Good morning, everyone. And welcome to the Cellectis Fourth Quarter 2021 and Year-End Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. Instructions will follow at that time. Please be aware that today's conference call is being recorded.

I would now like to introduce the first speaker, Arthur Stril, Chief Business Officer. You may begin..

Good morning. And welcome, everyone, to Cellectis fourth quarter 2021 corporate update and financial results conference call. Joining me on the call today with prepared remarks are Dr. Andre Choulika, our Chief Executive Officer; Dr. Carrie Brownstein, our Chief Medical Officer; and our new Chief Financial Officer, Dr. Bing Wang.

Yesterday evening, Cellectis filed its annual report and issued a press release reporting its financial results for the fourth quarter and year ended December 31, 2021. The report and press release are available on our website at cellectis.com.

As reminder, we will make statements regarding Cellectis' financial outlook in addition to its manufacturing, regulatory and product development plans.

These forward-looking statements which are based on our management's current expectations and assumptions and on information currently available to management, including information provided or otherwise publicly reported by our licensed partners, are subject to risks and uncertainties that may cause actual results to differ from those forecasted.

A description of these risks can be found in our most recent Form 20-F filed with the SEC and the financial reports including the management report for the year ending on December 31, 2021 and subsequently filings Cellectis makes with the Securities and Exchange Commission from time to time. I would now like to turn the call over to Andre..

Thank you, Arthur. Good morning and thank you everyone for joining us today. 2021 was a productive year for Cellectis. We are proud of the progress we've made as it relates to our corporate milestones as we evolve to become a full end-to-end cell and gene therapy biopharmaceutical company.

We have progressed on the clinical front with escalating doses of our product candidate. We completed our manufacturing plants and that gives us control of products' quality and supply line. We continue to innovate. We have been working on our first duel-targeted UCART product, UCART20x22, and plan to bring it to the clinic in 2022.

We have been able to leverage our valuable TALEN platform to provide Cellectis with business opportunities in the future cell therapy field outside of our core allogeneic dual CAR T area. Regulatory issues that had paused some of our partnered programs have been resolved. It is clear that none of these issues are due to Cellectis TALEN technology.

And our financial position is secure. Based on our term plans, our cash takes us not just through 2023, but to early 2024. First, I will touch on some of the clinical progress. Carrie Brownstein, our Chief Medical Officer, will give additional details later. We have trials running in three different forms of hematological cancers.

At the annual meeting of the American Society of Hematology held in December 2021, we released encouraging preliminary efficacy and safety data from our BALLI-01 trial evaluating UCART22 in patients with relapsed or refractory B cell acute lymphoblastic leukemia.

These patients received fludarabine, cyclophosphamide and alemtuzumab as lymphodepletion regimen and provides us strong confidence that we're moving into the right direction.

These results showed that our preconditioning regimen that includes alemtuzumab was well tolerated and promoted the expansion of clinical activity of our UCART22 in patients with relapsed or refractory B sold lymphoblastic leukemia. Currently, in the BALLI-01 trial, we are enrolling patients at the highest dose so far, dose level 3.

We also added alemtuzumab to the preconditioning regimen in another blood cancer clinical trial, AMELI-01 in acute myeloid leukemia.

So, in the clinic, we're moving into 2022, confident in our ability to execute our ambitious new program, focused on product development and patient recruitment into our three ongoing multicenter dose escalation clinical trial – BALLI-01, AMELI-01, MELANI-01.

We also plan to file a new IND for our new product candidate, UCART20x22, for patients with relapsed or refractory non-Hodgkin's lymphoma. With this roadmap, our cash runway takes us into Q1 2024. Let's turn now to the progress we have made in manufacturing.

In 2021, Cellectis made a meaningfully towards becoming one of the few end-to-end cell and gene therapy companies. Back in 2018. Cellectis made the decision to internalize the manufacturing of its therapeutics product candidate, providing the company with independence and stronghold over its cell and gene therapy processes.

We are thrilled to say that this goal has been achieved in 2021. Our two manufacturing sites in Raleigh, North Carolina and Paris, France are both now fully operational. We produce our own cell libraries, our plasmid DNA, our own messenger RNA, we produce two type of vectors, AAVs and recombinant lentiviruses.

