NextGen IO Exploiting the hypoxia response in T cells for Next-Generation Immuno-Oncology
Pointing the way to novel cancer immunotherapies Many lung tumours don’t currently respond to immunotherapy, now researchers are investigating new approaches to stimulate the immune system and combat the disease more effectively. Researchers in the NEXT GEN IO project aim to exploit the hypoxia response in T-cells and harness its wider therapeutic potential, as Dr Asis Palazón explains.
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CD8+ T-cells are an important part of the
NEXT GEN IO project
human immune system, with the ability to directly kill malignant cancer cells, while they also differentiate into memory cells that can offer long-term protection. However, T-cell infiltration is usually lower in hypoxic areas of a tumour, which represents a significant problem in terms of the effectiveness of the immune response. “The T-cells must infiltrate a tumour in order to kill the target cells,” explains Dr Asis Palazón. “On the other hand, when T-cells sense that there is no oxygen, this triggers an activation mechanism. So essentially T-cells are able to sense that tissues are not completely healthy when there is low oxygen availability. We are trying to boost this signalling pathway through therapeutic intervention.”
The hypoxia pathway forms the central focus of research in the NEXT GEN IO project, an ERC-backed initiative formed with the goal of developing new drugs. Sophisticated techniques are being applied in this research, including flow cytometry, which helps researchers gain deeper insights into specific cell populations. “The ERC funded the purchase of a very expensive flow cytometer, which we are using in our experiments. This equipment has really helped in the project,” says Dr Palazón, the project’s Principal Investigator. The focus in the project is primarily on lung cancer, which Dr Palazón says has some interesting features. “Solid tumours, and metastasis in
the lung, are very hypoxic, while outside, the lung is a very well-oxygenated organ,” he explains. This offers a contrast in oxygen availability between malignant and healthy tissue, from which researchers can look to gain deeper insights into the hypoxia pathway, which can then be applied in drug development. While the project’s aims centre around translational immunotherapy, Dr Palazón says this is built on a deep understanding of the mechanisms behind hypoxia. “The hypoxia pathway is covered by a type of transcription factor called hypoxia inducible factors, HIFs,” he outlines. “These HIFs can trigger the expression of different
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genes that promote adaptation to this low-oxygenation environment. So, when HIF is triggered, the metabolism of the cells change and angiogenesis is initiated. This vascularisation supplies oxygen and nutrients to solid tumours.” The researchers who discovered the hypoxia pathway won the Nobel Prize for Physiology or Medicine in 2019, now Dr Palazón aims to build on existing research foundations by developing new drugs to boost the immune response against lung cancer. A variety of different proteins are involved in oxygen sensing, some of them enzymes that can be targeted with drugs, which is a major area of interest in Dr Palazón’s lab. “One important oxygensensing enzyme is called factor-inhibiting HIF, which is the main focus of our project. This is an enzyme that acts as an oxygen sensor, and when oxygen is available, it inhibits the function of HIF,” he explains. “This mechanism exists in all our cells, but we are mostly focused on the hypoxia response in immune cells.” A technique called cell therapy is being used in the project, in which T-cells are taken from the patient, genetically manipulated, and then re-infused. This technique is also known as CAR T-cell therapy, and ensures that only the relevant
this is a huge field of research,” says Dr Palazón. The main priority at this stage for Dr Palazón is to discover targets in T-cells however, and he says significant progress has been made over the course of the project. “It’s important to say that we have already done the initial screening, to get these inhibitors of our targets,” he outlines. “Now we have hits against the target, and we are starting to do in vivo experiments in order to demonstrate that the drugs we have are effective.” A safe toxicity profile is also essential if these drugs are to be used in treatment, which will be assessed in the project. In general, immunotherapies have less dramatic side-effects than treatments like chemotherapy, but the toxicity of the compounds developed has not yet been fully established. “We have some hints, based on trans-genic mouse models, that they are safe, but we still have more to do in this respect,” says Dr Palazón. The aim in the project is to essentially de-risk these new drug candidates, so that they can then go forward to clinical trials, and researchers are collaborating with a pharmaceutical company in this work. “We essentially pay them to do some parts of the work, mostly focused on medicinal chemistry and drug screening,” continues Dr Palazón.
Project Objectives
The lab has a core focus on immuno-oncology, specifically on target discovery and drug development, to exploit several opportunities that the hypoxia pathway in T cells offers for the treatment of cancer. We employ a multi-disciplinary strategy, to deliver several early-stage drug discovery outputs. Our main objectives is the development of a novel small molecule inhibitor to modulate the hypoxic response in T cells. We also have a strong interest in therapeutic target discovery in T cells, and novel cell therapy approaches for the treatment of hypoxic solid tumors.
Project Funding
The NextGen IO project is funded by a European Research Council ERC Starting Grant.
Project Partners
• Domainex, United Kingdom domainex.co.uk
Contact Details
Asís Palazón Principal Investigator Cancer Immunology and Immunotherapy Lab Bizkaia Science and Technology Park, building 801A, Derio (Bizkaia) T: +4466 / 946 572 536 E: apalazon@cicbiogune.es W: https://www.cicbiogune.es/people/apalazon Asís Palazón
Hypoxia inducible factors can trigger the expression of different genes that promote adaptation to this low-oxygenation environment. So, when HIF is triggered, the metabolism of the cells change and angiogenesis is initiated. cells are targeted. “We can apply these drugs, or our manipulation of the hypoxia response, in the ex-vivo phase of the cell therapy approach. So that means that we will only modify the T-cells,” says Dr Palazón. The more advanced metastasis, the more hypoxic the tumour, so Dr Palazón believes this approach would be most effective against advanced stages of solid tumours and metastasis. “This is mostly because the bigger the tumour, the more hypoxia you can find,” he explains. The long-term effectiveness of this approach is an important consideration in terms of future therapeutic potential. While the first step is for the T-cells to rapidly kill the tumour cells, some of these T-cells must then also persist in the same function. “The effect of hypoxia on
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Drug development This work is part of the early stages of the drug development process, and there are many stages ahead before these drugs can be applied in treatment. However, Dr Palazón is looking towards the potential commercialisation of this research in future. “We aim to finish the efficacy studies at some point within the next year. Then, when we have that proof-of-concept, it will be very important for us to file for a patent, covering the chemical structures and the effects and applications of these novel compounds,” he outlines. “The patent is very important, in order to enable the future licensing of these compounds into a pharmaceutical company, or maybe a spinoff company from our institution which could be established in future.”
Asís Palazón is a pharmacist and biochemist (University of Navarre). After his PhD thesis in Cancer Immunology and Immunotherapy (2012), he joined Prof. Randall Johnson’s lab at the University of Cambridge with the aim of studying the role of hypoxia on immune responses in cancer. He then worked for the pharmaceutical industry (Medimmune, Cambridge, UK). In early 2019, Asís joined CICbiogune as a Principal Investigator where he leads the Cancer Immunology and Immunotherapy lab supported by an ERC Starting grant (2018) and Ikerbasque.
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