Diffuse Large B-cell lymphoma (DLBCL) is a common cancer in the US, causing tens of thousands of deaths each year and their incidence is on the rise. MicroRNA regulate the use of other genes and they are frequently mutated in human cancer One of these, miR-155 has been shown to be overproduced in several different lymphoma types, including cutaneous T-cell lymphoma (CTCL) and diffuse large B-cell lymphoma (DLBCL). This miRNA is an excellent target for therapy in DLBCL. miRagen Therapeutics, Inc. is currently testing the safety and efficacy of an inhibitor to miR-155 in patients with CTCL and DLBCL. This is an entirely novel class of drug, and as such requires some research into the parameters for successful delivery and monitoring. In this proposal we seek funding to allow studies that would support these clinical trials. We propose to identify biomarkers to help stratify patients to enroll in the clinical trial, biomarkers of response, and to determine the best route of delivery and the best source of tissue for miR-155 detection.
The studies of this proposal will address a central question in personalized cancer treatment. Many recent studies have generated three-dimensional tissue models of human tumors, known as organoids, which can be grown and analyzed in the laboratory. Thus, these organoids can be considered “avatars” of their corresponding patient tumors. However, it is unknown whether drugs that affect organoid growth in the laboratory would have similar effects in patients. If so, patient-derived tumor organoids could be used to predict effective treatment.
We will utilize patient avatars to investigate muscle invasive bladder cancer, a highly lethal disease that is treated by chemotherapy followed by surgical removal of the bladder, which drastically affects quality of life. We will use an approach known as “co-clinical trials” to simultaneously test drug response in the clinic with that of patient avatars in the laboratory. In particular, we will determine whether patient avatars are able to predict which patients who have no residual tumor after chemotherapy can safely avoid removal of the bladder.
We have assembled an outstanding research team to investigate whether the response of patient-derived organoids to chemotherapy in the laboratory correlates with the response of the corresponding patients in the clinical trial. In addition, we will examine whether there are specific genetic alterations that are associated with sensitivity to chemotherapy. Consequently, our findings have the potential to greatly improve the standard of care for patients with muscle invasive bladder cancer.
Synovial Sarcoma is a cancer that affects 800 Americans every year, generally teenagers and young adults. Although it can be cured if caught early, it often spreads though-out a patient’s body making it very difficult to eradicate. A new type of therapy, known as immune checkpoint inhibitors, can unleash anti-tumor immune responses against many types of cancer. But these treatments are not effective against Synovial Sarcomas. We think this is because immune cells rarely enter the tumor, and the few immune cells that are nearby cannot “see” the tumor. We have worked to address this barrier and our early findings suggest that combining checkpoint inhibitors with an old drug called interferon gamma can empower immune cells to eliminate Synovial Sarcoma.
In our new project, we will test the interferon + checkpoint inhibitor combination in a clinical trial. Using tumor and blood samples from patients, we will perform a thorough analysis of both tumor and immune cells in order to learn how to make this therapy work better and for even more patients. While Synovial Sarcoma is a rare cancer, there are other cancer types that seem to be resistant to checkpoint inhibitors for similar reasons, and our findings will likely be broadly applicable.
Cancer typically arises from a very small number of cancer stem cells. Cancer stem cells that survive initial therapy can hide for a long time. Even years after successful treatment, the cancer stem cells can prompt the cancer to return. If the cancer returns after treatment, it becomes much harder to treat, so doctors try to avoid this. On the other hand, killing cancer stem cells has proven to be an effective strategy to achieve long-term cure and to prevent the cancer from returning at a later time. In addition, this strategy helps to improve survival and reduce side-effects of treatment. This proposal studies cancer that arises from cells of the immune system, the so-called “B-cells”. Unlike other types of cancer, stem cells in B-cell cancer have not been identified. As a consequence, the therapies that are tailored to target stem cells in other types of cancer would not work for patients with B-cell cancer. We recently discovered that stem cells in B-cell cancers express a surface molecule, which allows to escape drug-treatment for some time. We have shown that a drug that delivers a poison into the cancer cells has strong effects in animals that bear the human cancer. In addition, we have engineered a patient’s own immune cells to recognize and fight B-cell cancer stem cells. This strategy will help the patient’s immune system to spot and kill B-cell cancer stem cells more efficiently. We will leverage these approaches to improve outcomes for patients with B-cell cancer while at the same time we aim at reducing the burden of side-effects that would come from typical chemotherapy.
RAS is a gene when mutated causes a wide variety of human cancers. However, there is no specific therapy against cancers driven by RAS mutations. Metastatic melanoma is an aggressive skin cancer, and up to a third of cases are caused by RAS mutations. In this study, we propose to develop a specific therapy against RAS mutated melanoma. This therapy involves starting with one drug that optimizes the patient’s own immune system against the cancer followed by adding on a second drug that blocks an overactive cancer-causing pathway driven by mutated RAS. We will first test this therapy in animal models in order to understand the mechanisms. We will then begin to design and initiate a clinical trial to test this regimen in patients whose melanoma harbor RAS mutations. Thus, we will test the hypothesis that distinct drugs when combined in a specific sequence may have dramatic anti-cancer effects not expected of individual drugs.
