ORIGINALLY PUBLISHED
27 April 2023
Written by:
Gavin M Bendle
VP, TCR Cell Therapy Research, Oncology R&D
Eric Tran
Associate Member, Earle A. Chiles Research Institute, Providence Cancer Institute, and Expert Consultant for AstraZeneca (Head of TCR therapy, Oncology R&D)
At AstraZeneca, we are harnessing the power of cutting-edge science with the aim to transform cancer care. A promising development in our oncology portfolio is T-cell receptor therapies (TCR T), a new class of engineered cell therapy that we believe holds the promise to redefine outcomes for people living with hard-to-treat solid cancers.
Designing TCR Ts to target cancer specific mutations
Cancer is driven by genetic mutations that fuel abnormal cell growth but also create a critical weakness that can be exploited therapeutically. These mutations often result in tumour-specific proteins called neoantigens, which can alert the immune system to the presence of cancer.1
This is where T-cell receptors (TCRs) come in. T-cells, one of the immune system’s primary defenders, use TCRs to scan for abnormal proteins presented on the surface of target cancer cells via major histocompatibility complexes (MHCs).
Through TCR T therapy, we are exploiting this concept and engineering T-cells to express TCRs that can detect specific neoantigens with great precision. Our goal is to deliver this advanced form of cancer therapy targeting common cancer mutations, such as those in the oncogenic proteins KRAS and TP53, as well as personalised therapies targeting neoantigens that are unique to an individual’s tumour. Importantly, these mutations are present only in cancer cells, allowing for selective targeting with minimal impact on healthy cells.1
TCR T targets tumour-specific neoantigens: Cancer cells containing nonsynonymous mutations present tumour neoantigens that can be recognised by engineered T-cells, enabling selective targeting of cancer cells while sparing normal cells with wild-type antigens. This approach allows engineered T-cell receptors to distinguish between healthy, normal tissues and tumour cells based on tumour-specific mutations.
Harnessing the TCR to expand the range of targets in cancer treatment
A unique aspect of TCR based therapy is its ability to use the cell’s natural antigen presentation mechanism, enabling the detection of intracellular proteins.2 This means TCR Ts can target a broad repertoire of proteins in cancer, making them pivotal to our cell therapy strategy.3
Early approaches to exploit the TCR in cancer treatment include tumour-infiltrating lymphocytes (TILs), which involves the isolation and expansion of immune cells from a patient. TILs have had some success in cancers like melanoma;4 however, challenges related to accessibility, the cell proliferation, and functional state of neoantigen-reactive TILs remain.
Our paper, published in Nature Communications, describes some of the foundational research we have led in this field.[iv] We have developed a platform capable of efficiently and rapidly identifying neoantigen-reactive TCRs from a patient’s tumour biopsy, which can be used to create a highly individualised TCR T. Our scientists successfully isolated neoantigen-reactive TCRs across a range of targets and cancer types, demonstrating the broad potential of this technology.
We are immensely proud of the progress we are making. Our published work is only the beginning: our platform is constantly being updated and expanded. For example, we are using AI-powered tools to advance our screening and the detection of new targets, and we are growing our capacity for engineering multi-specific TCR Ts.
Armouring TCR Ts to beat the tumour microenvironment
While TCR T therapies hold promise, the tumour microenvironment (TME) remains an obstacle. The TME is often highly immunosuppressive, making it difficult for T-cells to remain functional after reaching the tumour.6 Overcoming this barrier is critical for delivering durable and effective treatments to patients.
We’re armouring our TCR T-cells to resist these immunosuppressive conditions. For example, we’ve used gene-editing to disrupt the receptor pathway for TGFβ, a cytokine that promotes immunosuppression in the TME. By preventing TGFβ from inhibiting T-cell activity, we can potentially enhance the potency of our therapies in solid tumours.
Additional strategies that we are using to armour our TCR T-cells include knocking out the CBLB gene to enhance T-cell function and knocking in the CD8 co-receptor which improves the activity of CD4 TCR T-cells.7,8 These efforts are essential to the aim of ensuring that therapies remain active and robust within even the most challenging tumour environments.
Looking to the future
Cell therapy represents far more than just a scientific milestone; it could be a transformative opportunity to potentially drive cures across currently incurable cancers.
While there is still much to learn, our progress gives us confidence we can overcome the challenges ahead. By integrating advanced targeting capabilities, innovative cell engineering techniques, and robust armouring strategies, we are creating new avenues for treating cancer. Alongside this, we are developing ‘off-the-shelf' allogeneic technologies and in vivo cell therapy approaches, that can be applied to TCR T as well as CAR T therapies to increase their scalability and accessibility. We are deeply committed to accelerating this work, and we know the potential impact it could have for people living with cancer and their families.
Join us as we continue to explore the future of oncology
We welcome committed, talented cell therapy scientists to join us on what could be one of the most exciting, stimulating and rewarding journeys in 21st century medicine. We recruit scientists with relevant expertise to join us in our state-of-the-art research facilities in Cambridge, UK, Gaithersburg, US, Gothenburg, Sweden, Boston, US, Shanghai, China, and Beijing, China.
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