Bg boost for single donor CAR-T

BACKGROUND

About a year ago, my 4/13/2017 post “Big Pharma in the CAR-T sector” related Pfizer’s entry into the CAR T-cell sector.
http://discussion.fool.com/big-pharma-in-the-car-t-sector-326763…
On June 18, 2014, Pfizer Inc. (PFE) and Cellectis (CLLS) announced that they had entered into a global strategic collaboration to develop Chimeric Antigen Receptor T-cell (CAR-T) immunotherapies in the field of oncology directed at select targets.

Cellectis was taking an approach significantly different to those taken by its competitors. Cellectis’ CAR-T platform technology provided a proprietary, allogeneic approach which utilized engineered T-cells from a single donor for use in multiple patients to developing CAR-T therapies, which was different and distinct from other autologous approaches that engineered a patient’s own T-cells to target tumor cells.

I related that Cellectis licensed UCART19, its first allogenic CAR-T, to partners Pfizer and Servier who were currently conducting phase 1 trials in the United Kingdom, and that Cellectis recently obtained FDA approval of its IND (Investigational New Drug) application to begin phase 1 clinical trials with UCART123, its CAR-T treatment for patients with two acute blood cancers. The first trial was in acute myeloid leukemia (AML), conducted at Weill-Cornell in New York. The second was in blastic plasmacytoid dendritic cell neoplasm (BPDCN), led by the M.D. Anderson Cancer Center in Houston.

Cellectis is a clinical-stage biopharmaceutical company focused on developing a new generation of cancer immunotherapies based on gene-edited T-cells (UCART), including without limitation UCART123, UCARTCS1 and UCART22. By capitalizing on its 18 years of expertise in gene editing – built on its flagship TALEN® technology and pioneering electroporation system PulseAgile – Cellectis uses the power of the immune system to target and eradicate cancer cells.

PFIZER AND ALLOGENE THERAPEUTICS ASSET CONTRIBUTION AGREEMENT FOR PFIZER’S ALLOGENEIC CAR T IMMUNO-ONCOLOGY PORTFOLIO

Yesterday, 4/3/2018, Pfizer Inc. (PFE) and Allogene Therapeutics, Inc. (a newly created, privately held biotechnology company) announced that the two companies have entered into an asset contribution agreement for Pfizer’s portfolio of assets related to allogeneic chimeric antigen receptor T cell (CAR T) therapy, an investigational immune cell therapy approach to treating cancer. Allogeneic CAR T-cell therapies have the potential to become the next advancement in one of the most powerful anti-cancer agents, eliminating the need to create personalized therapy from a patient’s own cells. These therapies are developed from cells of healthy donors and stored for “off-the-shelf” use in patients, simplifying manufacturing process and reducing waiting time for patients.
https://www.pfizer.com/news/press-release/press-release-deta…

Here are the major provisions:

• Pfizer will continue to participate financially in the development of the CAR T portfolio through a 25 percent ownership stake in Allogene.

• Allogene, a Two River portfolio company based in San Francisco, was formed with Series A financing of $300 million from an investment consortium that includes TPG, Vida Ventures, BellCo Capital, the University of California Office of the Chief Investment Officer and Pfizer, among others. TPG, Vida Ventures, BellCo Capital and Pfizer will be represented on the Allogene Board of Directors. The $300 million - the third-largest Series A round in biotechnology history - was raised to acquire and advance a portfolio of experimental cell therapies previously controlled by Pfizer.

• Closing is expected in the second quarter of 2018, subject to closing conditions.

• Separately, Pfizer continues to have an 8 percent ownership stake in Cellectis through the equity agreement entered into in 2014.

• Allogene will assume the strategic collaboration and license agreement with Cellectis, with exclusive rights to develop and commercialize previously defined allogeneic UCART programs directed at select targets. Cellectis will remain eligible to receive clinical and commercial milestone payments of up to $2.8 billion, or $185 million per target for 15 targets and tiered royalties in the high single digits on net sales of any products that are commercialized by Allogene under the agreement. This new alliance, with Allogene’s dedicated team, is expected to lead to a strong acceleration of CAR T therapies.

