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Harnessing Gamma T Cells To Bring Effective Therapies to Patients

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GammaDelta Therapeutics is a company that focusses on utilizing the unique properties of gamma delta (γδ) T cells to develop novel immunotherapies for patients.

Through their research, the company’s scientists have discovered a number of targets and antibodies that have the potential to modulate the activity of γδ T-cells in situ. Therefore, GammaDelta Therapeutics recently announced the formation of Adaptate Biotherapeutics, a spin-out company that will focus on research in this area.

Technology Networks spoke with Natalie Mount, CEO of Adaptate BioTherapeutics, to learn more about the company's aims and the challenges faced when developing immunotherapies and advancing them into clinical studies.

Molly Campbell (MC) Please can you tell us more about γδ T-cell based cell therapy products and their potential applications?

Natalie Mount (NM):
γδ T cells play an increasingly appreciated critical role in immune surveillance, being able to recognize malignant/transformed cells through a pattern of stress markers. The recognition mechanism is not major histocompatibility complex (MHC) restricted and not dependent on a single antigen.

γδ T cells therefore have potential in a range of disease indications, including both hematological and solid malignancies and a positive correlation between γδ T cell infiltration and prognosis/survival in patients has been determined in a range of oncology indications in studies published in the literature by other groups. Additionally, as a cell therapy, γδ T cells can be used in an allogeneic setting (ie, γδ T cells can be used for unrelated recipients without a requirement for matching).

Both Adaptate Biotherapeutics and GammaDelta Therapeutics are focussed on harnessing the potential of γδ T cells, in particular the Vδ1 subtype which is the predominant γδ T cell type in tissue. This is based on data originating from the labs of Professor Adrian Hayday of King’s College London and the Crick Institute, supported by Cancer Research Technology and also from Professor Bruno Silva Santos of Institute for Molecular Medicine at the University of Lisbon, Portugal.

Previous clinical trials conducted by other groups/companies targeting or using γδ T cells in cancer have focussed on the Vδ2 subtype which is predominant in the blood. These trials have demonstrated safety, but efficacy has been limited. Compared to Vδ2 cells, Vδ1 cells, which are the focus of work at Adaptate Biotherapeutics and GammaDelta Therapeutics, are less susceptible to exhaustion and activation induced cell death. Expansion of donor derived Vδ1 has been shown to be a positive prognostic indicator for acute myeloid leukemia patients following hematopoietic stem cell transplant.

MC: Why are current immunotherapy treatment approaches limited?

Immunotherapy approaches have had very significant success and impact in Oncology recently, however, challenges and unmet needs remain.

One challenge is effective treatment of solid tumors. The hypoxic, low nutrient tumor environment provides a challenge for successful infiltration and activation of T cells. However, V
δ1 γδ T cells have real potential as they are naturally tissue resident and hence primed for this environment. In addition, their ability to recognize malignant cells by a pattern of markers expressed by dysregulated, transformed cells rather than one specific antigen presented by the MHC provides an additional advantage for both specificity of response and maintenance of efficacy.

γδ T cells act as orchestrators of an immune response and, following recognition of a cell as malignant, they induce maturation of monocytes and signal to alpha beta T cells, hence increasing immunogenicity of the tumor and providing a sustained response, with potential even in tumors with low mutational load which have proven challenging with other immunotherapies.

MC: The new spin-out company, Adaptate Biotherapeutics, will build on GammaDelta's knowledge to modulate γδ T-cell activity using therapeutic antibodies. Why have you decided to create a spin-out focusing on this area of research?

: GammaDelta Therapeutics was formed in 2016 to harness the unique properties of γδ T cells, and since then has gained extensive knowledge of γδ T-cell biology. In addition to gaining insight into cell growth and isolation, the company’s scientists have also discovered a number of targets and antibodies that have potential to modulate the activity of γδ T-cells in situ.

GammaDelta Therapeutics now has a pipeline of cell therapy products progressing into clinical development under the guidance of CEO, Dr Paolo Paoletti.

Adaptate Biotherapeutics will be developing antibodies which will be administered to cancer patients to modulate activity of the patient's gamma delta T cells in situ.

Delivery of cell therapy and antibody therapeutics each needs focus and specific skillsets and formation of two independent entities will facilitate this. The two companies share a common goal to harness the potential of γδ T cells to bring effective therapies to patients. Both benefit from support of the scientific founding team and have common investors, Abingworth and Takeda Pharmaceuticals.

MC; Your goal is to develop targets and antibodies that can modulate the activity of
γδ T-cells and advance them into clinical studies. What challenges exist here, and how do you hope to overcome them?

Our assets at Adaptate Biotherapeutics are currently at the pre-clinical stage and therefore face the non-clinical development risks for a novel therapy. However, these risks are mitigated by biology understanding from our scientific founders and the work at GammaDelta Therapeutics to date.

One of our challenges is in selecting the most suitable patient population for initial trials. There is potential for opportunity for our therapeutics in multiple indications but the utility of animal models in modelling the human immune compartment and human tumor setting is limited. Therefore in vitro and ex vivo models are important, in addition to the learnings from other clinical studies.

MC: GammaDelta Therapeutics formed in 2016 to gain extensive knowledge of γδ T-cell biology and to developing a portfolio of investigational cell therapies. Some of these cell therapies are poised to enter clinical development. Can you tell us any further information about these therapies?

GammaDelta was set up to develop cell-based therapy utilizing ex-vivo expanded tissue resident gd T cells. Subsequent acquisition of Lymphact SAS allowed GammaDelta to augment its capabilities with a platform for ex-vivo expansion of blood derived Vδ1 cells. GammaDelta is focussed on progressing ex-vivo expanded skin and blood derived Vδ1 cells to the clinic – both in unengineered and engineered formats. Clinical trials are currently on track to commence in the next 12-18 months.

MC: Your press release states: "The two companies will continue sharing their insights into γδ T-cell biology as they work towards developing different therapeutic modalities". How will you continue to share insights here?

Antibodies and cells represent complementary approaches to realizing the potential of γδ T cell activity for patients with solid and haematological malignancies.

The two companies will work together in areas of common interest in the biology of these fascinating cells, such as understanding the phenotype and behavior of γδ T cells in tumors and mechanisms of cell regulation as well as the effects of antibody on the γδ T cells.

We have deliberately established a contractual framework that allows efficient collaboration between scientists of both the companies via formal and informal meetings.

MC: What are your hopes for the future of Adaptate Biotherapeutics?

: This is a remarkable time in the development of new immune therapies, and the role of "non-conventional" cell types of the immune system is coming to the fore as we recognize the successes achieved to date and the needs of patients and related scientific challenges that remain.

Both GammaDelta Therapeutics and Adaptate Biotherapeutics are at the lead of translating our increasing understanding of γδ T cell biology and its potential into therapies to address these unmet needs.

Adaptate Biotherapeutics has a fantastic opportunity to build and accelerate a portfolio of antibody-based approaches in this novel area and I look forward to the successful translation of this science into therapies with the support of our investors at Abingworth and Takeda Pharmaceuticals.

Dr Natalie Mount, CEO of Adaptate Biotherapeutics was speaking with Molly Campbell, Science Writer, Technology Networks.