Funded by the Constellation Gold Network Distributors
Diffuse large B cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, can often be cured with chemotherapy. However, DLBCL will relapse in ~40% of patients. When this happens, currently available treatments are usually not effective. Treatments for relapsed DLBCL also cause many side effects that affect quality of life. Programmed death-1 (PD-1) blockade immunotherapy has been very effective in treating a number of human cancers, and is generally well-tolerated by patients. Unfortunately, PD-1 blockade therapy has not been very effective for patients with relapsed DLBCL. Therefore, we need to define biological markers that identify DLBCL patients who are likely to benefit from this type of treatment. In search of such a marker, we found that DLBCLs with an increased number of genes for the partner of PD-1, known as programmed death-ligand 1, were associated with strong evidence that an immune response had been generated against them. We will now test whether lymphomas with PD-L1 gene duplications will be more likely to shrink after treatment with PD-1 blockade therapy, and we will also attempt to determine what other features of these lymphomas are important in determining whether the immune system can recognize them. We expect that the knowledge gained from our studies will improve outcomes for patients who have DLBCL that has relapsed.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Gala
Children with liver cancers are hard to cure, if the tumor cannot be removed by surgery or has spread to distant organs. Current therapies cause significant toxicity and don’t work well against large tumors. These children need new approaches and immunotherapy may be a good solution. Immunotherapy relies on the body’s own infection and cancer fighting system.
A type of immunotherapy uses special white blood cells called T cells. T cells can be collected from patients and engineered with a molecule called chimeric antigen receptor or CAR. These CAR T cells can be infused back to patients to destroy the cancer cells.
We developed several versions of CARs which recognize glypican-3. This molecule is expressed in pediatric liver cancers. We systematically tested T cells expressing these CARs in preclinical models of liver cancer. We selected the CAR with the strongest antitumor activity. Now T cells expressing this CAR will be tested in a Phase 1 clinical trial in children.
With the help of the V Foundation, we will examine changes in the genetic programming of CAR T cells. We will evaluate the CAR T cell product, peripheral blood and biopsy samples. Our goal is to define the interaction between the CAR T cells and the tumor.
Our body’s immune system recognizes and destroys foreign invaders such as infections or cancer. Malignant tumors try to outsmart and hide from the immune system. Therapies that activate T cells, a key part of the immune system, are effective against multiple cancers. Myeloid cells are a second important part of the immune system. Myeloid cells can be activated by removing a protein called p50. Our laboratory finds that infusion of myeloid cells lacking p50 into mice leads to shrinkage of several types of cancer, including prostate and pancreatic cancers. We now seek to further improve the effectiveness of myeloid cells lacking p50, to develop human myeloid cells lacking p50 suitable for use in patients, and to evaluate the ability human myeloid cells lacking p50 to shrink human prostate and pancreatic cancers growing in mice. We anticipate that completion of these studies will allow us to begin clinical trials testing the benefit of human myeloid cells lacking p50 as a novel treatment for multiple cancers.
Immunotherapy has revolutionized cancer treatment. Immunotherapy drugs work with the immune system, which normally fights intruders such as viruses, to kill cancer cells. One approach involves taking down defenses set up by cancer cells to escape immune cells. Some tumors, such as kidney cancer, melanoma, and lung cancer, display on their surface a protein (PD-L1) that shuts off approaching killer immune cells. Drugs have been developed that mask PD-L1 allowing killer cells to dispose of cancer cells. Discoveries underlying these developments were recognized with a Nobel Prize in 2018.
However, not all tumors use the same defense mechanism. Here, we propose a novel strategy to identify patients most likely to benefit from drugs masking PD-L1. Up until now, most approaches have focused on evaluating PD-L1 on tumor biopsy samples. However, only one cancer site is sampled, few cells are evaluated, and the results are often unreliable.
We have developed a strategy adapting a radiology test, positron emission tomography (PET), and a PD-L1 masking drug, that allows us to evaluate PD-L1 across all tumor sites. In preliminary experiments, we show that we can label a PD-L1 masking drug so that it can be detected by PET. We then show, using patient tumors transplanted into mice, that we can identify tumors with high PD-L1.
Our goal is to evaluate immuno-PET (iPET) in patients in a clinical trial. If successful, iPET will better match patients to their immunotherapy drug, and identify patients unlikely to benefit and for whom other strategies should be developed.
Funded by the Stuart Scott Memorial Cancer Research Fund
Lung cancer is the main cause of death in the world. For unknown reasons, African Americans (AA) have more aggressive lung cancer compared to Caucasians. Recently, immunotherapy demonstrated that one out of five of patents have tumor shrinkage. Long term remissions are happening in one out of seven lung cancer patients. This is very exciting, but combinations of 2 or 3 immunotherapy drugs are needed to cure more patients.
We proposed the lung cancer treatment combination that can block tumor blood vessel growth, and boost immune system. We think that this combination approach will cure more lung cancers. We will soon start a clinical study combining two immunotherapy drugs. One out of four patients on our study will be AA. We hope to find immune or blood vessel growth related markers to help predict who would benefit from this drug combination. This can help to use the right drugs for the right patients. In this study, we also plan to investigate why AA have more aggressive lung cancer.
In Aim 1, we will perform detailed analysis of blood proteins and white cells from the blood of patients participating in our study. In Aim 2, we will correlate genes and other markers with response to immunotherapy combination. In Aim 3, we will compare blood proteins and tissue gene levels between AA and Caucasians.