We are set up to produce our own clinical grade allogenic CAR T product. In fact, in the second half of 2022, we plan to initiate dosing patients in the BALLI-01 trial with clinical supplies of UCART22 manufactured in-house in Raleigh and UCART20x22 in non-Hodgkin's lymphoma trial. We're becoming self-sufficient in clinical supplies.

This reduces our dependence on outside suppliers. These derisks are passed to the market. This removes bumps into the road. Cellectis is positioned to capitalize on clinical and commercial success of its product candidates. I already mentioned our plan to file an IND of a new product candidate, UCART20x22, in non-Hodgkin's lymphoma.

This is a very exciting product for at least two reasons. First, UCART20x22 will potentially be our first duel-allogenic CAR T to enter clinical trial. It is designed to hit two validated targets in B cell malignancy. The product candidate is also the first product candidate Cellectis has designed in-house, developed in-house and manufactured in-house.

In addition, the power of UCART20x22 is that it goes beyond overcrowded CD19 antigen on B cells. We believe it's a real allogenic CAR T alternative to the crowded of old CD19 targeting products.

I want to say a word now about our partnered product pipeline which remains important to Cellectis as a validation of our technology base and source of future revenues.

In January this year, Allogene announced that the United States Food and Drug Administration has removed the clinical hold on all of the Allogene's clinical trials, which was announced on October 7, 2021.

Allogene reported that, after investigation, it was determined that the chromosomal abnormality detected in some UCART cells of the single patient treated with ALLO-501A was unrelated to TALEN gene editing in B cells.

Allogene has announced that it has resumed clinical studies activities on TALEN gene edited product candidate, ALLO-715 and ALLO-605, targeting BCMA for relapsed or refractory multiple myeloma.

Allogene has resumed clinical studies activities on TALEN gene edited ALLO-316 targeting CD70 for advanced or metastatic clear cell renal cell carcinoma, and began enrolling patients earlier this month. Allogene also announced that it and its partner, Servier, will resume their clinical activities on CD19.

During the 2021 Annual Meeting of the American Society of Hematology in December 2021, Allogene in collaboration with Servier reported that the results from ALPHA and ALPHA2 clinical data continued to support the promises ALLO-501 and ALLO-501A to be safe and durable alternatives to approved autologous CAR T therapy in patients with relapsed or refractory non-Hodgkin's lymphoma.

Allogene announced its intent to initiate a Phase 2 pivotal trial on ALLO-501A in relapsed or refractory large B cell lymphoma is on track to commence mid-year 2022 pending FDA discussion. On the business development front, the utility of selective TALEN gene editing system continued to provide the company with expanded opportunity.

In February 2021, we entered into strategic research and development collaboration with Cytovia Therapeutics to develop TALEN gene edited products in new type of cells, IPS-NK and CAR T NK for series of different type of tumors.

In November 2021, that collaboration with Cytovia expanded to include a new CAR target and development in China by Cytovia joint venture entity, CytoLynx Therapeutics. Financial term include either cash payments and/or equity stake totaling $20 million depending on the satisfaction of certain condition by December 31st, 2021.

Cellectis is in discussion with Cytovia regarding the extension of the deadline for such conditions to be met. The agreement also provides us up to $805 million of development, regulatory and sales milestone and a single-digit royalty payment on the net sales of all partnered product commercialized by Cytovia.

After Allogene and Iovance Biotherapeutics, partnerships that we have signed, the collaboration with Cytovia in another cell therapy modality highlights TALEN as a gene editing technology of choice for cell therapy application. We have also expanded our general management team and board committee with top talent.

Firstly, Cellectis recently appointed Dr. Bing Wang, our new Chief Financial Officer. I would like to take this moment to welcome Bing to our executive committee and to Cellectis.

Bing is a highly accomplished executive who brings extensive global finance experience in the biotechnology industry, including a background with global public companies in corporate finance.

