Grant Archive - V Foundation

Nelson LaMarche, PhD

Immunotherapy has changed how we treat cancer. It helps the immune system find and kill cancer cells. But only some patients benefit. In many cases, tumors contain cells that weaken the immune response and protect the cancer. One important group of these cells is called myeloid cells. They are made in the bone marrow, the soft tissue inside our bones. From there, they travel through the blood to tumors. Once in the tumor, they can stop the immune system from doing its job. Our recent work shows that these harmful cells may be shaped very early, while they are still developing in the bone marrow. We discovered that a rare cell called a basophil plays a key role. Basophils send out signals that guide how myeloid cells develop. In cancer, basophils become active and produce signals that lead to more immune-suppressing cells.Basophils have not been well studied in cancer. We do not yet know what turns them on or how they control other immune cells.Our goal is to answer these questions. First, we will identify the signals basophils release that promote immune suppression. Second, we will learn what activates basophils during cancer. By targeting these early steps in the bone marrow, we hope to create new treatments that help more patients respond to immunotherapy.

Wenwei Hu, MD, PhD

Recent advances in cancer immunotherapy, a powerful treatment which helps our immune system find and destroy cancer cells, have changed how we treat cancer. For some patients, this can lead to long-term control of cancer, or even a cure. However, not all patients benefit from immunotherapy. One reason is that cancer can protect itself by weakening the immune system.Tumors grow in an environment made of cancer cells, normal cells, immune cells, and nearby tissue. This tumor microenvironment plays an important role in how cancers grow and treatments work. Many tumors release proteins that change this environment. These proteins can create an “immune-suppressive” state that shields cancers from attacks by immune cells. To date, we still do not fully understand how this shield forms and stays in place.Our research focuses on one such tumor-secreted protein, called leukemia inhibitory factor (LIF). Cancer cells release LIF into the tumor microenvironment, helping the tumor grow and leading to worse survival outcomes. This project will study how LIF works within the tumor microenvironment. We will study how LIF weakens the immune system, which lets cancer grow and escape attack. By learning how LIF affects the immune system, we hope to find new ways to block it and make immunotherapy work better. Because LIF is found at high levels in many cancers, this research could help improve treatment for many patients.

Zachary Schug, PhD

Cancer treatments that use the power of the human immune system have greatly improved survival for many cancer patients around the world. However, these treatments have not helped most people with breast cancer. One reason is that the environment inside breast tumors is very harsh. Because of this, the body’s normal white blood cells have trouble surviving and working properly in these tumors. As a result, the immune system cannot fight the cancer as well as it should. There is a critical need to find treatments that can change these conditions and allow the immune system to do its job. Our research has found a new way to do this. Our approach slows the growth of breast cancer, increases the activity of helpful immune cells, and reduces the activity of harmful immune cells. In this project, we will study how this process works in more detail. We will also test whether our approach works even better when combined with newer breast cancer treatments. Our goal is to learn how to use this strategy to improve treatment for patients. We believe our findings could quickly help guide new ways to treat breast cancer and, in the long run, improve the survival of breast cancer patients, including those with metastatic disease.

Jashodeep Datta, MD

Pancreatic cancer is very hard to treat. Even after surgery, it often comes back. One reason is the tissue around the tumor. This tissue can help the tumor grow and hide from treatment. Our work targets a key set of harmful signals in this tissue. Many of these signals use one helper protein, called IL1RAP. We will test a drug called nadunolimab that blocks IL1RAP. We hope this will quiet these signals and help standard treatment work better, especially when treatment is given before surgery. We will study the effect of IL1RAP in two main cell groups: 1. certain white blood cells that can block the body’s immune attack, and 2. support cells that can build a barrier around the tumor. We will also study tumor samples from patients. We will test whether the presence of IL1RAP-rich cell “neighborhoods” predict how well treatment works or does not work. In animal models of pancreatic cancer, we will test if adding nadunolimab before surgery can delay or prevent relapse after surgery. Finally, we will develop simple tissue and blood tests to show early if the drug is working. These tests can guide future trials and improve care for people with pancreatic cancer.

Yun Li, MD, PhD

This project aims to find better treatments for advanced prostate cancer. This type of cancer is very hard to treat once it spreads. Many treatments, including immunotherapy (which helps the body fight cancer), have not worked well for these patients. One reason is that prostate cancer can “hide” from the immune system.Our research focuses on combining two types of treatment: radiation and immunotherapy. Radiation can damage cancer cells, but it can also help “wake up” the immune system. When cancer cells are hit by radiation, they send out signals that make them easier for the immune system to see. In this project, we use a newer type of radiation that travels through the bloodstream and can reach cancer cells throughout the body. Unlike standard radiation that targets only one spot, this approach can find and treat cancer wherever it has spread and may help activate immune cells across the whole body. After this, we give a newer form of immunotherapy that helps immune cells find and attack the cancer more directly. You can think of radiation as turning on a signal, and immunotherapy as helping the immune system follow that signal to the tumor. We will study blood and tumor samples over time to learn how the immune system responds to this combination. Our goal is to find the best timing and way to give these treatments, so they work better together. This research could lead to more effective and longer-lasting treatments for patients with advanced prostate cancer and may help improve care for other cancers as well.

