CAR-T cell therapy refers to a treatment that uses transformed cells for cancer therapy. T-cells can be removed from a person, genetically altered and put them back into the patient for them to attack the cancer cells.
Smart T cell
Further improvements are being made to CAR-T cells. Smart T cells are engineered with suicide genes or other means to precisely control therapeutic function over the timing and dosage. This reduces cytotoxicity.
Several strategies to improve safety and efficacy of CAR-T cells are:
Suicide gene engineering: engineered T cells are incorporated with suicide genes, which can be activated by extracellular molecule and then induce T cell apoptosis. Herpes simplex virus thymidine kinase (HSV-TK) and inducible caspase 9 (iCas9) are two types suicide genes have been integrated into CAR-T cells. The suicide gene strategies does not act quickly enough to prevent all safety problems.
Dual-antigen receptor: T cells are engineered to express two tumor-associated antigen receptors at the same time. The dual-antigen receptor of engineered T cell module has been reported to have less intense side effects. An in vivo study in mice shows the dual-receptor T cells effectively eradicated prostate cancer and achieved complete long-term survival.
ON-switch: Engineered T cell have been made that are only active if they detect their target cell and if some other drug is present. This is an added control for more safety.
Bifunctional molecules as switches: The bispecific antibody targets CD3 molecule of T cell and tumor-associated antigen presented on cancer cell surface. This helps get precise targeting of bad B cells and cancer cells in mice.
SMDC adaptor technology – attempt at Universal CAR-T instead of cancer specific
SMDCs (small molecule drug conjugates) platform is an attempt to engineer a single universal CAR-T cell. Anti-tumor activity in mice is induced only when both the universal CAR T cells plus the correct antigen-specific adaptor molecules are present. Anti-tumor activity and toxicity can be controlled by adjusting the administered adaptor molecule dosing.
This could fix several current CAR-T problems
* the inability to control the rate of cytokine release and tumor lysis
* the absence of an “off switch” that can terminate cytotoxic activity when tumor eradication is complete
* a requirement to generate a different CAR T cell for each unique tumor antigen may be solved or mitigated using this approach
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,” says research lead Wilson Wong (BME). “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.”
The large immune response is what can cause severe side effects.
The original CAR-T can be compared to a charger for a cell phone–one piece that only allows one device to be connected; the SUPRA CAR-T can be compared to two AC adapters that allow for multiple, customizable attachments that can be removed and exchanged at any time.
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.
Armored CAR-T cells to attack solid tumors
CAR-T cells are more effective on liquid tumors and have not shown much promise in treating solid tumors. Ovarian cancer is one of the major killers of women since most cases of ovarian cancer (approximately 70%) are diagnosed at a late stage. Ovarian cancer is difficult to treat because it is a solid tumor with a microenvironment that suppresses adoptively transferred T-Cells.
The armored CAR-T cell is engineered to secrete potent cytokines such as interleukin 12 (I L-12) as well as other modifications to improve the efficacy of the CAR-T cell. A recent phase II clinical trial was carried out in ovarian cancer patients where they were administered IL-12. This treatment led to stable disease in 50% of the patients.
CAR-T against autoimmune disease
B-cells make and deploy antibodies which defend the body against invasive bacteria. Bad B cells can cause many kinds of deadly blood cancers and autoimmune diseases. CAR-T has been developed to kill cancerous B cells. New CAR-T can defend against autoimmune B causing cells.
Modifying regulatory T-Cells and not killer T-Cells
Autoimmune diseases often are caused or made worse by ineffective Tregs (regulatory T-Cells). Tregs enhanced with CAR protein claws help control immune response to organ transplants.