Initially, Pfizer had planned to conduct R&D in-house in collaboration with Cellectis and Servier, but later decided to seek and use outside expertise and capital to develop CAR-T products. Allogene closed the deal, beating other bidders.

WHO THE HECK IS ALOGENE?

Surprise, surprise! Two former Kite Pharma executives behind a game-changing cancer-killing technology launched their next act - a new company to develop a suite of so-called off-the-shelf CAR-T therapy assets, designed so that they do not need to be personalized for each cancer patient.
Dr. Arie Belldegrun, formerly Kite’s CEO, is Allogene’s executive chairman, and Dr. David Chang, formerly Kite’s chief medical officer, is Allogene’s CEO. The duo is legendary in biotech circles for turning Kite’s high-risk bet into a tour de force that last year resulted in the first CAR-T approval in adults and a $11.9 billion acquisition by Gilead Sciences.

Can they pull it off again? So far, the Servier/Pfizer-controlled lead asset, UCART19, has generated data seen as lackluster in early-stage clinical studies. In results presented late last year, five children with leukemia who were infused with the therapy went into remission, but two relapsed quickly and a third died from transplant complications. Here are the latest so-so results for adults.
http://www.epvantage.com/Universal/View.aspx?type=Story&…
The other 16 assets that Allogene gets in the Pfizer deal remain untested in patients.

Here are Allogene CEO Chang’s comments, observations and outlook:

• He was won over by an approach that he believes could help more patients and drive down the cost of CAR-T therapy.

• “When I actually looked at the clinical data, what I saw was more of a promise. We felt that all the right components were there. What we had to do was bring an experienced team into the equation — and also the financial backing.”

• Chang’s first orders of business for Allogene: (a) support and accelerate the ongoing studies testing UCART19 in leukemia; (b) start trials testing UCART19 in patients with non-Hodgkin lymphoma and other forms of cancer; (c) move a second asset into the clinic; and (d) take control of the manufacturing process.

As part of the deal, Pfizer will send 50-plus of its researchers who had been working on the CAR-Ts over to Allogene.

• Chang commented that it might take 5 years to find and deliver a viable allogeneic therapy.

Upbeat Allogene Chairman Arie Belldegrun commented:
"There’s no question—anyone, everyone you’ll ask, allogeneic is the future. Is it a challenge? Yes. Do we have to assemble the best team in the world to do it? Yes. Even Pfizer, the best company in the world, cannot do it alone. We’ll accept anyone who wants to help us to bring this therapy to patients. I never believed in anything more than I believe in that. I’m excited, more excited than anything else.”

Allogene is on my watch list for an IPO.

Off-the-shelf allogeneic CAR T-cell therapies will have substantially lower cost advantages over personalized autologous CAR-T therapies that currently have sticker shock prices. Kymriah, made by Novartis, was approved for patients under age 25 with B-cell precursor acute lymphoblastic leukemia, and is also part of an ongoing study of adults with diffuse large B-cell lymphoma; it costs $475,000. Yescarta, made by Kite/Gilead, is indicated for adults with relapsed or refractory large B-cell non-Hodgkin’s lymphoma; it costs $373,000. Those interested can google numerous articles that address issues regarding the rollout and delivery of these two approved therapies.