Douglas Mitchell, PhD

The immune system normally protects us from cancer by finding and removing abnormal cells before they grow. Many solid tumors develop when they learn how to hide from the immune system. Frequently, immune cells cannot enter the tumor because the tumor builds a strong barrier around itself. A major part of this barrier comes from a signal called TGF-beta. Tumors use proteins called integrins as “on-switches” that turn on TGF-beta. When TGF-beta is active, it creates conditions that keep immune cells out. If we can safely turn off this switch inside the tumor, the immune system may be able to enter and attack the cancer. Our research develops very small and stable proteins called lasso peptides that are designed to turn off this TGF-beta switch in tumors. By blocking the switch, these lasso peptides may open the door for immune cells to enter and may help existing drugs work better to kill the cancer cells. We will test these new agents in models of solid tumors to see how they change the tumor environment and support immune responses.We are also creating an imaging tool that lets doctors see whether the drug appropriately reaches a patient’s tumor. This information will guide future clinical studies and help match patients with the right treatment. If successful, this work will make immunotherapy effective for many more people with solid tumors and give patients a better chance at longer and healthier lives.

Marcela Maus, MD, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund

As we continue this study of a new treatment called TriPRIL CAR-T cells for patients with multiple myeloma that has come back or not responded to treatment, we want to understand why the treatment works for some people but not for others.To do this, we will study samples of blood and bone marrow from patients over time. We will compare what we find to results from patients who received other approved CAR-T cell treatments.We will look at how the CAR-T cells behave and work, how the cancer and the bone marrow environment change, and whether the body develops a response against the treatment itself. We will compare patients who improved with the treatment to those who did not.In the end, what we learn will help us improve CAR-T cell treatments for multiple myeloma.

Anupriya Agarwal, PhD

Blood cancers are challenging to treat. The main reason is that cancer is found at late stages, where current treatments often fail. To save more lives, we must change our approach. We need to shift our focus from treating late-stage disease to stopping it early. We can achieve this by understanding how cancer starts. Many studies report that warning signs appear decades before cancer diagnosis. As people age, mutated blood cells can form in the body. This raises the risk of blood cancer by twelve times. Our research found that more chronic inflammation within bones creates a hostile environment. This inflammation acts like fuel for mutated cells. It helps them grow while harming healthy ones. A primary driver of inflammation is obesity, a condition that affects 40% of U.S. adults, and is a cancer risk factor. This long lead time offers a vital window of opportunity for early treatment. We propose a strategy to starve these bad cells. We aim to cut off the fuel supply linked to cancer cells to prevent cancer. We will test how obesity-driven inflammation helps mutated cells grow and weakens the immune system. Using human and mouse models, we will determine whether anti-obesity treatments can prevent cancer. We will test whether these treatments can reduce cancer growth and improve immune function. We will use computational tools to find high-risk patients. This project will help detect and halt leukemia in people most affected by obesity. The goal is to prevent devastating diseases before they begin.

Andrea Schietinger, PhD

Our immune system has special cells called T cells that can recognize and attack cancer. Even though these tumor-fighting cells are often present, many tumors still grow because T cells stop working properly during cancer development. Cancers can be grouped into two main types based on how the immune system responds. Some are called “hot” tumors. In these cancers, T cells are able to enter the tumor, but the tumor environment weakens them so they cannot kill cancer cells. Other cancers are called “cold” tumors which comprise approximately half of all human cancers. In cold tumors, T cells are mostly missing from the tumors. Cold cancers do not respond well to immune-based treatments. Scientists still do not fully understand why T cells fail to enter cold tumors or why these cancers resist treatment. To study this, we created preclinical mouse models in which tumors grow naturally and show cold immune phenotypes. Using these models, we found that tumor-fighting T cells are present in nearby lymph nodes but do not move into the tumor. Over time, these T cells become resistant to immune treatments, which is linked to the loss of important genes needed for T cell function. In this project, we will study in mice and patients with cancer why T cells get stuck, fail to enter tumors, and stop responding to treatment. This research may lead to new ways to make immunotherapy work for patients with immune-cold cancers.

Yali Dou, PhD

Acute myeloid leukemia (AML) is a fast-growing blood cancer. It is hard to treat, and it often comes back even stronger after treatment. One reason AML is so difficult to fight is that cancer cells take control of the normal systems that turn genes on and off. These systems are called epigenetic controls. When they do not work properly, leukemia cells can grow quickly, avoid treatment, and push out healthy blood cells.This research focuses on one of these gene regulators called MLL1. MLL1 helps turn on important genes in blood cells. In some leukemias, the MLL1 gene is broken or rearranged. However, we now know that a small group of adult AML patients have extra copies of the MLL1 gene. These patients often develop AML after having other blood disorders or after receiving chemotherapy. Sadly, they usually do not respond well to current treatments. Right now, there are no therapies made specifically for this group.Our study uses new knowledge about how MLL1 helps cancer cells grow. We will test whether leukemia with extra or altered MLL1 has weak points that new drugs can target. We will also explore ways to directly target MLL1. Our goal is to develop more personalized treatments that help patients live longer and healthier lives.