On Cellectis

Since Cellectis was one of the four Car-T companies I had been following, and since Tinker pointed out its advantages, I thought I’d post my notes on it.

Ray introduced it to the board in April. Here is my editing of Ray’s post:

When I assembled the latest CAR-T partnerships and agreements in a previous post, I noticed the following:

There were only 3 big pharma participants –
Novartis AG (NVS)
Pfizer (PFE)
Merck KGaA

Two were foreign companies in partnership with American companies and organizations, i.e., Novartis, a large Swiss pharma with U.S. partner U of Penn; and Merck KGaA, a large German company, with U.S. partners Intrexon, ZioPharm, and M.D. Anderson Cancer Center.

The only American pharma company, Pfizer, one of the world’s largest, had only French partners, Cellectis and Le Laboratories Servier.

I knew that Pfizer was sitting on a gigantic $193 billion stockpile of offshore profits, second to Apple’s $200 billion and thought that the high U.S. corporate tax rate 35% perhaps deterred Pfizer partnering with and investing in U.S. companies. Surely, Pfizer was fully aware of the perils, risks and extremely low success rate taking on biotech ventures. So I started to dig further.


Pfizer’s entry into the CAR T-cell sector
In June 2014, Pfizer and Cellectis announced that they had entered into a global strategic collaboration to develop CAR-T immunotherapies.

Pfizer and Cellectis Enter Into collaboration to utilize Cellectis’ proprietary allogeneic CAR-T platform technology to develop immunotherapies against select targets in the field of oncology.
Cellectis’ CAR-T technology provides a proprietary, allogeneic approach (using engineered T-cells from a single donor for use in multiple patients) to developing CAR-T therapies that is distinct from other autologous approaches (engineering a patient’s own T-cells to target tumor cells).
Pfizer has exclusive rights to development and commercialization of CAR-T therapies directed at a total of 15 targets selected by Pfizer. They will work together on preclinical research and Pfizer will be responsible for the development and potential commercialization of any CAR-T therapies for the Pfizer-selected targets. In addition, 12 targets will be selected by Cellectis. They will work together on preclinical research on 4 Cellectis-selected targets and Cellectis will work independently on 8 additional targets.

Cellectis received an upfront payment of $80 million, as well as funding for research and development costs associated with Pfizer-selected targets and the four Cellectis-selected targets within the collaboration. Cellectis is eligible to receive development, regulatory and commercial milestone payments of up to $185 million per Pfizer product. Cellectis is also eligible to receive tiered royalties on net sales of any products that are commercialized by Pfizer.
Additionally, Pfizer purchased approximately 10% of the Cellectis capital through newly issued shares at 9.25 Euro per share. Cellectis expected to open a site in the U.S. to work more closely with Pfizer.

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. This is different and distinct from other autologous approaches that engineered a patient’s own T-cells to target tumor cells.

Subsequently, in Mar 2015, Cellectis (CLLS) raised more than $228 million in its IPO debut.

Although I (Ray) am trying hard to stay focused on CAR-T, the situation warrants a diversion. A U.S. collaboration of Merck & Co. and Bristol-Myers Squibb 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.

In spite of starting behind the front runners, Pfizer Inc. announced on 11/17/2014 that it had entered into an agreement with Merck KGaA, Germany, to jointly develop and commercialize MSB0010718C, an investigational anti-PD-L1 antibody that was at that time in development by Merck KGaA as a potential treatment for multiple types of cancer. Pfizer and Merck KGaA would explore the therapeutic potential of this novel anti-PD-L1 antibody as a single agent as well as in various combinations with Pfizer’s and Merck KGaA’s broad portfolio of approved and investigational oncology therapies.

Under the terms of the agreement, Merck KGaA received an upfront payment of $850 million [back then the largest ever by Pfizer] and was eligible to receive regulatory and commercial milestone payments up to approximately $2 billion. Both companies would jointly fund all development and commercialization costs and all revenues obtained from selling any anti-PD-L1 or anti-PD-1 products generated from this collaboration will be shared equally.

After a 3-1/2 year effort, on Mar 23rd , 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. The FDA approval was achieved under an accelerated approval process, and the therapy, which will be sold as Bavencio, was given breakthrough drug status. Checkpoint inhibition is a big field, and the Pfizer/Merck KGaA team plan to make their mark as the pioneers divvy up leadership roles in a wide array of cancers. This is also tremendous reassuring news for the Merck KGaA, Intrexon, ZioPharm, CAR-T partnership because it marks a major win for Merck KGaA, which came away with a package of regulatory and commercial milestones on avelumab worth up to $2 billion when it partnered with Pfizer in 2014. Merck KGaA also demonstrated that it could swiftly execute a development program from start to first approval. Also, I brought up this example to debunk any notions that it’s too late to jump in to the CAR-T fray. Some pundits assert that the Pfizer/Cellectis partnership is lagging far behind the others, i.e., KITE and JUNO. But the CAR-T field is wide open.