The City of Hope in my neck of the woods is one of the first medical centers in the nation to provide axicabtagene ciloleucel (also known by the brand name Yescarta), for adult patients with refractory aggressive non-Hodgkin lymphoma.
https://www.cityofhope.org/research/car-t-cell-therapy/nhl-c…
I mention this because my daughter is currently on the frontline as a City of Hope clinical RN in hematology, caring for in-patients, some of whom either are receiving Yescarta therapy, or are clinical trial participants (e.g., Celgene/Juno Therapeutics JCAR017 in B-cell Non-Hodgkin Lymphoma). It seems like only yesterday, she was taking calls in Care Management at one of Southern California’s largest medical group, where RNs and her boss (a VP and Nurse Practitioner with an MBA) finally mentored and pushed her out the door to pursue a BSN degree from highly-rated Azusa Pacific University that offered an array of nursing programs (e.g., BSN for LVNs and RNs with 2-year associate degrees and 4-year BSN degrees). My daughter, who holds a bachelor of health science degree, chose the Entry Level Masters of Science Nursing (ELMSN) path for Nurse Practitioner. Her cohort group of 14 earned their BSN degrees last August, all on their first try passed the NCLEX to obtain their RN California licenses, and all got jobs in order to take certain graduate courses that require clinical experience. My daughter was very fortunate to learn from friends (City of Hope employees) at our local gym that the City of Hope was hiring new grad RNs for temporary 3-month long positions to assist the company, which was installing the new EPIC electronic medical record program, to train employees and provide follow up assistance. During the EPIC training, my daughter manned the hematology in-patient floor, was invited to apply for a full-time clinical nurse position, and was hired the day after her interview. Along this path, I shared with her all my CAR-T and cancer research which she quickly left me behind in the dust. Her group of new grad RNs has undergone an intensive 3-month long training in the classroom and in the trenches under the guidance of assigned clinical RN preceptors. She loves her job and soon will be fully assigned to at least 3 patients with her preceptor available if needed. It will take almost 3 years to complete all her graduate school nurse practitioner coursework while working full-time. Best of all, she is debt free, paying all her educational expenses from her savings.

Regards
Ray

20 Likes

Ray,

Sounds like you are (rightfully) quite proud of your daughter.

Any quick comparison of how this more generalized CAR-T therapy might compare to the “push/pull” cancer fighting strategies that Nektar Therapeutics (NKTR) seems to be working on with NKTR-214 and NKTR-262, in particular.

In case you happened to miss it, here is a link to an excellent thread from 10 days or so ago started by Motley Fool One’s Ted Yun on Nektar and their method of attacking cancer.
http://discussion.fool.com/nktr-nktr-214-deep-dive-33021896.aspx…

Shortly after that thread, Saul provided this concise post/thread about finally getting checkpoint inhibitors.
http://discussion.fool.com/okay-i-finally-get-checkpoint-inhibit…

Perhaps you or your daughter could have some insights? Is CAR-T more of a “cure cure”, but more expensive?

Thanks in advance,
volfan84
who is a mechanical engineer and a fan of systems, with tons unknown about biological systems

2 Likes

Congrats to your daughter. I’m shocked she is able to work towards an NP while working full time, quite the feat.

Now, onto the biotech analysis. I saw these headlines on CART, KITE & Chang, and read this as Pfizer trying to unload their CART segment, but try to keep a small ownership position.

Read: Pfizer probably doesnt think their CART is close to clinic, thinks its probably close to useless, but wants some position in Allogene “just in case”. 8% of 300m is nothing to Pfizer; funding all of their development is quite costly, and besides, who wants do that when the VC / IPO market is perfectly willing to fund its development?!?!

It’s looking more like Chang is great at hype and knowing when to bail. Current CART development is looking more and more like Westport and ZIOP than an early genentech. Allogene may be profitable for some investors, whether or not it will be for patients is highly suspect.

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volfan84: Any quick comparison of how this more generalized CAR-T therapy might compare to the “push/pull” cancer fighting strategies

In the OP my referenced post “Big Pharma in the CAR-T sector” provided the
following:
http://discussion.fool.com/big-pharma-in-the-car-t-sector-326763…

Although I’m trying hard to stay focused on CAR-T, the aforementioned Pfizer-Merck KGaA deal in the Ian Read interview warrants a diversion. An American collaboration of Merck & Co. and Bristol-Myers Squibb Co. had launched another impressive group of cancer drugs called checkpoint inhibitors, which took the brakes off the immune system rather than genetically tweaking immune system cells to spot and destroy cancer cells. For those interested, here are websites on what is a checkpoint inhibitor.

