T_SCM: Better CAR-T

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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 T_SCMs, are one of the most important types of these stemlike T cells. As such, targeted, intentional expansion of T_SCMs 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 T_SCMs —to the most inflexible phenotypes—effector memory (T_EM) and terminally differentiated effector memory (T_EMRA) 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 T_SCM, have already shown great potential in cancer and HIV treatment.

What Is a T_SCM Cell?

T_SCMs 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 T_SCMs their enhanced ability to self-renew and further differentiate into other T cell subsets, including effector memory T cells.

T_SCM Phenotype and Markers

The unique T stem-cell memory phenotype can persist for years or decades in the human body. T_SCM 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, T_SCM 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 T_SCM 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 T_SCM population during adoptive T cell therapy.

Choosing a T Cell Therapy

T_SCM 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 T_SCM 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 T_SCM cells as the basis of treatment has a beneficial effect on safety, longevity, and efficacy.

T_SCM CAR-T Cell Safety

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 T_SCM CAR-T cells reduces instances of CRS and related neurotoxicity. This effect held independent of which CAR domain was expressed, indicating that having T_SCM cells as the basis of treatment inherently made the therapy safer.

Longevity of T_SCM Treatment

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, T_SCM 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.

T_SCM Treatment Efficacy

CAR-T therapies with higher T_SCM 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 T_SCM 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 T_SCM 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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TSCM: Better CAR-T