Welcome to Biotechr

Biotechr is written by Dr. Robert Kruse (@RobertLKruse), who holds a PhD and is currently completing his MD. His research work focused on infectious disease and immunology. This blog is focused on analyzing the latest developments in biotechnologies being developed in academia and industry, with a particular focus on biomedical therapeutics. I hope that the posts are interesting and useful, and hope you join in the discussion with guest posts on the site!

Disclaimer: The thoughts on this blog are not intended as any investment advice regarding any companies that might be discussed, and represent my opinion and not the opinions of my employer. This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual.

Friday, December 11, 2015

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.

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