In layman language, the Dana-Farber Cancer Institute explains “What is a Checkpoint Inhibitor? Immune Checkpoint Inhibitor Definition”
http://blog.dana-farber.org/insight/2015/09/what-is-a-checkp…
This website provides an excellent Dana-Faber’s Science Illustrated drawing presentation of what a checkpoint inhibitor is and does. Click the following:
https://www.youtube.com/watch?v=AbmEt_E8kfo

Again in layman language, the second Dana-Farber website explains “What is the Science of PD-1 and Immunotherapy?”
http://blog.dana-farber.org/insight/2015/05/the-science-of-p…
It was Dana-Farber scientists who discovered that many cancer cells wear one of those same proteins, called PD-L1 – part of an elaborate masquerade that allows the cancer cells to live and multiply without harassment from the immune system. The implications of that finding, published in 2001, were self-evident: find a way to block PD-L1, or the proteins on immune system cells that “see” PD-L1, and the command that once prevented an immune system attack on cancer would be lifted.

I was going to post the above in the NKTR thread, but Saul’s post gave an excellent explanation.

BTW, after a 3-1/2 year effort, on 3/23/21017, the Pfizer-Merck KGaA collaboration received its first FDA approval of their checkpoint inhibitor avelumab, the fourth drug in this category to make it to the marketplace.

Regarding CAR-T, here’s an excerpt from my April 2017 post here that best explains what became to be called a chimeric antigen receptor, or CAR:

“To fight cancer, T-cells have to recognize cancerous cells.

Each T-cell in the body has unique receptors, sort of like claws that jut out from its surface. T-cells patrol the body looking for protein fragments that indicate a cell might be infected by a bacterium or virus. If one of its claws latches on to such a fragment, the T-cell destroys the cell displaying it.

But cancer cells are mutated versions of the body’s own cells, not outsiders. T-cells do not always recognize them as something to kill.

So scientists like Dr. Sadelain decided to put a new claw on the T-cells, one that could recognize cancer by latching on to a telltale protein on cancer cells.

The new claws came from another part of the immune system known as antibodies. Drug companies already knew how to make antibodies with claws that bind to specific proteins in the body.
But the claw was not enough. Once a claw binds to a target protein, it needs a molecule to signal the T-cell to go into killing mode. Yet another signal helps sustain the killing. The DNA instructions for all three components are inserted into the patient’s T-cells.

Since this concoction is part antibody and part T-cell, it is a chimera, like the monster of Greek mythology that is part lion, part goat and part serpent. The claw is called a receptor and the protein it binds to on the cancer cell, the target, is called an antigen. So the whole construct is called a chimeric antigen receptor, or CAR, and the use of it to treat cancer is called CAR T-cell therapy, or CAR-T.”

Now regarding the single donor allogeneic approach, here’s an illustrative presentation and explanation of Cellectis’ gene edited CAR T-cells and how these work:
https://www.youtube.com/watch?v=TzSurHZjoy0’

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Fuma102: Read: Pfizer probably doesnt think their CART is close to clinic, thinks its probably close to useless, but wants some position in Allogene “just in case”. 8% of 300m is nothing to Pfizer; funding all of their development is quite costly, and besides, who wants do that when the VC / IPO market is perfectly willing to fund its development?!?!

In a 2015 interview (mentioned in my “Big Pharma in the CAR-T sector” post) Pfizer Chairman and CEO Ian Read made the following comments:

Ian Read:
Business units in a certain way try and mimic the agility and the speed of a Celgene. But for every Celgene there’s a hundred that didn’t make it.
Stephen Sands:
And it only took 20 years for Celgene too, right?
Ian Read:
I mean it’s a great company, a great company, great leadership, but it’s a high-risk business. And so it’s easy to point to the two or three that really break through and make it, and make some bets that work out. And no one talks about the other 99 companies that didn’t succeed, right?