My Question to Ray –
Ray, after working your way all the way through that, what did you think about Cellectis??? Having a method that can use T-cells from anyone sounds fantastic, but they seem to be going nowhere so far. I’d appreciate any words of wisdom.

Ray’s Answer -
Here’s a quick response: In my second post I commented that prior to 2010, pharma companies showed little interest, preferring mass-produced drugs, one size fits all, rather than a treatment that would be made separately for each patient.

One reason Pfizer partnered with Cellectis was because the Cellectis allogeneic approach is compatible with Pfizer’s mindset, i.e., mass-produced drugs, one size fits all. Pfizer, with Cellectis’ technology, aims to manufacture and standardize off-the-shelf CAR T-cells that can be used immediately. Instead of using the patient’s own T-cells, the Cellectis approach involves a single healthy donor who can potentially supply T-cells that can treat thousands of patients. The big question is, can it be done?

The paucity of progress news about Cellectis, Pfizer, and Servier is because they recently started trials:

Cellectis licensed UCART19, its first allogenic CAR-T, to partners Pfizer and Servier who are currently conducting phase 1 trials in the U.K.

Cellectis recently got FDA approval of its IND application to begin phase 1 clinical trials with UCART123, its CAR-T treatment for patients with two acute blood cancers. The first trial is in acute myeloid leukemia (AML), to be conducted at Weill-Cornell in New York. The second is in blastic plasmacytoid dendritic cell neoplasm (BPDCN), to be led by the M.D. Anderson Cancer Center.

BTW, Dr Carl June, professor of immunotherapy at the U of Penn, commented at the recent NIH Director’s Lecture that, “since CAR T-cell therapy is personalized, new T cells must be grown from a patient’s own cells, and it isn’t clear yet whether cord blood or T cells from a healthy donor can be used.” Sounds like the Penn-Novartis team might be looking at the Cellectis’ allogeneic approach.

Apr 2017 – Press Release
Cellectis announced that data on its gene-edited allogeneic off-the-shelf CAR T-cell immunotherapies (UCART) will be presented at the ASGCT Annual Meeting from May 10th to 13th

Oral presentation:
Development of Gene Edited Allogeneic CAR T-Cell Therapy
Friday, May 12, from 8:35 AM to 9:10 AM

Poster presentations:
176 - Genome-Wide Analysis of TALEN® Activity in Primary Cells
Wednesday May 10, at 5:30 PM

114 - UCART22: An Allogeneic Adoptive Immunotherapy for Leukemia Targeting CD22 with CAR T-cells
Wednesday May 10, from 5:30 PM to 7:30pm

372 - Manufacturing of Gene-Modified Mouse CAR T-Cells
Thursday May 11, 2017 from 5:15 PM to 7:15 PM

Cellectis is a biopharmaceutical company focused on developing immunotherapies based on gene-edited CAR T-cells (UCART). Its mission is to develop a new generation of cancer therapies based on engineered T-cells. It capitalizes on its 17 years of expertise in genome engineering - based on its flagship TALEN products and meganucleases as well as its pioneering electroporation PulseAgile technology - to create a new generation of immunotherapies.

May 2017 – Important Patent Upheld
Cellectis, a biopharmaceutical company focused on developing immunotherapies based on gene edited CAR T-cells (UCART), today announced that its patent, which claims the use of chimeric restriction endonucleases for directing chromosomal gene editing in cells by homologous recombination, initially issued in Dec, 2014, has been upheld by the US Patent Office after a reexamination initiated in October 2015.

It claims a general method for modifying chromosomal DNA sequences at a genomic site of interest within a cell by using a chimeric restriction endonuclease such as zing finger nucleases, TAL-effector nucleases, Mega-TALs and CRISPR/Cas9. This technique, commonly referred to as gene targeting or targeted insertion, is now frequently used to modify the genome within plants, animals and cell lines.

The inventors of this patent are Dr. André Choulika, Cellectis’ CEO, and Dr. Richard C. Mulligan, a Harvard Medical School Professor. Institut Pasteur and Boston Children’s Hospital, the owners of the patent, have granted exclusive rights to Cellectis under this patent. It belongs to a patent family that claims the basic uses of chimeric restriction nucleases for gene editing in cells.
Following the patent’s reexamination, the USPTO issued a Notice in which it is stated that all 55 claims of the patent are upheld.

May 2017 - March quarter results

UCART123 - Cellectis’ most advanced, wholly controlled TALEN® gene-edited product candidate

IND approval received from the U.S. FDA to conduct Phase I clinical trials in patients with AML and BPDCN.
First clinical trial approval by the FDA for an allogeneic, “off-the-shelf” gene-edited CAR T-cell product candidate.
AML clinical program to be at Weill Cornell
BPDCN clinical program to be at MD Anderson Cancer
Completion of cGMP manufacturing runs of UCART123 at large scale, to provide doses for initiating planned Phase I clinical trials in AML and BPDCN patients.