He comes to us from Refuge Biotechnologies, the cell therapy in oncology biotechnology company leveraging synthetic biology and gene engineering, where he was co-founder and the chief executive officer.

Bing's extensive experience in financing clinical stage biotech companies will be critical as we enter our next stage of development of our clinical trials. Welcome to Cellectis team, Bing. Secondly, Cellectis appointed Dr. Donald Bergstrom as an observer on the company's board of director in November 2021. Dr.

Bergstrom brings with him 15 years of experience in the biopharmaceutical and medical industry and serves as Head of Research and Development at Relay Therapeutics, the clinical stays precision medicine company. [indiscernible] clear plan to transform opportunities in cellular biology to the production of multiple focused clinical candidate.

We already have in place of many of the elements that Cellectis needs as its products prove themselves. We have invested in the future and we have the resources to continue to push forward in that future. Now, I would like to turn the call over to Dr.

Carrie Brownstein, our Chief Medical Officer, to give an overview of our three sponsored clinical trials and preclinical product pipeline. Carrie, please go ahead..

Thank you, Andre. As Andre mentioned, 2021 has been a productive year for Cellectis with our proprietary clinical programs making substantial progress.

I would like to start with UCART22, our CD22-directed TALEN gene edited allogeneic off--shelf CAR T cell product candidate currently being evaluated in patients with relapsed or refractory B cell acute lymphoblastic leukemia. We presented preliminary data at the 63rd Annual Meeting of the American Society of Hematology in December of 2021.

The presentation included data from patients who received UCART22 after lymphodepletion with fludarabine, cyclophosphamide and alemtuzumab. Alemtuzumab was added to the fludarabine and cyclophosphamide to deepen and sustain host lymphocyte suppression, thereby promoting UCART22 expansion and persistence.

As of the clinical cutoff date of October 1, 2021, 12 patients had received lymphodepletion, 11 were administered UCART22, of which 6 received UCART22 and fludarabine, cyclophosphamide, alemtuzumab. Three patients at the dose level 2 and three patients at dose level 2 intermediate. UCART22 after FCA lymphodepletion was well tolerated.

No patients experienced protocol-defined dose-limiting toxicities and immune effector cell-associated neurotoxicity syndrome nor UCART22-related severe treatment-emergent adverse events. Three patients experienced mild-to-moderate cytokine release syndrome.

One patient reported grade 2 GVHD of the skin in the setting of prior allogeneic transplant donor stem cell reactivation. Encouraging anti-leukemic activity was observed in two patients in the FCA cohort.

Both patients, one at dose level 2 and one at dose level 2 intermediate, achieved [indiscernible] reductions to less than 5%, 0.4% and 0% respectively, by day 28 accompanied by measurable UCART22 expansion and changes in relevant inflammatory markers.

Overall, UCART22 after fludarabine, cyclophosphamide and alemtuzumab lymphodepletion demonstrated promising signs of anti-leukemic activity without unexpected or significant treatment-related toxicity.

The addition of alemtuzumab to fludarabine and cyclophosphamide was well tolerated, improved host lymphocyte suppression and promoted UCART22 expansion, which was associated with anti-leukemic activity.

These data are encouraging and supports the further development of UCART22 for patients with relapsed or refractory B-ALL, who remain in dire need of additional treatment options, particularly those who have failed CD19 therapy. BALLI-01 is currently enrolling patients at dose level 3 with FCA with the depletion.

Next I'll move on to UCARTCS1, our CS1-directed TALEN gene edited allogeneic CAR T cell product candidate being evaluated in patients with relapsed or refractory multiple myeloma. Early preliminary data from the first patients enrolled in the MELANI-01 trial was presented at the American Society of Gene and Cell Therapy 24th Annual Meeting.

These data validate CS1 as a target for allogeneic CAR T cells in multiple myeloma as UCARTCS1 expansion and persistence was observed and correlated with changes in relevant serum cytokines and with anti-myeloma activity. Cellectis is currently enrolling patients at dose level 1 with FC lymphodepletion.

