Immunity vs Cancer: Boosting CAR-T cells’ potential against solid tumors
Cancer Immunity CAR T

Immunity vs Cancer: Boosting CAR-T cells’ potential against solid tumors

Dr. Talia Henkle
Dr. Talia Henkle

In 10 seconds? Scientists are using tons of ingenious methods to produce next-generation CAR-T cells that provide hope that this therapy may have improved success against solid tumors in the future.

What’s the story? In our last Immunity vs Cancer digest we talked about CAR-T cells and their success against B cell cancers – i.e. blood cancers. But the big win would be if they could be successfully deployed against solid tumors (AKA most cancers). Unfortunately, progress has yet to be seen in this field. But, momentum continues and scientists are working hard to ensure that CAR-T cells can wipe out blood cancers and solid tumors alike.

Remind me, why are solid tumors trickier to tackle? Multiple reasons. Firstly, while humans can live without all of their B-cells (a type of immune cell that can get cancerous, the target of multiple FDA-approved CAR-T therapies – read more in our previous Digest), the same is not true for most of your other cells or tissues. That means researchers must search for targets (AKA neoantigens) that are unique to each tumor in a patient and absent from healthy tissues. These targets must be easily ‘visible’ on the surface of the tumor cells (versus inside the cell) and be present on every tumor cell–which is far from a given since tumors are a hodgepodge mix of shapeshifting cells that will become resistant to treatment if not all tackled right away. Another complication is finding a target that fits all these metrics that is also relevant to a sizable proportion of patients.

That does sound tough... I know, right? And even if the perfect target exists, unlike smooshy, gooey blood cancers, solid tumors are tough for CAR-T cells to penetrate. What's more, is that solid tumors house their own team of immunosuppressive immune cells that spit out tons of proteins with the ability to make killer CAR-T cells stand down.

So, what are scientists doing to overcome these barriers? Pretty much every trick in the cellular engineering book. (Cellular engineering = adding genes to cells to change their characteristics and/or function). As I mentioned in our last digest, many CAR-T patients experience serious side effects due to the constant attack mode of the CAR-T cells and, hence, the subsequent unchecked release of toxic proteins. (Remember we talked about how important it is to turn off T cells in healthy people?). So, one of the focuses of ‘next generation’ CAR-T cells is adding in an off-switch… to avoid friendly fire, so to say.

How do they do that? One method involves engineering CAR-T cells that default to ‘off-mode’ and will only be able to be activated under certain conditions that are frequently associated with tumors (like hypoxia or the presence of certain proteases—more on these conditions later). Another method implants ‘suicide genes’ into CAR-T cells which can cause them to self-destruct when the patients are treated with a certain drug–a useful feature for patients who experience serious side effects to CAR-T cells.

What else are they working on? Since finding solid-tumor-specific targets (neoantigens) is tricky, another safety feature, some scientists are working on is making CAR-T cells that have dual specificity for activation through multiple modalities. In one method, the CAR-T cells are only activated when two separate targets are recognized–hopefully minimizing the chance of them killing healthy cells alongside cancerous cells in tumors. Another method adds a second recognition domain that deactivates CAR-T cells when they find certain targets associated with healthy cells. This could be useful in cases where healthy cells have certain features that are not present on tumor cells. Scientists have even engineered ways for CAR-T cells to only be activated when a second intracellular target (AKA Proteins inside our cells. Think: confetti inside a balloon) is recognized–widening the range of potential targets for future therapies.

Some of the strategies being used to improve the function of CAR-T cells against solid tumors Source: Hong M, et al. Cancer Cell. 2020; 474(38): 473-488

So cool! Another exciting (but less fine-tuned) pipeline involves creating CAR-T cells that use a universal adaptor receptor that can allow for interchangeable CAR receptors with different specificities (kind of like a USB plug adaptor that can connect to many different types of cords).This method still needs to undergo substantial optimization before it's ready for patients but lends hope that this therapy might be able to keep up with tumors as they shapeshift. In theory, researchers could use this approach to track how tumors develop resistance, develop new CAR adaptors accordingly and inject them into the patient where they would stick to previously existing CAR-T cells without further need for cellular engineering. Hopes for this technique are purely experimental at this point.

Pretty amazing! Right? And there’s more! Scientists are also working on ways to make CAR-T cells release additional anti-cancer proteins upon activation. Some methods help CAR-T cells find and break into solid tumors while others aim to improve the killing capacity of CAR-T cells and empower other immune cells to join in! The CAR-T field is rapidly evolving and data from the hundreds of ongoing and planned clinical trials will tell which of these many ingenious methods are best for tackling each type of cancer.

Inspired by Chimera, the deadly mythological creature

CAR-T cells, aka Chimeric Antigen Receptor T cells, are named after the 'chimera'- a fire-breathing Greek mythological creature that has a lion's head, a goat's body, and a serpent's tail. This is quite an apt comparison due to the mashup of cell types and organisms needed to make a CAR-T cell.

The gene encoding of the CAR receptor is inserted into T cells using a virus. Each component added to the next generation of CAR-T cells implements features from different cell types, like other immune cells, and even viruses. See, viruses aren't always bad for us! (Stay tuned for our next series on the use of viruses in cancer vaccines).

All things taken together, CAR-T cells are mismatched killers that have great potential to target a vast array of cancers. Basically, these CAR-T cells are real-life chimeras!

Dr. Talia Henkle has distilled 3 research papers, saving your 10.5 hours of reading time

The Science Integrity Check of this 3-min Science Digest was performed by Dr. Jacquelyn Bedsaul.

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