UCART19, exclusively licensed to Servier
The FDA has granted Pfizer and Servier IND clearance to proceed in the U.S. with Phase I clinical development of UCART19 to treat patients with relapsed/refractory acute lymphoblastic leukemia.
Phase I clinical trials in pediatric and adult ALL patients are ongoing at University College London and Kings College London, sponsored by Servier.
Calyxt Inc. – Cellectis’ plant science subsidiary

In April 2017, Cellectis announced that it is exploring the possibility of an IPO of a minority interest in its plant sciences business, Calyxt.

Financial Results
Cellectis’ financial statements have been prepared in accordance with IFRS.
First quarter 2017 Financial Results
Cellectis expects that its cash, cash equivalents and current financial assets will be sufficient to fund its current operations to 2019.

Financial Gain (Loss): The financial loss was almost nil result compared to a loss of €9.1 million for the first quarter of 2016. The change in financial result was primarily attributable to foreign exchange.

June 2017 – They announced an IPO for their fully owned agricultural gene-editing company/division, Calyxt.

June 2017 – They announced the first subjects in their Stage 1 trial at Weill Cornell in New York. These are the first humans to receive off-the shelf Car-T.

July 2017 - Calyxt, the wholly owned gene-editing agriculture subsidiary of Cellectis has reportedly cut the price of its pending IPO from the announced $15-$18 to a new price of $8-$10. Net proceeds will be trimmed to about $49 million from $91 million. (Wow!) It finally went off at $8, the bottom of the reduced range.

I sold half my small position when Cellectis failed at their money raising Calyxt effort. Then Kite came out with their 4-year results and I decided to concentrate in Kite and sold out of the others. From Cellectis’ first patients in a Stage 1 trial to commercialization will be years.



Note that off the shelf CAR-T will be the Holy Grail if they get it going, but even if they do, it will be years away, and Kite is starting to work on it too.

Saul, actually, Cellectis’ lead product UCART123 was administered twice in 2015 to infants near death from leukemia. The first such compassionate use (in London) was widely reported in the news, and even the subject of a National Geographic telecast in their “Breakthrough” series earlier this year. Here are two links about the first two times that UCART123 was administered to humans:


Correction to my previous posting about the two previous compassionate uses of Cellectis’ allogenic CAR-T tx in human infants. Actually, the Cellectis’ product used then was UCART19, not UCART123 as my first posting stated.

Hi zuzu,

A product being administered twice two years ago as “compassionate” use doesn’t shorten the approval process. Look, they just administered their first doses to humans in a Phase 1 study. According to Wikipedia, Phase 1 is to test for dosage range, safety, and side effects. It’s usually done on healthy volunteers, but for anti-cancer drugs it’s often tested on cancer patients (with the appropriate cancer, I presume). I believe Cellectis is testing it on cancer patients.

Wiki says that there usually are 20 to 100 patients in a Phase 1 study. Let’s give them the benefit of the doubt and say they are going for 30 patients. Say it will take a minimum of six months (maybe even nine months to a year, I don’t know), to find and enroll 30 cancer patients with the right cancer of the right severity. Then, assuming there is a 3 month to 6 month observation period afterwards to check for side effects and therapeutic results at various dosages, they’ll bring the study to a close in roughly a year. Then, assuming no major problems or deaths, they have to prepare and submit it to the FDA, and get permission to do a Phase 2 study. The FDA isn’t going to consider the data and make a decision in less than three to six months. Meanwhile Collects is working away on a plan for a Phase 2 study, based on approval (and assuming the FDA doesn’t send the first one back for more data). Then Cellectis submits their plan for a Phase 2 study and awaits approval…and then enrolls all the patients (Wiki says 100 to 300, but the FDA may settle for less in a case like this), and the whole process repeats.

We are looking at at least three to four years from now (optimistically) before clinical approval, in a best case scenario. Especially since there will already be CAR-T effective treatments on the market already, even if a little klunky, so approval is no emergency.

Do we want to wait four years or go with the one going to market it November? While Novartis will also be approved, they are a big company where this won’t move the needle, and they apparently have defunded the division that brought out their successful candidate in an attempt to save money. No pipeline. Kite looks good.



Saul, thanks for reminding us of the time lapse that will be involved on the road to approval of any tx just entering phase 1 of clinical trials. This is important to know, and especially from the perspective of an investor.

Still, I believe that the two “compassionate use” occasions suggest the continuing possibility/likelihood of similar instances arising anywhere at any time. There are always patients who are too sick, with too little time remaining, who have failed all previous tx attempts. So why not try an existing “universal donor” product specific to their type of cancer in a last-ditch effort to save their life? If/when this does happen, then it will surely hit the news wires, just as it did in the two previous cases, at least if the product works as it did before. I do realize that such ad hoc administrations don’t count towards the drug’s approval, but they would serve to keep the company’s name in the news.