Lastly, I will speak to UCART123, our CD123-directed TALEN gene edited allogeneic CAR T cell product candidate, being evaluated in patients with relapsed or refractory acute myeloid leukemia. This trial addresses a patient population with severe unmet medical need where a successful CAR T cell product candidate could be a major breakthrough.

We are currently enrolling in our Phase I dose escalation trial with FCA lymphodepletion. Enrollment at dose level 2 is ongoing. We look forward to sharing data from this program when it becomes available.

Building on the technology platform of our current proprietary clinical programs, I'm excited to report that we plan to submit an IND for UCART20x22, our first allogeneic dual CAR T cell product candidate for patients with B cell non-Hodgkin's lymphoma in the second half of 2022.

CD20 and CD22 are both well validated targets in B cell malignancies and represent a therapeutic alternative to CD19-directed therapies. Targeting two antigens has important advantages. Firstly, it has the potential to increase efficacy by strengthening the contact of the CAR T cells with the tumor cells for more effective killing.

Secondly, it increases the breadth of antigen targeting and, therefore, may increase the addressable patient population. And lastly, it provides potential to overcome antigen escape. Preclinical data supports moving UCART20x22 into the clinic and I'm very excited to start the clinical trial for patients with relapsed/refractory NHL.

With that, I would like to hand the call over to Bing Wang, Cellectis' Chief Financial Officer, for an overview of our financials. Bing, please go ahead..

Thank you, Carrie. And good morning, everyone. I'm pleased to be here and thank everyone for the warm welcome. I will provide a brief overview of our financials for the fourth quarter and full year of 2021.

I would like to highlight that the cash, cash equivalents, current financial assets and restricted cash position of Cellectis, excluding Calyxt, as of December 31, 2021, was $177 million compared to $244 million as of December 31, 2020.

This difference mainly reflects $116 million of net cash flows used in operating, investing and least financing activities, which were partially offset by $45 million of equity proceeds raised from the sales under the company's at-the-market program established in April 2021 and $10 million proceeds from stock option exercises.

This cash position is expected to be sufficient to fund Cellectis standalone operations into early 2024. The net loss attributable to shareholders of Cellectis, excluding Calyxt, was $97 million in the full year of 2021 compared to a loss of $54 million in 2020.

This $43 million increase in the net loss between 2021 and 2020 was primarily driven by a decrease in revenues and other income of $21 million and by an increase in operating expense of $40 million, partially offset by $18 million increase in net financial gain.

The consolidated net loss attributable to shareholders of Cellectis, including Calyxt, was $114 million or $2.55 per share in the full year of 2021 compared to a loss of $81 million or $1.91 per share in 2020.

The consolidated adjusted net loss attributable to shareholders of Cellectis, excluding non-cash stock-based compensation expense, was $102 million or $2.27 per share in the full year of 2021 compared to a loss of $67 million or $1.57 per share in 2020. In 2022, we are focused on spending our cash on developing our core programs.

This allows us to extend our cash runway, excluding our subsidiary, Calyxt Inc., into early 2024..

Thank you, Bing. To close this call, I would like to reiterate how excited and proud we are of what's Cellectis has accomplished in 2021 and how the success propels us forward into 2022.

More than 170 patients with relapsed or refractory malignancies have been administered with TALEN-edited allergenic CAR T cell product candidate built on Cellectis technologies in trials sponsored by Cellectis and its licensed partner, with a promising safety profile, making the largest and the most robust, disclosed clinical data set of any gene editing technology in the world.

Our products and clinical development, with the diversity of targets and indications as well as our allogenic UCART platform, positions us at the forefront of developing novel CAR T therapeutics that ushers in the next generation of cancer therapy.

We continue to leverage our expertise in gene editing and clinical development to transform the lives of patients with cancer and rare genetic diseases. And we look forward to accelerating this momentum in 2022 and beyond.

At Cellectis, we strongly believe that our product candidates, our technologies, and our in-house manufacturing capabilities will lead us to a paradigm shift for patients with hard-to-treat cancers positioning us at the forefront of this promising medical and scientific field. With that, I would like to open the call for Q&A..

[Operator Instructions]. Our first question comes from Yigal Nochomovitz with Citibank. .

