Does Cellectis have an infection problem?

by Robert Kruse

Cellectis ($CLLS) has sparked much interest among investors, scientists, and patients for the allogeneic CAR T cell therapy platform. It offers the potential for a centralized manufacturing of T cells at a single site, and then distribution of frozen vials around the world to hospitals to infuse locally to cancer patients. The manufacturing, distribution, and payment model fits well within pharmaceutical paradigms today. This contrasts with the autologous approaches being pursued by Juno ($JUNO), Kite ($KITE), and Novartis ($NVS) for their CAR T cell therapy platforms.

The Cellectis strategy consists of a few key elements: (note I will focus on their lead UCART19 product and not their other proposed strategies. more information here).

1) Knockout of the TCR genes removes the ability of allogeneic cells to bind to host MHC class I molecules and become activated, attacking host tissue (graft versus host disease). Another human's T cells will not have undergone thymic deletion to your different set of HLA molecules, which is the biological reason behind this discrepancy.

2) Knockout of CD52 in transfused allogeneic cells allows the use of an anti-CD52 antibody (Alemtuzumab) to kill host T cells, providing an ongoing selective advantage for the transfused T cells, and also to prevent host T cells from attacking those T cells.

3) General chemotherapy and lymphodepletion, like the UPenn and Novartis protocols, helps CAR T cell homeostatic expansion, but also in the case of Cellectis, helps protects their cells from other immune effectors, which would recognize the varied MHC class I molecules on the infused product surface as foreign.

4) Suicide gene in addition to CAR T cell expression for additional safety feature to eliminate the T cells

5) Cellectis has an opportunity in the market for patients whose chemotherapy has rendered their cells ineffective donors. Having healthy T cells from another human being should be a major advantage in this instance.


There are potential issues with this approach that I have yet seen discussed among press releases by the company and other scientific commentary. Prominently, I see the potential for the Cellectis strategy to make the patient highly susceptible to infections, mitigating the ability of the therapy to achieve its endpoints.

Before the start of therapy, the patient is conditioned to remove most of their current immune cells. This lymphodepletion leads to loss of T and B cells fighting infection. CAR T cell therapies right now are similar to patients undergoing bone marrow transplants. When one infuses the allogeneic CAR T cells, these cells aren't matched to the patient's HLA molecules, so can't recognize any viral peptides inside host cells. Indeed, the CAR T cells don't even have TCR molecules even if Cellectis did try to match donor CAR T cells to patients' HLA types. During the provision of cancer therapy, the patient must constantly be in an immunosuppressed state in order to avoid Cellectis' CAR T cell destruction by the host immune system, which alternatively makes the patient highly susceptible to infections. The T cell population in the patient is mostly incapable of the regular job of surveying peptides inside cells, presenting major potential issue in the clinical management of these patients, who could perhaps require hospitalization during the duration of their CAR T cell treatment while immunosupressed, causing the costs of the procedure to skyrocket, in spite of the initial allogeneic manufacturing costs being much cheaper. I am making an assumption here that the UCART19 clearance of cancer will take 20-30 days, similar to the autologous trials from UPenn. In the UPenn trials, the most monitored time is just the first few days for cytokine release syndrome, but otherwise the patients can leave the hospital after emerging from this window and return as necessary.

Contrast this with the approach of Juno, Kite, and Novartis. The patient is lymphodepleted, but the infused autologous CAR T cells are polyclonal in their TCRs and should have the capacity to fight off any infections, in essence, re-constituting the immunity to pathogens in addition to their tumor fighting capabilities.

A solution that Cellectis or any other company could pursue is a compromise of the two models. The answer is possibly found with Bellicum's ($BLCM) strategy of infusion allogeneic haploidentical T cells in order to provide infection protection in bone marrow patients, and some measure of graft versus host disease. It could easily be imagined that these haploidentical cells retaining TCR genes could be manufactured with CAR T cells. A bank of CAR T cells could be created with various HLA types, and then infused into patients with some partial HLA matches in order to provide a measure of limited infection protection. Of course, these partially HLA-matched T cells would likely cause some measure of GVHD in some patients meaning that a safety switch would be needed (Cellectis has their own safety switch for this purpose). As an aside, this proposal is different from allogeneic (but not off-the shelf) CAR-T cells that are made from donor T cells after an allogeneic transplant, with some data recently presented at ASH here. Furthermore, lymphodepletion would still be necessary in the protocol to protect the proposed allogeneic T cells from being recognized as foreign. Nevertheless, this strategy of using partially HLA-matched allogeneic T cells as the CAR T cell effector would solve the infection problem and permit a safer and more judicious use of allogeneic products for cancer immunotherapy.

