September Newsletter

Welcome back to the That’s Good Science newsletter. This month, we’re highlighting exciting advancements in immunotherapy, we'll be looking at a paper that explores the use of engineered gamma delta CAR T cells for solid tumour treatments and another investigating the efficacy of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in mitigating osteoarthritis associated inflammation. As part of our technical support highlights segment, we're also discussing a recent paper on the role of piRNA pathway genes in male infertility.

While CAR T cell therapies have made significant strides in treating blood cancers, their success in solid tumours has been more challenging due to the complex tumour microenvironment. This month, we’re highlighting the pioneering work of Caroline Malai Hull and colleagues at Leucid Bio , who have developed a novel approach using Granzyme B-activated IL18 (GzB-IL18).

This innovation enhances CAR T cell efficacy by linking IL18 activation directly to CAR T cell engagement, reducing inflammation-related risks. The results show particular promise for treating γδ T cells, demonstrating enhanced tumour-killing potential and a safer therapeutic profile for solid tumours.

Key Takeaways:

1. Controlled IL18 Activation: GzB-IL18 remains inactive until CAR T cells are activated, ensuring targeted enhancement of immune responses without the risk of uncontrolled inflammation, a crucial factor in solid tumour therapy.
2. Enhanced Tumor Microenvironment Modulation: The activation of GzB-IL18 promotes, not only CAR T cell cytolytic activity, but also beneficial changes in the tumour microenvironment (TME), including myeloid cell reprogramming. This could be a game-changer in overcoming the immune-suppressive nature of solid tumours.
3. Superior Efficacy in γδ CAR T Cells: The study highlights the increased metabolic fitness of GzB-IL18-armored γδ CAR T cells, leading to improved tumour eradication. This finding aligns with emerging research into γδ T cells as a promising off-the-shelf therapy for solid tumours.

Read the full paper >>

For more insights on γδ T cell therapies, watch our on-demand webinar with first author Caroline Hull, PhD, Innovative Strategies for Improving Potency of Allogeneic Gamma Delta T-Cell Therapies, where she explores novel manufacturing processes and IL-18 inducible variants for optimised therapeutic outcomes.

The use of mesenchymal stromal cells (MSCs) in cell therapy is increasing due to their potential for treating diseases that currently lack effective treatments. MSC-EVs offer a cell-free therapeutic option that retains many of the benefits of MSCs while minimising the risks associated with live cell transplantation. However, prolonged culture expansion is required to obtain therapeutic doses, which can heavily affect the therapeutic properties of MSCs and EVs.

This month, we are highlighting a preprint by Palamà et al, 2024, assessing the anti-inflammatory potential of EVs derived from induced pluripotent stem cell-derived MSCs (iMSCs) compared to primary MSC cultures.

Key Takeaways:

1. iMSCs have a greater expansion capacity: To meet the clinical demand, large-scale in vitro expansion is essential. Results show that iMSCs outcompete MSCs in their capacity to be expanded.
2. Senescence is delayed in iMSCs: 2. Long-term expansion of MSCs is associated with loss of biological functionality and increase in senescence over time. Study shows that MSCs exhibit high senescence-associated β-galactosidase activity already at passage 5 while similar senescence is observed in iMSCs at passage 16.
3. iMSCs have a larger therapeutic window: Anti-inflammatory effects of iMSC-EVs and MSC-EVs were evaluated on osteoarthritic chondrocytes in an in vitro model. MSC-EVs anti-inflammatory effect decreased with MSC ageing while iMSC-EVs showed an effect independent of the culture passage. Altogether, iMSC-EVs provided a larger window of activity for therapeutic purposes.

The results of this study suggest that iMSC-EVs hold significant potential for clinical treatments, although some challenges still need to be addressed.

Read the full paper >>

That's Good Science — Tech Support Highlights

This recent publication by Stallmeyer et al., uncovered mutations in piRNA pathway genes that led to male infertility by disrupting sperm production and transposon silencing. They identified 39 infertile men with such mutations, linking reduced piRNA levels and increased LINE1 expression to spermatogenic failure. PrimeSTAR Max and LA Taq were used in this article respectively for Sanger and ONT sequencing.

Key Takeaways:

1. piRNA Pathway Genes as Major Contributors to Male Infertility: This study reveals that genes involved in piRNA biogenesis, previously underexplored in the context of male infertility, play a significant role in human spermatogenic failure. The identification of biallelic loss-of-function (LoF) variants in key piRNA-related genes, such as PIWIL1, GTSF1, PLD6, and others, positions them as important autosomal recessive disease genes for male infertility due to impaired spermatogenesis.
2. Species-Specific Differences in piRNA Dysfunction Effects: The study highlights significant differences in the consequences of piRNA pathway dysfunction between humans and animal models, such as mice. While some variants in humans lead to less severe phenotypes or altered responses compared to mouse models, this indicates that piRNA biogenesis-related dysfunction and its downstream effects, such as transposon silencing, may not be fully extrapolatable between species.
3. piRNA Dysfunction Beyond Transposon De-repression: The research suggests that while transposon de-repression is a recognised consequence of piRNA biogenesis impairment, it is not a universal outcome in humans. Impaired biogenesis of piRNAs can also result in transcriptional dysregulation affecting spermatogenesis without necessarily leading to harmful transposon activity, revealing a complex relationship between piRNA dysfunction and fertility.

Read the full paper >>

Our technical support team consists of PhD-level scientists. They constantly monitor the literature to stay up-to-date with techniques and trends. Visit our Tech Support Highlights page to see some standout papers recently published by scientists using our Takara Bio products.

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Diwas Srivastava , Loora Laan, PhD , Benjamin R. , Isadora Cavalcante and Claire Leyden contributed to this newsletter.