On UCART22, you're moving from the CRO product to the in-house product in the second half of the year.

Could you just talk a little bit about the comparability between those two products, whether the FDA has signed off on the comparability and presumably you will need an IND amendment to start the studies with the in-house version?.

This is Arthur.

Andre or David, you want to take this one?.

So, we have already started the conversation with the agency as for how we will compare the P2 product, the one made in Raleigh and the one that we've been using so far that was originally made out of CMO, CELLforCURE. So, this is an ongoing conversation.

And we're very confident we'll come to the definition of an appropriate means to do that swiftly..

Regarding the three Phase I datasets that you're working on, at this point, are you able to give any more granularity on which of those we might see data for in 2022?.

We're definitely in the process, as announced by Carrie – this is Arthur – to go through the various escalation datasets of these trials.

We're not committing in particular to giving data on one specific program as we would want to get a meaningful data set – a meaningful clinical data set prior to sharing at a conference as we have done for UCART22 at ASH last year.

But what is safe to say is that we will definitely provide an update on at least one of these programs in the course of the year, if not more, depending on how data matures over the course of the year..

And last question. Obviously, the CD 20x22 is a very, very interesting product.

Can you talk at all about what other combo CARs you might be contemplating beyond 2022?.

No. Actually, if someone wants to answer. This is Andre answering the question. So, listen, I think this strategy that Cellectis is in today, I think it's going to have – go into a very interesting payoff.

Probably people have been criticizing us on the fact that we're on unvalidated targets, even if we don't consider that these targets are unvalidated, such as 22 123, CS1 or 20x22. But we have very interesting positioning to develop and commercialize these products. They're not 19, they're not BCMA.

This is a great positioning because we don't have to face, for example, the product such as the BCMA products competition or 19 competition that is already commercial and we have a different type of angle.

So, disclosing the next product we're going to develop is probably going to tip our competition, and this is not something I think would be wise on our side to disclose.

We'd like to have all your attention on 2022 and the data releases that we're going to happen this year, as Arthur had said, because we believe that we're in a very good place concerning the development of these type of products so far. So, this is the thing that excites us.

But disclosing what's going to happen in the future for dual target that we believe is a very interesting approach for numbers of reasons, first, for potentially lots of targets, but also for enhancing the tumor associated antigen density and the formation of [indiscernible] to have a better killing of these products is something that would be crucial and potentially also increase the safety and the performance of these products in general..

Our next question is from Gena Wang with Barclays..

I have two. The first one is regarding UCART22 in-house manufacturing. Can you lay out the steps you need to complete in order to start dosing in-house product? My second question is regarding UCART20x22.

Just wondering any updated thoughts on initial doses based on the UCART22 data?.

I think the first question may be for Steve and the second question for Carrie..

This is Steve. In Raleigh, in terms of the UCART22 produced in-house here in Raleigh, we've already done so. The clinical materials have been produced and analytical testing is ongoing, as well as preparations for an IND amendment. So we're well on track to be using that material in the second half of the year..

Sorry, what's the second question again with the doses for 20x22?.

That's correct.

Any updated thoughts on initial doses?.

Yeah, I'm not going to provide details on what the clinical trial design is going to look like. When we start the trial and it's in clinicaltrials.gov, you'll see, but we have lots of data from both internal and external data to help support where we start.

And hopefully, given that it's a very well understood patient population and space in terms of CAR T cells with NHL, we have a lot of data to help support where our starting dose will be and potentially could help expedite the trial. .

Our next question is from Kelly Shi with Jefferies..

This is Dave on for Kelly Shi at Jeffries. My first question is on CAR T 20x22.

Just wondering, in your clinical trial design, are you thinking of enrolling both CD19 naïve and relapsed patients?.

I can take that. So, we're thinking about enrolling a broad patient population to start because that always helps expedite clinical trials. And then, based on what we see, we would make decisions on how we would expedite moving things forward in one or more specific subsets. .

Another one is on your solid tumor program.

Do we expect any update during the course of this year?.

I can start. This is Arthur. So, basically, what we've announced is here is a focus….

