CAR-T technology seems to be evolving and progressing faster than smartphones, at least in theoretical prototypes if not actual treatments. The latest exciting move comes from AbbVie (ABBV), which is moving to the CAR-T space in a licensing partnership with the California Institute for Biomedical Research, a.k.a. Calibr.
In my previous piece on CAR-T developments, we covered Cellectis (CLLS) and its CubiCAR concept, which removes antigens from the T-cell and only carries the antigen engineered to make the T-cell recognize and attack cancer. In addition, CubiCAR contains an on-off switch sensitive to Roche’s (OTCQX:RHHBY) Rituxan, which functions as an on/off switch in the event of severe life-threatening side effects, which are actually quite common with CAR-T. Removal of other antigens allows for a potentially off-the-shelf product because it removes immunogenicity, or the activation of an immune response, which addresses cost issues. The off switch addresses safety issues.
Now, a new development has arisen from pharma giant AbbVie and private group Calibr, which seems to be going one step further still in honing and perfecting CAR-T technology, though still in the very early preclinical stage. Before we get into the details, the advantage of AbbVie going into CAR-T for investors is that it gives another potential deleveraged option to CAR-T investment. AbbVie, the Humira king, has its own merits and one of the highest dividend yields in biotech at over 4%, and is of course not primarily a CAR-T company nor identified much with that space. This gives investors who would like exposure to the space with less of the risks another avenue of getting it.
Here’s how it works. Research published in a German peer-reviewed journal, Calibr, calls its new vehicle sCAR-T for “switchable” CAR-T. Addressing one theoretical weakness with CubiCAR, though not directly or by name, the research team states.
One method that has been proposed is a safety switch that can eliminate engineered cells in the case of an adverse event. However, this strategy results in irreversible loss of therapeutic cells from circulation and does not solve the intrinsic lack of control associated with conventional CAR-T cell therapy.
This could refer to Cellectis’s advancements with CubiCAR with the Rituxan off switch. The downside to such an off switch is that once it is added, the cells cannot be reactivated nor antigens changed to recalibrate the target, and the patient is back to square one, a place you don’t want to be with cancer. So how does sCAR-T attempt to solve that problem?
sCAR-T Is Like An All-In-One Screwdriver
Here is how it works conceptually, to the best of my understanding. First, antigens are removed so there is no immunogenicity just like CubiCAR. However, unlike CubiCAR, the on/off switches make the T-cell interchangeable instead of just alive or dead. The T-cell functions like one of those all-in-one screwdrivers that have a connector piece and an interchangeable bit, so you can change it from flathead to Phillips to Allen wrench and so forth. Depending on what kind of screw you need to turn – in this case what kind of cancer you want to attack – you just change the bit.
How is the switching done? The sCAR-T cell is covered with antigens that are not present in any normal tissue, called bioorthogonal. These are the connecting pieces of the screwdriver analogy that fasten the bit to the driver. Cancer antibodies fused to the connecting antigens are then in turn fused to the bioorthogonal antigens on the surface of the T-cell.
This approach potentially solves the problem of aggressive CAR-T cells in the body killing healthy cells off target but with the same antigens after the cancer is eradicated. This is the case with many types of blood cancer where CAR-T cells are targeted to B-cells, and then they just keep killing off B-cells even after the cancerous ones are gone, resulting in long term B-cell aplasia. This is a serious long-term problem in CAR-T treatments which CubiCAR also solves, but only by killing the T-cells permanently. After Rituxan is added to CubiCAR, the cells cannot be reactivated. But with sCAR-T, all that needs to be done is to remove the screwdriver bit, and you end up with just an inactive T-cell, like an empty screwdriver with no bit, but that can be reactivated with any chosen antigen if and when the cancer returns.
This method may also help fight the phenomenon of cancer “hiding” from weaponized CAR-T cells. In many cases, in a sort of natural selection survival-of-the-fittest cancer cell scenario, some cancer cells lack the target antigen, and then continue to proliferate after the bulk of the cancer is gone. With sCAR-T, once again you just change the switch and the remaining cancer can’t hide, or better yet, add more than one switch to the cell so it can attack both antigens at once.
Obviously, there is a lot of complicated microbiological fine-tuning involved in pairing the right switches of the right lengths and angles to the right CAR-T cells and testing their activation against various cancers, which the rest of the paper goes into for those interested.
Preclinical Results So Far
This is still in the very early stages, but xenograft mouse models (where human cancer cells are grafted onto mice) show that it does work in theory. What the research team did was test sCAR-T versus conventional CAR-T against HER2 solid tumor breast cancer. The only difference between the two was that sCAR-T needed a regular IV infusion of switch molecules to keep the cells active, and conventional CAR-T did not. Both treatments eradicated the HER2 tumors with no relapse.
There is still a long way to go here, but the technology being licensed by AbbVie dilutes risks considerably. If you’re looking for a relatively low risk way to enter the CAR-T space, AbbVie could be a good pick. Regarding the Humira patent expiry issue, Bloomberg published a piece last year commenting on the company’s nearly impregnable patent fortress around Humira. From Bloomberg:
The company listed 22 patents for various diseases or methods of treatment, 14 on the drug’s formulation, 24 on its manufacturing practices, and 15 “other” patents. The latest expiration date is 2034-providing more than double the protection span a drug such as Humira might normally expect.
The Wall Street Journal though more recently commented on a settlement between AbbVie and Amgen (NASDAQ:AMGN) that will keep competitors off Humira’s back until 2023. That gives a minimum of 5 years and maximum of 16 until AbbVie has to worry about 65% of its annual revenues, which come from Humira. With any luck though, by 2023, sCAR-T will be well advanced in the clinic.
With AbbVie 27% off its high and a dividend of over 4%, I see low risk in slowly scaling in at these levels.
Disclosure: I/we have no positions in any stocks mentioned, but may initiate a long position in ABBV over the next 72 hours.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.