TSCM: Better CAR-T

The cell composition of the final product matters when developing or manufacturing a T cell based cancer therapy such as CAR-T or TCR-T. Cell composition ultimately impacts the effectiveness and longevity following treatment, as well as the safety of the therapy itself.

T cell based treatments that are enriched in more stemlike T cells have been shown to last longer in vivo and be more effective and safer for patients. Stem cell memory T cells, or TSCMs, are one of the most important types of these stemlike T cells. As such, targeted, intentional expansion of TSCMs and enrichment in the final adoptive T cell based product is one of the most promising strategies for making improved and better T cell based cancer therapies.

Understanding T Cell Maturity Basics

Like many types of T cells, memory T cells exist along a continuum of maturity. The developmental path of a T cell is dictated by a complex signaling network of growth factors and cytokine pathways that result in a naive T cell expressing or suppressing specific phenotypic traits during a process called differentiation. This differentiation creates functionally different subsets of T cells that perform clinically distinct roles in a patient’s immune response.  The continuum of maturity for memory T cells ranges from the least differentiated functional phenotypes—naive and TSCMs —to the most inflexible phenotypes—effector memory (TEM) and terminally differentiated effector memory (TEMRA) T cells. In the last two decades, significant scientific research has gone into understanding the effect maturity state has on clinical outcomes. Less mature memory T cell states, specifically TSCM, have already shown great potential in cancer and HIV treatment.

What Is a TSCM Cell?

TSCMs are one of the least differentiated types of memory T cells, surpassing only naive T cells in their level of phenotype maturity. This lack of differentiation affords TSCMs their enhanced ability to self-renew and further differentiate into other T cell subsets, including effector memory T cells.

TSCM Phenotype and Markers

The unique T stem-cell memory phenotype can persist for years or decades in the human body. TSCM cells retain the distinct molecular surface profiles and long-term self-renewal capacity of naive T cells while acquiring many effector functions of memory T cells. This creates an enhanced T stem-cell memory state ideal for both high proliferation and multipotent differentiation potential. However, TSCM cells only make up a small fraction of circulating T lymphocytes, about 2% to 4%. They are identified by their naive-like phenotype in combination with functional surface markers associated with memory T cells—CD95, CXCR3, IL-2Rβ, CD58, and CD11. These receptors and ligands give TSCM cells their ability to proliferate rapidly and release inflammatory cytokines in response to antigen re-exposure. The discovery of CD95 and the other key stem cell memory T cell markers has been critical to the efforts of clinical scientists to identify and enrich the TSCM population during adoptive T cell therapy.

Choosing a T Cell Therapy

TSCM cells are an ideal enrichment target for T cell immunotherapy due to their long-lasting and robust immune response against cancers and pathogens. Ex vivo genetic modification of a patient’s T cells to express chimeric antigen receptors (CARs) further enhances the effectiveness of T cell immunotherapy. Unlike regular TSCM cells, CAR-T stem cell memory cells can directly bind antigens that are highly specific to the target cell, mitigating off-target inflammation effects. Using TSCM cells as the basis of treatment has a beneficial effect on safety, longevity, and efficacy.
Cytokine release syndrome (CRS) is the most dangerous common side effect of CAR-T therapy. If left unchecked, CRS quickly becomes fatal to the patient. This is the main reason CAR-T therapies are not considered for first-line cancer treatment over other established treatments, such as chemotherapy and radiation therapy.  Specific infrastructure and expertise are needed at CAR-T treatment facilities to manage side effects and prevent escalation of CRS, which severely limits patient access. However, studies have shown that having a higher concentration of TSCM CAR-T cells reduces instances of CRS and related neurotoxicity. This effect held independent of which CAR domain was expressed, indicating that having TSCM cells as the basis of treatment inherently made the therapy safer.
Given the complexity and labor of a CAR-T therapy cycle, treatment should ideally consist of a single session, with therapeutic effects that would last for the rest of the patient’s life. First-generation CAR-T products lacked this longevity. Patients were often required to return for follow-up cycles or seek alternative therapies if initial treatment failed.  CAR-T therapies must be long-lasting to make a sustainable impact on patient care. Luckily, TSCM cells have been found to persist in the body for over a decade, bolstered by their enhanced ability to self-renew. Using these cells contributes significantly to the available CAR-T stem cell memory pool in the patient’s immune system, greatly enhancing the treatment’s overall longevity.
CAR-T therapies with higher TSCM content have also been shown to be more clinically effective, with higher survival rates and increased tumor shrinkage than other types of adoptive T cell immunotherapy based on central or effector memory T cell subsets. In addition to the longevity and enhanced safety of treatment, this benefit may be inherent to the metabolic fitness and proliferation of stem cell types.

Enhance Your T Cell Activation With Higher TSCM Content

The cell composition of CAR T cell therapy and the maturity of the T cells in the end product are critically important for treatment success and patient health. Ensuring the highest concentration of TSCM cells possible also ensures the commercial success of your best-in-class therapy.  Nanotein Technologies developed CAR-T technology specifically to enhance the efficacy of your T cell therapy by stimulating the expansion of CAR-T stem cell memory cells with self-renewing and multipotent qualities, ex vivo. Using the NanoSpark STEM-T Soluble T Cell Activator, you can focus on developing the best therapeutic CARs and leave selective expansion to Nanotein.  Our team is ready to help you build the CAR-T therapy of tomorrow, so contact us today. 

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