Enhancing immune T-cell therapy with the innate immune response: Are two systems of immunity better than one?

TIL Programming via cGAMP for the Treatment of Melanoma

The programming and injection of lymphocytes to enhance immunotherapy against melanoma, is an innovative and effective way to destroy skin cancer cells, or melanoma. However, it does not always work. This project aims to enhance tumor-infiltrating lymphocyte (TIL) therapy by engineering the lymphocytes to secrete a molecule that activates a second, innate immune response, which is independent of a T-cell adaptive immune response.

This TANDEM project combines expertise in clinical TIL therapy (Prof. Haanen) and cGAS-STING pathway biology (Prof. Ablasser). Their study will be pursued using an ex-vivo system, called explants. Long-term persistence of the modified TIL cells will be critical for the therapeutic success which these outstanding applicants are aiming for.

Preventing leukemia stem cells from suppressing the immune system

Targeting metabolic interactions between leukemic stem cells, macrophages, and T cells to overcome immune evasion in acute myeloid leukemia

This project focuses on acute myeloid leukemia, an aggressive form of blood cancer that frequently relapses. These relapses are primarily linked to leukemic stem cells capable of resisting treatment and persisting in the bone marrow and creating an immunosuppressive microenvironment.

The researchers aim to understand how these cells alter their environment by releasing certain metabolic intermediates, notably adenosine and creatine, and secreting these to their environment. These substances can weaken the activity of macrophages and T cells, thereby allowing leukemic cells to evade the immune system. The project will assess whether blocking these metabolic mechanisms can restore immune defenses and improve the effectiveness of standard treatments, using a mouse-human bone marrow model.

Optimizing Radiation Therapy to Preserve the Immune System’s Ability to Fight Cancer

Optimizing therapies that combine radiation and immune modulation by protecting tumor-draining lymph nodes from radiation damage

This research aims to generate a more efficient combination therapy of radiation treatment and immune therapy by mitigating the negative effects of lymph node irradiation on anti-tumor immunity. During radiation therapy, the lymph nodes near the tumor are often irradiated to destroy any invading cancer cells. However, these lymph nodes also play a crucial role in activating T cells, which contribute to the immune response against the tumor. Irradiating them at the same time as the tumor could therefore limit the effectiveness of immunotherapy.

The researchers want to understand exactly how radiation therapy disrupts the function of the lymph nodes and determines best to protect them. They will investigate whether delaying their irradiation—or adjusting the doses and treatment schedule—can preserve the immune response without reducing disease control. Ultimately, these findings will be used to prepare a clinical trial in patients with head and neck cancer.

Mobilizing the liver’s immune cells to better fight cancer

Enhancing immune-therapeutic approaches to liver cancer by using endogenous liver immune cells to enhance the response.

This project aims to develop new immunotherapy approaches for hepatocellular carcinoma, the most common form of liver cancer. The researchers are focusing on Kupffer cells, immune cells naturally present in the liver that can capture tumor-derived molecules and activating CD8 T cells against cancer cells.

The goal is to restore and strengthen this immune response, which is often weakened by chronic inflammation, viral infections, or tumor progression. The project also aims to identify specific markers on the surface of cancer cells and to develop antibodies capable of bringing these cells into close contact with Kupffer cells. This strategy could improve the quality and duration of the immune response, both in liver cancers associated with the hepatitis B virus and in those of non-viral origin. This daring approach is a new immunotherapeutic paradigm and as such may be game-changing.

Innovative tools to replace radical surgical approaches to bladder cancer

Ultrasound Embolization for Minimally Invasive Local Treatment of Bladder Tumors

Persistent or recurring non–muscle-invasive bladder cancer (NMIBC) usually requires radical surgery that removes much of the bladder. This severely affects the patient’s quality of life. This proposal concerns a bladder-preserving alternative through image-guided therapy using a biocompatible liquid called “sonoink.” The material would be injected into the tumor, and then focused ultrasound will trigger it to solidify only within the tumor area. This may block tumor blood supply, mechanically consolidate the lesion, and possibly kill tumor cells allowing efficient resection that preserves the bladder wall, ideally avoiding radical surgical intervention.

How can we identify lung cancer patients that will respond to immunotherapy?

Chemokine spatial profiling in lung cancer: improving prediction of potential response to immunotherapy

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, and in many patients, but not all, it responds to immune checkpoint inhibitor therapy. This project aims to identify patients that will or will not respond to immunotherapy based on the mapping of cytokines, small signaling molecules that control the immune response. Combining cytokine data with other information derived from lung tumor biopsies, this team aims to understand why many NSCLC patients do not respond to the treatment. 

Using a human cohort of patients, made up of 27 responders and 14 non-responders, chemokine-driven immune niches will be mapped using high-dimensional molecular imaging of human biopsies. Collaborating with skilled AI experts, they hope to be able to predict response to immune-checkpoint inhibitor therapies.

Preventing immune exhaustion during cancer immunotherapies

Spatial NFAT5 activity as Determinant of Immune Failure and Target for Next-Generation Cancer Immunotherapies

This team has long been interested in why the immune cells that are responsible for attacking cancer cells gradually lose their effectiveness within certain tumors, compromising immunotherapeutic approaches. The researchers focus on NFAT5, a protein that is particularly active in necrotic areas of the tumor, where local conditions appear to contribute to the exhaustion of immune cells. They will study this mechanism in samples of melanoma and lung cancer to determine whether NFAT5 activity can help predict treatment response.

The project will also evaluate a strategy aimed at blocking NFAT5 to restore the antitumor activity of T cells. The researchers will test this approach in preclinical models and on patient-derived tissues, as well as in the context of cell therapies. The goal is to improve the persistence and efficacy of immune cells used in cell-based immunotherapies against many tumors.