TSCM: Better CAR-T

Nanotein’s T-cell technologies can enhance the efficacy of your T-cell therapy by stimulating the expansion of stem cell memory T cells with self-renewing and multipotent qualities during ex vivo expansion

TSCM: Safety, Longevity, and Therapeutic Efficacy

To many in the industry, it won’t come as a surprise that a T cell ≠ T cell ≠ T cell. Some important types of T-cell categories include cytotoxic T cells (CD8+), T-helper cells (CD4+), gamma-delta T cells, regulatory T cells (Tregs), etc.; all of which perform biologically – and clinically – distinct and important functions.

In parallel, and generally underappreciated – but no less important – is that T cells exist along a “continuum of maturity” from less differentiated and stem-like to highly differentiated and effector-like.

From less differentiated to more, the ‘maturity’ states of T cells are: naïve (TNaive), stem cell memory (TSCM), central memory (TCM), effector memory (TEM), and terminally differentiated effector memory (TEMRA). Through many studies, it has emerged that the less mature states are capable of self-renewal and re-expansion, while the more mature are not (Cancers, 2016; Semin. Immunol., 2016).

Self Renewal Capacity of Memory T Cells
When designing a T-cell therapy (e.g. CAR-T) it has become abundantly clear that the cell composition of CAR T-cell therapies and the maturity of the T-cells in the end product are critically important. It influences: (1) how safe, (2) how clinically effective, and (3) how long-lasting, for the patient, the T-cell therapy will ultimately be, largely independent of the CAR itself. This is where TSCM’s absolutely shine, and it is one reason (among others) that Nanotein’s activation and expansion reagents are so powerful, unique, and valuable. We help to endow CAR T-cell therapeutic end-products with higher TSCM content, and in turn, help create the best-in-class T-cell therapies, that yield superior performance and deliver the best outcomes for patients.

Safety

Cytokine Release Syndrome (CRS) is one of the more feared and common side effects of modern-day CAR-T therapy. Indeed, it’s one of the chief reasons – currently – that CAR-T therapy is only administered in a relatively small number of tertiary care centers (limiting patient access). It’s in these centers that the infrastructure and expertise, to manage patients that get CRS, exist. CRS results when monocytes are inappropriately activated as a result of CAR-T infusion; acutely flooding the patient with high levels of cytokines, and driving nausea, fever, multiple organ dysfunction, blood-brain barrier disruption, severe neuropsychiatric symptoms and not uncommonly death.

Interestingly, it has been found that having higher TSCM content, in CAR-T therapy, makes for a safer product (J. Clin. Invest, 2022), limiting CRS and accompanying neurotoxicities.

 

 

Longevity of Treatment

It is critical for CAR-T products to be long-lasting in the body. Hopefully, it will be a one-time treatment, persisting for the rest of the patient’s lifetime. First-generation CAR-T therapies often lack this longevity. Even after initially responding to therapy, it’s not uncommon that patients will relapse and become refractory to further treatment. CAR-Ts with higher TSCM content help decrease this risk. In fact, TSCM’s have been found to persist for over a decade, if not longer (Science Trans Med, 2015). Indeed, TSCM’s act as long-lived/highly persistent, “founder-like” cell populations, that are able to self-renew, as well as being highly multipotent and proliferative (Nature Cancer, 2021 ; Science Trans Med, 2016).

 

 

Treatment Efficacy

CAR-T therapies with higher TSCM content have also been shown to be more clinically effective. For example, preclinical studies carried out by Gattinoni and colleagues, have shown that CAR-T therapies with high TSCM content deliver significantly higher survival rates, while driving superior tumor shrinkage (Nature Medicine, 2009).  Study after study has shown a similar effect (J. Clin. Invest., 2022; Blood, 2016; Science Trans Med, 2015; Clin Transl Immunology, 2021).

 

Getting the composition of your cell therapy right is critical not only for the success of your therapy and the health of the patient, but also for the success of your company. Biopharma is an industry where the market-winning therapies, those that result in high prescription rates, need to be first-in-class or best-in-class. Thus, for commercial success, your product must accomplish this. Optimizing your biomanufacturing process with Nanotein’s TSCM -enhancing activation and expansion reagents will help you achieve this.

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