The Science

What are γδ T cells?

Gamma delta T lymphocytes (γδ T cells or γδ T lymphocytes), alongside alpha beta T lymphocytes (αβ T-cells) and B Lymphocytes, form a critical and highly conserved triumverate of the adaptive immune system. These cells act at the interface of the innate and adaptive immune systems, recognising molecular patterns of dysregulation in stressed, pathogen infected or transformed cells and rapidly responding to maintain homeostasis. γδ T lymphocytes are capable of eradicating cancerous or infected cells and triggering a systemic response via the adaptive immune system, without harming healthy cells.

Unlike other types of T lymphocyte, γδ T cells identify target cells via mechanisms that are independent of Major Histocompatibility Complex (MHC) protein presentation. Consequently, tumour cells cannot evade detection by downregulating MHC protein expression in response to treatment. This property also means that γδ T cells do not require prior antigen priming, have equal potential for killing tumours cells with low mutational loads, are less likely to be affected by therapeutic resistance issues and are suitable for allogeneic therapy as they are not limited by patient-specific factors as are autologous therapies.

Recent studies indicate that γδ T cells play an important role in anti-tumour responses. A bioinformatic study of large number of solid tumour samples showed that, amongst all different immune cell types, γδ T cell infiltration correlated highest with survival(1). A retrospective study of acute leukaemia patients receiving αβ T cell depleted allogeneic stem cell transplant (ASCT) showed that event free and overall survival correlated strongly with expansion of donor-derived γδ T cells(2). These results were confirmed recently by another laboratory in a prospective study which also showed that patients with high concentrations of γδ T cells two months after ASCT had lower incidence of acute graft versus host disease(3).

1.       Gentles et al. Nat Med. 2015 Aug; 21(8):938-945
2.       Godder et al. Bone Marrow Transplant. 2007 Jun; 39(12):751-7
3.       Minculescu et al. Front Immunol. 2019 Aug 22; 10:1997

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A pioneering approach to immunotherapy: Vδ1+ T cells

Vδ1+ T cells are:

  • a subset of γδ T lymphocyte that have shown promise in cancer immunotherapy
  • typically found in tissues such as the skin and colon, while lower levels are also present in blood
  • capable of recognising and infiltrating tumour tissue to specifically target and kill the affected cells

Although Vδ1+ T cells are present at relatively low concentrations in blood, compared with to Vδ2+ T lymphocytes which recognise bacterial phosphoantigen, studies suggest that these cells can provide particular benefit for haematological cancer patients undergoing ASCT in terms of long-term survival.

In addition to cancer, Vδ1+ T cells have also been shown to have potential for treatment of infectious diseases (CMV, HIV) and may play an important role in inflammatory bowel diseases.

Vδ1+ T cell characteristics

  • Inherent anti-tumour activity
  • Suitable for allogeneic T cell therapy – lack of GvHD
  • Cytotoxic activity is unrestricted by MHC recognition
  • Enhanced cytokine secretion
  • Resident in tissues, especially epithelium rich tissues
  • Less prone to activation induced cell death
  • Large numbers in Tumour Infiltrating Lymphocytes (TILs)

Vδ1+ T lymphocyte isolation and expansion

Compelling evidence concerning the clinical efficacy and potential benefit of innovative treatments that harness the unique cytotoxic properties of Vδ1+ T lymphocytes has driven an urgent requirement for clinical-grade selective isolation and expansion protocols capable of generating large Vδ1+ T cell populations.

In partnership with academic experts at Kings College London, The Francis Crick Institute and the University of Lisbon, GammaDelta Therapeutics is leading the field in this respect through the development of innovative and robust clinical isolation and expansion protocols that provide high-quality Vδ1+ T cell enriched preparations derived from human blood or tissue. Our isolation and expansion protocols have been optimised to simultaneously achieve a high yield whilst retaining desired cytotoxic phenotype.

Whereas both the blood- and tissue-based protocols generate highly enriched and cytotoxic Vδ1+ T cells, they have distinct properties. Hence, ability to expand distinct populations of Vδ1+ T cells from both tissue and blood allows us to compare their properties and explore their complementary potential for treatment of various diseases.

Skin-derived Vδ1+ T cell platform

Our tissue-derived isolation and expansion protocol delivers unprecedented Vδ1+ T cell yields with exceptional levels of cellular activity and tumour killing capacity. The T cells are isolated from tissues such as skin without enzymatic digestion or physical disruption. They are then subjected to an expansion process using our optimised proprietary cytokine cocktail with minimal receptor stimulation which results in a highly enriched Vδ1+ T cell population maintaining its tissue resident biology. This is a scalable process with the potential to vastly reduce the costs associated with immunotherapy for many solid tissue malignancies.

Blood-derived Vδ1+ T cell platform

Vδ1+ T cells represent a very small proportion of the γδ T cell population found within human blood. Isolation and expansion of this important cellular subtype from blood samples with a clinically applicable process has posed a significant challenge to date.

Our Vδ1+ T cell platform leverages complementary technology and expertise drawn from our tissue-derived isolation and expansion platform to enable consistent and high-yield production of active blood-derived Vδ1+ T cells. During this process, γδ T cells are purified from blood samples and grown in optimised culture conditions that result in a highly enriched Vδ1+ T cell population.

Engineering Vδ1+ T cells

Advances in cellular and genetic engineering allows us to further enhance the desired properties of Vδ1+ T cells combining the innate power of γδ T cells with antigen specific selection and expansion. We are exploring introduction of Chimeric Antigen Receptors (CAR) and other gene constructs into our Vδ1+ T cells to target cancers and other serious diseases. Vδ1+ CAR T lymphocytes can be used for allogeneic treatment without any further engineering. Furthermore, CAR expressing Vδ1+ T cells would provide dual targeting capacity and, hence, has potential to reduce therapeutic resistance due to down regulation antigen expression within target cells.

Benefits of Vδ1+ CAR T cells therapy

  • Dual cytotoxic activity
  • Enhanced efficacy with allogeneic T cell therapy
  • Avoidance of GvHD
  • Recruitment of additional immune effector cells due to enhanced cytokine secretion
  • Greater potential for solid tumour penetration