Actually, it's a good question. As we announced it, given the hyperfocus of the company today on our three clinical trials and 20x22, IND and start of the development, there will be probably some scientific conferences with the development of certain solid tumor products that are currently still in R&D and shelf.

But the fact is that the strategy of the company is trying to push as hard as we can to get these products rapidly into expansion, pivotal trial for product that we're considering.

And we'll see how the market evolves and the global situation evolves, the pressure that we have – that external pressure on the international situation and the market conditions and the market conditions for selling gene therapy space before we can reconsider pushing these type of products into clinical trial.

We're extremely excited by these candidate products that we have. Very, very excited, but we have to choose our fights. And we think that the most mature product that we have, all of them huge potential.

And I think it's in the interest of our shareholders and the company and, of course, the patients to put all our power into developing these hem-onc product that we have..

Our next question is from Raju Prasad with William Blair..

I just had a quick question on the CD52 conditioning regimen. I know Allogene has to run a trial to show the impact of CD52 on engraftment.

Is that something that you anticipate having to do? Have you had any discussion with the agency on any conditioning trials you may have to run?.

Sorry, I could start. If anyone else wants to chime in. I think that – oh, okay. Sorry, it looks like the folks in Paris got disconnected. I can take this. So, it's a little bit different. I'm not going to speculate here what we may or may not need to do for our BLA filings.

But, remember, the Allogene program is using a different anti-CD52 antibody, which is their own proprietary ALLO-647, which is not a product that's ever had a marketing authorization anywhere. So, it's a little bit of a different situation. But, obviously, as we move forward with development, we'd have these discussions and see what we would need.

But I think what we're doing right now is we've already looked at, in all of our trials with them, that we're using the alemtuzumab with and without the antibody. And I think there's – as we showed at ASH in December, there's strong data to support that we're not seeing expansion and persistent without it.

And personally, I would find it unethical to continue dosing without it, but that would be something we'd have to discuss as we move forward with our development plans. .

Just curious, as you get data from the 20x22 product kind of in concert with the 22 product, how are you thinking about making decisions on pivotal trial and how to move forward? Are you planning right now to kind of move both products forward? Or would there be kind of a decision point at some point, maybe next year or following year?.

Yeah, I think that's a really interesting question because, obviously, given what we're talking about with 20x22, it could potentially also be working not just NHL, but in, for example, ALL, but I think as it is right now, given we have UCART22 and we're moving it forward in ALL, we would likely continue to move that forward for this niche patient population that has high unmet medical need as a separate product.

But, again, those are conversations and discussions we would have as we move forward with both programs..

Our next question is from Jack Allen with Baird..

I have two quick ones here. I guess, first, on the clinical side of things, I was hoping that you provide a bit more color on your progress with the CS1 candidate.

Sounds like you've moved it in dose level 1, but I'm curious as to how many patients maybe you've dosed in dose level 1 and, I guess, maybe any color you can provide around the totality of that cohort and your plans to move on to dose level 2.

And then, on the financial side, I was hoping you could just lay out a little bit around the timing of potential milestone payments that we could see in the coming year. I think ALLO-615 just moved into the clinic. And then, they do have that ambition to initiate a pivotal study in the middle of next year.

So, I'd love to hear any color on those milestone payments. And then, any comments on milestone payments from the other collaborators as well, Iovance and Cytovia..

It's Carrie here. I could start with the questions about the CS1 program. So we are moving ahead with the UCARTCS1 program in myeloma. And we have disclosed that we're in dose level 1. I'm not going to speak to how many patients and when we're going to plan on getting into the next sets of data.

I think suffice it to say we have extremely excited investigators, there's still high unmet medical needs. As you know, we did come off a clinical hold and we had previously disclosed that there's some long waiting periods in between patients and things that were required by FDA.

And so, we're moving through it as quickly and expeditiously and safely as we can and hope to provide a data set for external disclosure when we have a reasonable data set worth sharing, and probably add a pivot point for when we would potentially be starting to move more quickly, like in an expansion of some sort.

And I will now pass it on to Arthur and Bing for the financial questions..

