treatments.

Understandably if you take the time to make a personalized treatment (harvesting, engineering and re-injection) for each patient, this naturally drives the cost of commercialization up. However, the main advantage of Autologous CAR-T is that there is almost no immunogenicity, since its the patients own cells. But it is long and expensive to develop…

So how are CAR-T Therapies made? The raw material of CAR-T is blood cells, which will be transformed in a 5-step process:

Step 1: Leukapheresis. Which consist in extracting T-cell, among the Peripheral Blood Mononuclear Cell, from the blood and isolate it with a standard process of affinity.

Step 2: Activation of T-cell through stimulation of TCR and Co-stimulation receptor (e.g., CD3 and CD28) to transform them into a Cytotoxic T-Cell (CD8+).

Step 3: Transfection. Once a T-cell is activated, the CAR need to be expressed by the cell to recognize the tumors. This is achieve by inserting a gene thanks to a vector (e.g., Lentivirus developed by GEG-Tech). In case of allogeneic, the immunogenicity is reduced at this step.

Step 4: Cell expansion. Need to find a time balance for proliferating the culture… The period has to be long enough for good CAR insertion, but not too long as overtime cells lose their function.

Step 5: Conservation and then administration. Cell are purified and cryo-conserved. Then it will be used as treatment to cure cancer. For autologous, no cryoconservation is needed (72h of survival, but transport to patient’s bed remains critical)

Source: Springer Publications

(Source:  Shi et al. (2014) Molecular Cancer 13:219, doi: 10.1186/1476-4598-13-219)

As we mentioned, the Autologous nature of most commercialized types of CAR-T is a problem with making therapies on a mass scale…

Allogenic (Universal) CAR-T on the other hand comes from donors and will be then given to several different patients, bringing forth the possibility of ‘industrialising’ CAR-T production, which reduces the cost and time for treatment to be made.

Currently, the cells developed are TCR knock-out, meaning they’re almost no risks of attacking the patient’s own cell (aka graft-vs-host disease). However, there is still a risk of rejection by the patient, which is limited because the patient is immunodeficient during the period of therapy.

Such a product, however, cannot reach the market without Biotech companies…

And Who Exactly is Leading the CAR-T Race?

The starting line in CAR-T is far behind us now, and the technology does exist…Indeed, the first clinical results (complete remission from a terminal cancer patient) was achieved by Novartis back in 2011. This breakthrough was essentially responsible for the hype take-off in Immuno-Oncology.

Now many actors jumped into the field and are advancing their own programs. Here’s the top four players:

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Other ‘Early-Stage’ Players around the World…

Bellicum, Bluebird BioTransposagenbioApcethAutolusCelyadFortress biotechMaxCyteOxford BioMedicaPoseida Therapeutics, Cellerant, TX CellZio-Pharm, Cellulare BioMedecine Group, CARsgene.

To summarise, over 25 players have jumped into the CAR-T space. Most of them focus on autologous, even though allogeneic could have a higher potential on the long run…

At the end of the Day, it’s all about Clinical Trial Results…

And these are really impressive until now: Over 90% (!!) of recovery with autologous cell for Juno Therapeutics for acute lymphoblastic leukemia (ALL) . Results are really encouraging as well as Phase II clinical trial of Novartis.

Asides this, a first proof of concept in human of  allogeneic has been presented by Cellectis in a baby girl who with ALL at Great Ormund Street Hospital in London (UK). This recently stormed the headlines, and really brought CAR-T to the public’s attention.

So definitely, CAR-T is a good treatment and adverse effects can be controlled so far (e.g. Cytokine Release Syndrome). However, these are still early results and the road to market access is still long. I hope it won’t be like bi-specific antibodies where 130 are under development and only two approved.

But what about the limits? Companies love to highlight the successes but we are here to balance it with the reality…which is what Cellectis is trying to do after we interviewed their CEO André Choulika last week. As he said:

I’m just trying to be realistic, CAR-T is not THE miracle cure for Cancer”

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Layla, aged one, was treated with UCART19 which is still limited to the pre-clinical stage, as a last resort for her ALL (Credit: Great Ormond Street Hospital /PA Wire)

Why?