Final Thoughts on Bluebird Prior to ASH

Here's what I'll be looking for in the ASH data bluebird bio will present over the next week. I thought it was worth a short post since there has been some new and relevant data relating to the BCMA CAR-T program partnered with Celgene, and also there was some confusion before/during their Piper Jaffray presentation over the path forward with LentiGlobin. I previously wrote a more detailed post on the data in the ASH abstracts for bluebird's LentiGlobin gene therapy product here.

LentiGlobin in B-Thalassemia
My main focus for B-Thalassemia will be how the new data influences the development path forward. Bluebird presented at the Piper Jaffray healthcare conference where they tried to clear up some confusion over whether the development path for LentiGlobin had changed. The confusion came from an investor meeting prior to the conference (link). Bluebird reiterated that its development path had not changed. They added that they are constantly trying to improve their products, and they look at minor changes that can be incorporated into the current program, as well as other changes that might be for "next-generation" products that would require a new IND.

Just as a refresher, in May, bluebird gave an update on their regulatory path forward in June after discussions with both EU & US health agencies (link).

For the EU, they believe they could apply for conditional approval based on their current HGB-204 & 205 studies, which are expected to complete enrollment soon. Importantly, the proposed primary endpoint would be transfusion reduction. For the US, they believe they could apply for accelerated approval based on their pivotal studies HGB-207 and 208, which have yet to be initiated (15 B-Thal patients per study), with accelerated converting to full approval based on longer term follow-up data. For the US, the proposed primary endpoint is transfusion independence. While this was the current thinking in May, the plans were subject to change with further data and discussions with regulators.

Considering the consistent ability, so far, of LentiGlobin to induce transfusion independence in non-B0/B0 B-Thalassemia patients, but not B0/B0 patients, bluebird has mentioned the possibility of developing the product differently for these 2 populations. However, bluebird emphasized it was still too early to be making decisions yet. To completely speculate with this in mind, and the above regulatory outlook, I could see bluebird developing LentiGlobin, as is, for the EU since transfusion reduction is the proposed primary endpoint, and LentiGlobin should cause reduced transfusions in B0/B0 patients as well. For the US, I could see them splitting off the B0/B0 patients, and focusing on the non-B0/B0 patients, which they say are 2/3rds of the addressable population. If, later, they can improve the amounts of T87Q hemoglobin LentiGlobin treated patients produce to consistently 8+ g/dl with either future production tweaks or follow-on products, then I could see them going after the B0/B0 genotype again, with the goal of consistent transfusion independence.

So with this in mind, what I'll be looking for in the B-Thalassemia data from their ASH data is - are 100% of the non-B0/B0 patients transfusion independent (or trending) by 1 year post-treatment, and what is the level of transfusion reduction in B0/B0 patients?

LentiGlobin in Sickle Cell Patients
There has not been as much recent discussion about LentiGlobin for sickle cell disease (SCD), but I'll be looking for longer follow-up on the 1st treated patient on clinical & blood endpoints, and their current T87Q level. I would not expect much of an increase in T87Q at this point, as I've mentioned in previous posts, however, the ~50% T87Q would seem likely to be sufficient for significant clinical benefit.

There will also be a poster presentation with data on at least 2 new patients treated with LentiGlobin. These patients were treated with a lower cell dose than the first patient, and also one patient had a lower vector copy number (VCN) in the drug product. So I will be looking for the levels of T87Q these patients have been able to produce, both in terms of the total amount of T87Q and the relative amount of T87Q to sickle hemoglobin (HbS).

Bluebird has also suggested that they have been performing assays to determine the percent of modified cells, in addition to just giving the average VCN across all cells. This is another way to measure how well they are able to transduce the CD34+ cells with the LentiGlobin vector in their drug product, and potentially track the levels in the patient. I could see this being a useful number to know, particularly for SCD, where in hematopoietic stem cell transplants (HSCT), mixed chimerism can occur, with data suggesting that you only need 10-30% of HSCs to be corrected to functionally cure a patient. I previously wrote about mixed chimerism and other considerations for LentiGlobin in SCD in more detail with Zack, @BioTerp, which can be found here. How much a single copy of the LentiGlobin vector can protect a red blood cell from sickling is unknown, but is likely to be at least somewhat beneficial based on levels of fetal hemoglobin of 30% being known to be protective.