Jack, for the milestone payments, so basically, first of all, on the Servier, Allogene collaboration on CD19, we're definitely eligible for a milestone payment upon the initiation of the pivotal trial, which Allogene had guided for mid this year. And we haven't disclosed the size of the milestone payment, but there will definitely be one.

To the other partnerships, again, we haven't disclosed either the terms of the Iovance collaboration. But for Cytovia, this is going to be with the recent amendments, up to $805 million of milestones. And we're also getting an equity stake of $20 million into Cytovia stock.

And so, we expect that, as Cytovia progresses these products in the coming months, we will start seeing some economics..

Our next question is from Hartaj Singh with Oppenheimer & Company..

Two questions. Just a quick question on the manufacturing. Just going back to that, I think you had highlighted previously you might have to do an IND for 22 from the Raleigh facility.

Will that then set you sort of – as you go through clinical trials and hopefully get ready to file a BLA, will you be set sort of on the clinical manufacturing side of the potential BLA at that point after doing this IND? And then, secondly, in that same vein, would you have to – assuming you can enroll CS1 and 123 and get materials from the Raleigh manufacturing facilities, might you have to do future R&D there if you were to convert using the Raleigh manufacturing facility?.

Steve, you want to take this one?.

In terms of UCART22 being produced from Raleigh, that's going to be an amendment to the existing IND because it's considered a major change in the manufacturing when you move from one location, namely a CDMO, to internal manufacturing. So there will be an IND amendment.

And on BLA as a future state of course, dependent upon where we are in the clinical trials and how well they progress. But, yes, we are very hopeful this would progress at some point to a BLA. But for 22 at the moment, the focus is on submitting an IND amendment to enroll Raleigh as the manufacturing site..

And then, just on CS1 and 123, would you ever consider moving those, producing them in the Raleigh facility?.

Yes, we're planning to do this, of course..

Just last question….

They are next in line, both of them..

And your dual-targeting CARs, do you see those in the future with 20x22 and then others being more competitive against the current CAR Ts, so that'd be sort of a second generation kind of approach with CAR Ts – with dual CAR Ts or do you see it as sort of moving a little bit more further along and kind of going up against the bispecifics, which some people believe might be a bridge to CAR T.

[indiscernible], but just any thoughts there. .

From a development perspective, I'm happy to take it. I think that, again, a lot of where you were going to end up positioning these programs and these products in the market space is going to be dependent on the data.

I think what's extremely important to recognize when we're talking about allogeneic CAR T cells versus the current autologous space is that I don't know if competition is the right word, but, again, given their easy accessibility, the fact that they're in the clinical ready, they're in the freezer, you don't need to wait for manufacturing between patients.

It changes the entire paradigm of treatment for CAR T versus the autologous space.

So, while the autologous space has been great and has been more of a kind of a second line or after, as you said, the bispecifics, I think provided these data are strong enough, I think that we don't need the specialized centers and, and, and, and, even if data isn't as strong, let's say, as – which I think it will be, but let's say it's not as strong as an autologous 19 or something, I don't think that's going to matter.

I think the fact that physicians can get their hands on it and give it to patients quickly is going to be huge and really change how the treatment paradigm is set up from standard of care purposes, so to speak, from all of the key players who are treating patients. So, I think, again, it'll depend on the data.

If the data, obviously, aren't as strong, then maybe it would come after. But I think our positioning is going to be as strong as possible based on the data.

And then, you have to also remember, when we're looking at data and comparing, it's actually more helpful to almost compare against bispecifics versus the CAR Ts because, remember, when you look at the data and the labels for all of these autologous therapies have been approved, their denominators are based only on patients who've received cells and they throw out all of the patients who either they had a manufacturing failure or it was an out-of-spec product or that the patient progressed prior to getting treated.

And so, if you actually redo a lot of those numbers, the response rates and PFS and everything, it's just much, much, much lower than what's in the label. And so, we need to be extremely careful when we're comparing. And that's part of the reason those CAR T cell therapies look so much better than bispecifics as well. So, yeah.

So, I think we could be clearly in any position, which is what makes this so exciting..

