Could next-generation “switchable” CAR-T cells help improve the safety and efficacy of CAR-T therapies?

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Switchable CAR T

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No one can doubt that chimeric antigen receptor (CAR)-T therapies have had remarkable success in treating blood cancers. But as the years have passed since their initial approval, questions have arisen regarding both their efficacy and safety, particularly when it comes to “off-tumor, on-target” effects and the possible link between certain CAR-T treatments and T cell malignancies in patients taking them.  This is why some companies have started to look at developing “next-generation” CAR-T therapies – in other words, treatments that can overcome these current limitations. 

One such area of exploration for the creation of these so-called next-gen CAR-T therapies is “switchable” CAR-T cells, which essentially offer more control over the activation of CAR-T treatments. In this article, we take a look at how these cells work to improve both the safety and efficacy of CAR-T therapies, as well as the current clinical landscape around switchable CAR-T cells.

Table of contents

    How switchable cells can improve safety and efficacy of CAR-T therapies

    Standard CAR-T therapies, like those that have already been approved to treat hematological cancers, consist of the infusion of engineered T cells that carry a CAR on the cell membrane. The external domain of the receptor is designed to recognize specific molecular markers on a tumor cell and, when this happens, the internal signaling domain of the molecule is activated, stimulating the T cell’s innate cytotoxic weaponry to destroy cancer cells. 

    However, once given to the patient, these treatments proliferate and kill tumor cells over weeks to months, with no way to control them or turn the dose up and down. This uncontrolled proliferation can potentially trigger cytokine release syndrome (CRS) – the release of inflammation-causing signals throughout the body that can cause toxicities ranging from mild fever to life-threatening organ failure.  

    There is also the risk of “on-target, off-tumor” effects with traditional CAR-T therapies, as most therapeutic targets happen to be tumor-associated antigens that are expressed at low levels on healthy cells. Ultimately, the engineered CAR-T cells end up mounting a direct attack on normal tissues that express the same antigen as the tumor cells, provoking destructive and life-threatening immune responses that are challenging to control. 

    And, in terms of efficacy, the immunosuppressive conditions of the solid tumor microenvironment can push T cells, including CAR-T cells, into a state of dysfunction known as “exhaustion”, limiting the actual effectiveness of the therapy. 

    Switchable CAR-T cells look to overcome these limitations through their ability to be switched on and off after they have been administered to the patient, meaning they are not constantly proliferating in the body, and the amount of CAR-T cell activity can be controlled, potentially from day to day, helping to reduce toxic side effects.

    Greta Maria Paola Giordano Attianese of the Lausanne Branch of the Ludwig Institute for Cancer Research commented in a recent press release about switchable CAR-T cell research conducted by Ludwig Cancer Research that, not only would switchable CAR-T cells improve the safety of this type of therapy, but the remote control of CAR-T cell activity “could also be used to mitigate T cell exhaustion, improving the durability of patient responses to the therapy.”

    But how exactly do you switch CAR-T cells on and off once they are inside the body?

    Well, different methods can be used, but generally speaking, it involves giving the patient a separate administration of another substance – whether that be an existing drug or a novel antibody, for example. The presence of this substance is then an indication to the CAR-T cells that they should activate – or “turn on” – and start killing the target antigen. Otherwise, the CAR-T cells simply stay dormant (“switched off”) in the body.

    Switchable CAR-T candidates in the clinic

    Several studies have already shown that switchable CAR-T cells could be a great step forward for the safety and efficacy of future CAR-T therapies. And, when it comes to testing these types of CAR-T cells being tested in the clinic, there are currently two frontrunners that are leading the pack, both of which currently have candidates in phase 1 trials. 

    Calibr reports promising results for its switchable CAR-T therapy

    Calibr, a division of Scripps Research focused on the “bench to bedside” development of transformative medicines, has a lead candidate that combines its CLBR001 switchable CAR-T cells, which are “universal” – meaning they are not targeted at a specific antigen when they go into the body – and companion antibody SWI019, which acts as a switch when administered, directing the CAR-T cells (in this case) to CD19 antigens on B-cell cancers. When SWI019 is absent, however, the CAR-T cells are dormant. 