It appears Read reassessed the high risks and, as I pointed out in my OP, decided to seek and use outside expertise and capital to develop CAR-T products.

From the start in the 1980s, there have been lots of naysayers and doubters about such a concept, that is, development of a cancer immunotherapy, involving genetic modifications of T lymphocytes extracted from a cancer patient to produce chimeric antigen receptor (CAR) T-Cells, which are then injected back into the patient in a process called adoptive cell transfer. However, the recent successes of Kite and the Novartis/University of Pennsylvania team have finally proven them wrong.

Fuma102: I’m shocked she is able to work towards an NP while working full time, quite the feat.

Thank you for the congrats.
Another City of Hope RN friend of ours recently received her Master of Science Nurse Practitioner degree from Azusa Pacific University and just passed in her first try the California test for her license. It took her 2-1/2 years while working full-time as a clinical RN. Needless to say, it was not easy, but doable. She will be a terrific mentor for my daughter, who intends to fully focus on her job for at least one year before taking on any graduate school classes. Her boss at her previous job took time off from her full-time job to earn a Nurse Practitioner Masters degree concurrently with her MBA.

Regards,
Ray

11 Likes

Thanks Ray, for keeping us up to date on this interesting field.
Saul

Any quick comparison of how this more generalized CAR-T therapy might compare to the “push/pull” cancer fighting strategies that Nektar Therapeutics (NKTR) seems to be working on with NKTR-214 and NKTR-262, in particular.

To build on Ray’s post, there are two main differentiators between the push/pull and the CAR-T approaches.

  1. They will be for different indications. CAR-T has not been shown to be very effective for solid tumors yet. Yescarta and Kymriah are designed basically to compete against Rituxan. This may change as companies play around with what receptor to engineer, but for now, the strategies are in different spaces. The push/pull strategies, particularly what we will be seeing from Merck soon, will rely on intratumoral injections into solid tumors. With NKTR-214 and Opdivo, this combo may address tumors that are not easily accessible for intratumoral injection, like RCC.

  2. CAR-T will never be front-line or even second-line. This is primarily due to the cost, which is primarily due to the technical difficulty in the technique. Patient cells have to be extracted, purified, sorted, cultured, transduced, then reinfused back into the patient. That entire chain takes a lot of training and specialized expertise. I personally have done retroviral transfection on mouse cells - a technically easier feat - and there is a certain combination of science and art that is required in order to achieve consistent results.

Push/pull on the other hand has a good chance at being second line therapy. Technically, there is more space on the pricing because the drugs are more in line with “traditional” biologics.

Ted

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Ted,
Following up on your comments, I think it is too early to say whether or not CAR-T will ever become first line. I agree it is incredibly expensive. If autologous CAR-T consistently delivers cures of previously uncurable blood cancers like lymphoma, leukemias, and myelomas it may be acceptable to insurers, patients, and clinicians in spite of cost. The more aggressive varieties of these might warrant first line treatment with CAR-T and the less agressive, due to requiring round after round of treatment, might also eventually be viewed as suitable candidates for CAR-t due to the cost of multiple rounds of treatment vs. “one and done”.

I believe one of the promises of allogenic CAR-T should be that it is cheaper as it would be “off the shelf” and presumably produced in larger quantities. If it combines cure and lower cost (than CAR-T) it seems like it could be a contender for first line therapy.

Dave

2 Likes

Hi Dave,

You’re right, and I should learn to never say “never.” Especially if the companies develop CAR-T’s for cancers where there is no sufficient treatment. I was thinking about the current therapies which seem to go be designed for DLBCL and the like that do not respond to Rituxan (ie., the anti-CD19 mAb). But they probably have a commercial strategy to expand the indications for Yescarta, so we will see.

Ted