State: Texas

Pancreatic cancer is the 3rd leading cause of cancer-related death in the United States, with a five-year survival rate of less than 9 percent. Activation of the immune response in the microenvironment is associated with better outcomes in pancreatic cancer patients. The tumor and gut microbiota has recently been shown to influence tumor progression by modulating the tumor microenvironment.

We have recently demonstrated that the composition of the gut microbiome may determine tumor behavior and outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. We have identified specific bacteria signatures in the tumors of long-term survivors (LTS) compared to the stage-matched- short-term survivors (STS). We have also shown that transplantation of fecal microbiome from LTS or healthy controls of pancreatic cancer patients into a mouse model of PDAC significantly reduces pancreatic cancer growth. These important findings prompted us to target tumor microbiome as a therapeutic approach in pancreatic cancer patients. Here, we propose to transplant stools from PDAC long term survivals or healthy controls into PDAC patient to change their immune suppressive behavior to immunoactivated one. To this end, we will first analyze the changes in microbiome of PDAC patients after the transplantation of gut microbiome from long term survivals or health controls. Next, we will evaluate the tissue obtained from biopsy and surgical specimen for the changes in tumor microbiome of PDAC patients. Finally, we will characterize the tumor immune infiltrates from tissues obtained from PDAC patients to see if we can switch PDAC immunosuppressive TME into immunoactivated by fecal microbial transplantation. This proposal would be the stepping stone to move forward efficacy trials in PDAC patients combining FMT with standard treatment or immunotherapy.

Funded by the Dick Vitale Pediatric Cancer Research Fund

Sarcomas are cancers of connective tissues in the human body. It affects children and teenagers more than adults. Cancers that spread to other parts of the body are difficult to treat and are not often curable. A new treatment approach called immunotherapy uses the body’s own immune system to fight cancer. Our approach uses immune cells of the body, namely T cells, to find and kill tumor cells after introducing an artificial molecule called chimeric antigen receptor (CAR). These CAR-enhanced T cells developed in our laboratory recognize a protein on the surface of the cancer cell, namely HER2. Patients with advanced sarcoma received these HER2-specific CAR T cells in our ongoing clinical trial. The CAR T cells did not cause severe adverse reactions in any of the treated patients. More than half of the 10 patients who received the cell treatment benefited from it, with 2 patients achieving tumor elimination and 4 others achieving cancer stabilization. We will now test if larger dose of T cells can be tolerated or increase the chances of benefit. We will also study immune responses in these patients to identify mechanisms, if any, that can lead to improved treatments. Finally, we will evaluate a new molecule that can help CAR T cells overcome tumor signals that turns them off. The insights gained from this study will help design and develop targeted treatments for sarcoma.

Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund

While immunotherapy can sometimes result in dramatic and prolonged responses, it can also cause major toxicities.  Immune-related adverse events (irAEs) are quite different than the toxicities seen with other cancer treatments, such as conventional chemotherapy.  They occur when immunotherapy causes the patient’s own immune system to attack normal organs in the body.  These toxicities may occur at any point in treatment, may be severe, and—of particular concern to cancer survivors—may be permanent.     

irAEs remain poorly understood partly because immunotherapy research has focused almost exclusively on tumor biology, which is certainly relevant to immunotherapy effectiveness.  However, we believe that toxicities irAEs have more to do with patients’ own immune systems.  Our research team has expertise in cancer, immunology, and genetics.  We have already collected clinical information and blood samples on hundreds of patients receiving cancer immunotherapy.  With this information, we have identified some blood-based tests that may predict the future development of irAEs.   

We now take this research to the next level by proposing genetic and functional tests to identify underlying predisposition to irAEs.  Specifically, we will study DNA and RNA in blood samples from our existing patient cohort.  If successful, our research could ultimately help (1) identify high-risk patients, (2) customize therapy, (3) tailor monitoring, (4) expand immunotherapy use, and (5) prevent toxicities. 

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.

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.