The main issues are related the production challenge, to which disease can be targeted and ultimately to who will pay for such a high-tech drug.

T-Cells are difficult to produce…

This list is far from being exhaustive, otherwise we would have to write an article per bullet point…but the following reasons are relevant:

  • Production of Autologous takes at least 14 to 21 days then has to be characterized.
  • This product handling and manufacturing are majority handling, leading to high production cost
  • Risk of cross-contamination between different patients cells is high, as they are manipulated in the same labs. Automated and closed production system could help this issue…
  • T-Cells are extremely sensitive to changes in the production environment
  • Cell transfection remains not fully mastered
  • Allogenicity may resolve the problem of cross-contamination but involves to use a working and a master cell banks, and bring the constraints of using donors (selection etc.)
  • Scaling up the process for marketing at a GMP standard is yet to be proven…

Those challenges are not related only to CAR-T but to Cell therapy in general. Will not be easy, but challenges are made to be overcome!

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UCART19 Production by Cellectis – timescale and steps involved in potential mass production of their Universal CAR-T (Source: Cellectis)

And CAR-T is not the solution for every cancer!

It seems so easy to think CAR-T will be the ultimate cure to cancer, but as always with biology, it’s never as simple  as it seems in practice. Four main limitations seems to be critical:

(1) Patients need to have T-Cells left to be able to engineer them (for autologous). This is not always the case as the patient often received a chemotherapy. Allogenic sources could be the solution.

(2) It’s mainly for liquid tumors (such a multiple myeloma and leukemia) at the moment, as penetration into solid tumors is very challenging (‘melting snowball’ analogy – where by the time the inside is reached, CAR-T cells have expired).

 (3) Most CAR-T targets the same tumor antigen (CD19) which is not specific to tumours and may lead to adverse events. Other antigens are still being investigated.

(4) CAR-T do not staying indefinitely in the body meaning the patient could enter into remission after the treatment.

(5) CAR-T is an acute tool only, so works well against cancer but not necessarily for chronic relapses. Multiple injections could be a solution.

And of course, the cost of treatments is an issue…

Who Will Pay for CAR-T?

That’s probably the biggest problem. Cost of autologous CAR-T therapies are estimated to at €250k / treatment. This is extremely high, almost at the same level as the worldwide most expensive drug (from Genzyme).

But in this case, we are not talking about an ultra-rare disease but about cancer. This could be a real challenge for the purchasers and limit the availability of CAR-T for the patients… so once again, Allogenic may be the solution.


So as you can see…

…CAR-T is indeed very promising, despite there still being many challenges from the production to administration scale. The final application is also still uncertain – i.e. is CAR-T a long term therapy or just a cell transplant ‘bridge’ (an intermediary therapy following chemo)?

Also, for cancer it is important to consider other types of therapy, such as mRNA therapeutics which also has a good proof of concept.

However CAR-T remains the breakthrough. As a matter of fact, it helps many patient in lack of therapeutic solutions: The rate of positive response and total remission is just amazing.

So hold on guys, keep tackling those challenges! Because with such technology, you give hope to many, and only with time can revolutionary breakthroughs be refined to something truly great!

P.S. I am personally really impressed by CAR-T. Keep up the good job:

 

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  • Carlos Azuaje

    Nice article, thanks for sharing.

    I hope to see even more and better results from this technology in the upcoming future!

    • Thanks Carlos! Indeed, but did you see our latest news on Novartis trial for relapsed/refractory ALL? Their CAR-T candidate resulted in a 93% remission rate… I’m still excited by CAR-T, even if we’re trying to remain level headed over the progress.

      • Carlos Azuaje

        Just read about it, Dani!

        I am very excited about all these results also =)

      • Tim C

        I am disappointed to hear that for all practical purposes, Novartis is pulling out of the CAR-T race ! 🙁

  • bagus

    excite good articles