BCMA CAR in Multiple Myeloma
The importance of ASH data for Bluebird's BCMA CAR program has increased, as an additional late-breaking abstract will have 1st in human clinical data of a different BCMA CAR in a phase I trial at the NIH - to be presented on Tuesday December 8th.

This study comes from James Kochenderfer, whom bluebird has a cooperative research agreement with. I believe bluebird has licensed the BCMA patents from the NIH as well. The BCMA CAR used in this program does have some differences from the one bluebird will use, but considering the relative consistency of the data across different CD19 CARs (CD28 or 4-1BB), there is significant read-through to bluebird's program (comparison of different BCMA programs). In the NIH study, the CAR has a CD28 costimulatory domain, versus the 4-1BB domain bluebird is using. Importantly, in two patients at the highest cell dose given, both had responses, with one patient achieving a complete response. It will be important to see how durable these responses are, and if any additional patients have been treated at this dose, although not much time may have elapsed from when this abstract was submitted. The cytokine release syndrome seen in both patients who received this cell dose is still significant, but was considered similar to those seen in CD19 CAR treated patients. This is probably the most crucial safety parameter I'll be keeping an eye on. I could see this presentation getting substantial attention at ASH, as the expansion of CAR-T therapies beyond CD19 has been a big open question.


Bluebird has mentioned the study in recent webcasts, and I expect them to try to use it to draw excitement to their program. Bluebird itself has 3 poster presentations at ASH on their BCMA program (1, 2, 3), however, I would say none of them really adds that much new data to what they've already presented. On using CD28 versus 4-1BB as a costimulatory domain, it is still too early to tell the differences in safety or efficacy yet for CD19 targeted CARs. A recent preclinical paper suggests that on a per cell basis, CD28 costimulatory cells have greater tumoricidal activity whereas 4-1BB costimulatory cells have better persistence. In the clinic, results using either costimulatory domain have been impressive, but it's still too early to tell if either has an advantage - reviewed here. Despite the potential differences in the CAR construct, my confidence and interest in bluebird's BCMA program has increased after the release of this new abstract, and I will be very interested in any updates from the NIH trial.


Competing Approaches in B-Thalassemia and SCD
Lastly, a big thing I will be keeping an eye on at ASH are data from other approaches in B-Thalassemia and SCD. Specifically, I am interested in clinical data from Bellicum on their approach to make allogeneic HSCTs safer (including in B-Thalassemia and SCD), clinical data from Global Blood Therapeutics on their small molecule drug for SCD, and preclinical data on a different gene therapy approach for both diseases by Sangamo. I discussed them a bit more in my previous post on ASH abstracts. Additionally, Timothy Sullivan had a very good post on Bellicum's approach here. One interesting way bluebird could improve the safety of their approach compared to even the presumably improved-safety allogeneic approach of Bellicum would be to change their conditioning regimen, such as depleting only CD34+ cells, instead of myeloablation with busulfan. This might improve some of the negative effects of the conditioning regimen, such as immune recovery. Bluebird has mentioned this as a possibility, so it will be interesting to follow any potential updates on that, however, this would be a significant change and would certainly be a follow-on product requiring separate clinical development.

Edit: @BioTerp also reminded me about additional similar approaches using viral transduction of HSCs with a hemoglobin (or modified hemoglobin) expressing vector - one being developed by Donald Kohn, whose lab has published many preclinical papers here, as well as another from MSKCC with economic partner Errant Gene Therapeutics. Although I do not believe there will be new data from either group presented at ASH.

Conclusion
There will be a lot of new information coming out of ASH to consider for bluebird - new LentiGlobin data, 1st in human BCMA CAR data, as well as early data from other competing approaches. I'll be looking for more clarity on the development pathway for LentiGlobin, and the consistency of the results given the current treatment protocol. I think the BCMA CAR data from the NIH program might generate additional focus on bluebird's program, and it will be interesting to see how bluebird tries to frame that data in the context of their program.






Disclosure: I own shares of BLUE, BLCM, SGMO