Significant Improvements to Chimeric Antigen Receptor T Cell Therapies Lie Ahead

Chimeric antigen receptor T cell (CAR-T) therapies have proven to be a promising advance in the state of the art when it comes to cancer immunotherapy, though there are certainly challenges remaining to be overcome. The real promise is not only the improved effectiveness, however, but rather that this technology platform offers the ability to treat many different cancers with only an incremental cost in adaptation to each new target.

Over the long term, economics is the driver of success in cancer research. Given that there are hundreds of types of cancer and only so many scientists and only so much funding, the most important lines of research and development are those that can be cost-effectively turned to address many or all cancers. The defeat of cancer in our lifetimes requires universal therapies. CAR-T as a technology platform is now well enough known and proven to be attracting a great deal of interest in its evolution and improvement. This is now beginning to manifest in proof of principle results such as those noted here.

There have been few cancer treatments with such a promising future as using the patient's own immune system. Known as chimeric antigen receptor T-cell therapy, or CAR-T, this treatment uses re-engineered killer T-cells to attack cancer cells, but it also causes potentially deadly side effects. Now, research is opening doors to making such therapy safer and more effective. The researchers see the current CAR-T system as having three major flaws: target specificity; strength of response; and lack of adaptive capability, which is essentially the issue of relapse. "Our system has the ability to address those three problems."

Traditional CAR-T is a treatment engineered for one specific patient to treat one specific type of cancer cell. The new refined system - called split, universal and programmable (SUPRA) CAR-T - can be continuously altered to target different types of cancer cells, turned on and off, and overall offers a significantly more finely tuned treatment than the current therapies. "Instead of thinking about CAR-T as engineering cells that kill cancer, the way I think about it is as an antibody that drags a killer T-cell with it. What's amazing about it is that once the CAR T-cell binds and activates, it will recruit more T-cells and make copies of itself. Drugs don't do that."

This overwhelming immune response is also what causes the severe side effects. And there have been advances in drug therapy to mitigate these side effects by blocking unnecessary portions of the immune response while still allowing the CAR-T to attack the cancer cells. And the greater number of cancer cells means a stronger immune response. But the SUPRA CAR-T system would let doctors deactivate the entire treatment in case the side effects became too severe. The normal immune system requires T-cells to sense two targets coming from an invader cell before it attacks it and SUPRA CAR-T works in the same way. Before SUPRA CAR-T attacks cancer cells, it needs to sense that both targets are present on the cell. If only one is present, the system isn't activated.

SUPRA CAR-T also splits the T-cell from the target-sensing portion of the system. The target on cancer cells is called an antigen and whichever antigen is chosen is sought out by an antibody on the CAR T-cells. The new system breaks apart the T-cell from the antibody and allows for the ability to switch targets. The ability to switch targets is what can prevent relapse in patients. Cancer cells are smart and will mutate to no longer display the target when they sense the T-cells attacking after attaching to it. The SUPRA CAR-T system allows the T-cells to attack a new target by simply injecting the patient with a new batch of antibodies rather than having to re-engineer the T-cells, which is the most expensive portion of the treatment.

The third feature this split system produces is the ability to finely tune how active the T-cell response, which helps mitigate the dangerous side effects of previous CAR-T systems. By introducing a third component that can block the bonding of the T-cell and the antibody, the SUPRA CAR-T system can be deactivated. The level of deactivation can be tuned by choosing the strength to which this third component binds to the antibody.

Link: http://www.bu.edu/eng/2018/04/26/upgrading-the-immune-system/

Comments

Obsidian Therapeutics is also doing some interesting stuff with next gen CAR T:

https://lifescivc.com/2017/12/operating-systems-living-medicines/

"Think about what happens when a cancer patient receives an infusion of CAR-T cells. First of all, these patients have been "preconditioned" - a euphemism for a nasty program of chemotherapy to burn out their existing hematopoietic system to "make room" for the incoming therapeutic cells. What does that mean? Mainly, it means the patients will have responded homeostatically to depletion by cranking up a bunch of proliferative cytokines like IL15, which is pretty much the first thing the infused cells see and to which they respond accordingly. Soon enough they encounter antigen on tumor cells and are further stimulated to proliferate through their CAR. In short order, the cells expand explosively and uncontrollably. Within days, most patients experience a cytokine storm that puts many of them in the ICU. Most make it through - and those who do can experience dramatic and previously undreamt-of anti-tumor responses - but, sadly, some don't...

...And what if we could equip CAR-T cells with a cell-autonomous antigen-independent proliferative engine that we could dial up and down at will? That would allow the physician to keep the therapeutic cells alive and active even after antigen-driven signaling has subsided. That's important because persistence of the therapeutic cells is critical to long-lasting remissions or cures.

Maybe we could dispense with brutal preconditioning regimens entirely and drive incoming cells into the host with an internal IL15-like signal. If we can eliminate preconditioning as a prerequisite for adoptive immunotherapies, then these therapies can be made available to patients who are not sick enough - or too sick - to suffer through preconditioning."

Posted by: Jim at April 27th, 2018 9:55 PM

@Jim

The treatment is brutal but it is very experimental too. But look at what treatment options existed for tuberculosis or syphillis in the pre-antibiotics age...

At least we are honest enough to acknowledge that it is a barbaric treatment done out of desespperation

Posted by: Cuberat at April 28th, 2018 9:23 PM

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