Thanks for all the updates and the wood that you're chopping on the manufacturing side..

[Operator Instructions]. Our next question is from David Dai with SMBC..

Congrats on the progress. I have a question on your CAR T 123. We know that your CAR T 123 is an updated product with new constructs and new manufacturing process.

Could you just share some additional color on the changes on the construct, also the manufacturing process?.

This is David. So we did evolve UCART123 to incorporate the CD52 knockout and that allows us to explore this adaptation, including alemtuzumab which is what we have disclosed. And that was a major change in terms of molecular constructs.

We also evolved the process itself, taking into account all the teachings that we had gained from working with UCART22 and UCARTCS1. In a nutshell, we are basically producing a much, much better product. And we think it's much more robust and reproducible so far.

So, I won't get into the details of the process evolution, but those are the elements that we can share at this stage..

Just as a follow-up, if you could just provide some quick update on the in vivo programs, maybe share some additional color on the timing of potential IND filings for those in vivo programs?.

I'm not sure what you're saying about the in vivo programs because we definitely have plans in this space.

But I'm going to reiterate the fact that, in the current situation and the roadmap that we have currently, we're putting 100% of our focus on the four assets we have, UCART22, UCART123, UCARTCS1 and UCART20x22 that we believe have a huge traction, are exciting and mature product.

We are extremely excited and interested also in in vivo approaches using TALEN or TALEN-based editors also potentially for different types of applications because we have a fantastic technology on base editing because it's a split activity between the two arms of TALEN that has a very high accuracy. And we're excited about that.

But today, in the current situation and the current market conditions, et cetera, all the focus of the company is on these four trials. When the situation will improve, resume, et cetera, of course, we'll put the pedal on the metal on these in vivo programs.

And today, they're essentially developed at the R&D stage that is perfecting and polishing and finessing all of these programs..

Our final question is from Silvan Tuerkcan with JMP Securities..

I just had two quick questions. I don't know if you can comment on this. But on UCART123, I believe the last comment was that you are looking to enroll in dose level 2.

Could you just give us some color on where you're at in terms of dosing on that program?.

This is Carrie. I can speak to that. Again, we are not disclosing exactly where we are in terms of number of patients and which dose levels. Other than that, beginning of this year, we're starting at dose level 2, we've been working on filling out that cohort and we'll continue to move forward as the time goes on.

And when we have a reasonable data set to share and we're ready for the next stage, we'll be sharing data..

And on UCART22, I think there was going to be an additional data cut this year.

And is there any chance that this could have some of the new material from the Raleigh facility in the data? Or do you think that that's premature?.

As Arthur spoke to earlier in the call, we actually haven't disclosed per se exactly which dataset we'd be sharing this year. We will share data on at least one of the programs, but we did not specifically speak to it being 22 or not.

As I've said with all of the programs, I think it's really important that we share/disclose datasets when there's a meaningful data set that's giving us the support to move to the next stage and not just be giving dribs and drabs over time because we fill the cohort. So, that's not something that I want to do.

So, we will be figuring out which will make the most sense based on where we are and what the meaningfulness is of the set at the time..

We have reached the end of our question-and-answer session. I would like to turn the call back over to management for closing comments..

Well, thank you very much. And thank you for all the attendees for our earnings call this year. We're extremely excited. We're excited by 2021, which was a very productive year for Cellectis because we've been pushing on our three clinical trials. And also, one thing that is transformative for the company, it's a different company in 2022.

We're now producing our own IMP from A to Z. And this is convertible to producing pivotal product and convertible to commercial in the future. And this is a huge change for Cellectis. You know the history of the company, how much difficulties we had in the past with certain products that were produced at CMOS.

But today, it's a different type of Cellectis that you have. We're entering into a very interesting phase into all our clinical trials. And 2022, I cannot be more excited about what's going on in the company and for this year. I hope that we will be sharing very exciting and interesting data in the coming future.

And passing this step, Cellectis is unstoppable. With that, I would like to thank you all and wish you a great day..

Thank you. This does conclude today's conference. You may disconnect your lines at this time and thank you for your participation..