    In an initial phase 1 readout for this therapy in 2022, Calibr reported very promising results. Out of the nine patients treated in the study, seven (78%) showed a response to the treatment, with six (67%) having a complete response. Furthermore, most responses came after only a single dose of the CAR-T cells and antibody switch. Given that patients had already experienced around five prior lines of therapy, the efficacy of Calibr’s CAR-T therapy was considered to be extremely impressive. 

    It also came without an increase in CRS or immune effector cell-associated neurotoxicity syndrome (ICANS), another side effect seen with current CAR-T therapies. Patients who did experience CRS or ICANS had a shorter duration of these events, limited to around two or three days, compared to five to 17 days for patients who took currently approved CD19-targeted CAR-T therapies. This is largely because SWI019 has a relatively short half-life to minimize the risk of such side effects.

    Calibr’s therapy received fast track designation from the U.S. Food and Drug Administration (FDA) in 2020, and is being developed in partnership with AbbVie. The two have a long-standing partnership, the scope of which was recently expanded again to develop novel cell therapies for solid tumors and autoimmune diseases. There are also plans for Calibr to expand its switchable CAR-T platform into solid tumors. 

    AvenCell secures funding to test its switchable CAR-T cells in the clinic

    Created by Blackstone Life Sciences, Cellex Cell Professionals and Intellia Therapeutics, AvenCell launched with $250 million in 2021, already armed with universal CAR-T platforms from Cellex and CRISPR/Cas9 genome editing technology from Intellia.

    The company currently has two switchable CAR-T assets in phase 1 clinical trials aimed at treating CD123-associated acute myeloid leukemia (AML). According to the company, the on-target off-tumor toxicity of CD123 makes a conventional CD123-directed CAR “very challenging”, and the company hopes to overcome this with its switchable CAR-T cells. 

    Both of these therapies utilize AvenCell’s proprietary Universal Targeting platform, the company’s regulatable CAR-T technology that can turn CAR-T cells on and off by means of a separately infused soluble adaptor called a Targeting Module, which has a short half-life and fast internalization, meaning the CAR-T cells can potentially be silenced in less than four hours if desired. 

    AVC-201 also makes use of AvenCell’s second platform, which the company got from Intellia. The platform is an in-licensed allogeneic cell engineering technology that allows for unrelated donors to provide cells for patients. These cells are uniquely engineered via CRISPR/Cas9 to avoid graft-versus-host disease (GvHD) and rejection via the host/patient immune system by either innate or adaptive mechanisms.

    With backing from Blackstone, as well as Cellex and Intellia, AvenCell has the means to potentially take its switchable CAR-T therapies to the market if they perform as expected in clinical trials. Earlier this month, the company received a further $112 million in a series B round led by Novo Holdings to accelerate clinical validation of its Universal Switchable CAR-T therapy platform.

    The broader picture: Biotech’s mission to develop next-generation CAR-T therapies

    As mentioned previously, issues surrounding safety of CAR-T therapies has primarily been the driver behind biotech companies wanting to develop newer versions of this breakthrough therapy. Plus, the fact that CAR-T therapies do not work as effectively on solid tumors as on hematological malignancies has also led companies to try new avenues.

    For example, last year, BioNTech reported positive phase 1/2 results for its CAR-T therapy, BNT-211, for solid tumors, which consists of cells directed at Claudin-6 on cancer cells, combined with an mRNA vaccine designed to amplify their activity. 

    Meanwhile, U.K.-based startup Leucid Bio is developing CAR-T cells that are engineered in a more natural biological configuration, designed to enhance their potency, extend responses, and reduce side effects.

    And, similar to Calibr and AvenCell, other research groups are looking into using switchable CAR-T approaches to activating the cells, using “switches” such as existing small-molecule drugs, viruses, and light and heat.

    These are just a few examples of biotech’s mission to make CAR-T therapies safer and more effective for patients, in the hope that they can one day overcome solid tumors as well as blood cancers. Will switchable CAR-T therapies ultimately be the answer to this? Only time will tell, as we will have to wait and see whether AvenCell or Calibr can eventually bring their products to the market.

    Explore other topics: CAR-TCell therapyImmunotherapy