Glioblastoma is the most common and aggressive type of primary brain tumor. Despite therapeutic advances over the past decade, the diagnosis of glioblastoma is associated with a median overall survival time of 15-18 months and a 5-year survival rate of less than 5%. Even if treatment with the current standard of care for glioma patients, which consists of surgery, temozolomide, and radiotherapy, is initially successful, nearly all malignant gliomas eventually recur. At the moment of recurrence, no treatment successfully cures the disease. 

Naturally occurring or genetically modified viruses that selectively kill cancer cells are called oncolytic viruses. 

In our laboratory, we have developed a platform of oncolytic viruses termed Delta-24. A new generation of this cancer-selective oncolytic adenovirus model, Delta-24-RGD, has arrived in the clinical arena and has been tested in patients with recurrent glioblastoma showing encouraging safety and efficacy results. Thus, 20% of patients treated with Delta-24-RGD as a single treatment survived more than 3 years after a single dose of this biological agent. Unfortunately, rapid clearance of the virus by the immune system prevents a response in a higher percentage of patients. In addition to other pre-clinical and clinical evidence, data from our clinical trial demonstrate that to improve the percentage of patients that respond to the therapy, we need to decrease the immune response against the virus, which in turn will increase the immune response against the tumor. 

Therefore, this proposal aims to improve the response to virotherapy by attenuating the immune response against oncolytic adenovirus, with the goal of boosting the anti-tumor efficacy of this strategy. To this end, we propose two different strategies that can eventually be combined in a clinical trial. The first approach consists of making the virus less detectable by the immune system via substituting the most immunogenic viral protein with another viral protein for which the patients have not developed a pre-existing immune response. This new virus will persist longer in the tumor environment and thus maintain the window of opportunity to develop an anti-tumor immune response for a more prolonged time. 

Our second approach involves the generation of tolerogenicity for the virus. To achieve this objective, we will target dendritic cells, which are in charge of the antigen presentation to the immune effector cells, using nano molecules to deliver viral antigens. 

This strategy will diminish the response of the immune system against viral antigens, allowing the immune defenses to be focused on the tumor. If this highly innovative project is successful, we have the resources and infrastructure already in place to further translate these two strategies, as single approaches or in combination, to treat malignant brain tumors in the clinical scenario. 

Children with diffuse midline gliomas (DMGs) – a type of brain cancer – continue to have a dismal prognosis, and most children die within one year of diagnosis. Recent studies have shown that the majority of these tumors carry a specific mutation referred to as H3.3K27M. Researchers have shown that this specific mutation is present in almost all DMG tumor cells but not in normal cells within the body, making this an attractive target for immunotherapy approaches that activate an immune response against the cancer cells. Immunotherapy has shown phenomenal improvements in the outcome of adults and children with specific types of cancers, such as melanoma and leukemia. However, we are just starting to implement such novel and promising approaches for DMGs in the clinic.

With this proposal, we will test the benefit of a specific immunotherapy approach referred to as adoptive T-cell transfer, which gives the patient a large number of killer T cells. More specifically, we will test an approach known as engineered T-cell receptor (TCR) therapy, in which killer T cells are engineered to be specific to a piece of protein on the surface of tumor cells.

We have been able to show in the laboratory that we can make T cells specifically recognizing DMG cells with the H3.3K27M – and that these specific T cells can kill tumor cells. Based on these exciting data, we propose to test this new therapy approach in the clinic. Participants who are newly diagnosed with an H3.3K27M DMG are eligible for this clinical trial. They will undergo collection of their own T cells, and these T cells will subsequently be engineered in the laboratory to recognize the specific H3.3K27M mutation. These modified T cells will then be given back to the participants once they have completed standard-of-care radiation therapy and a conditioning short chemotherapy course. We hypothesize that these modified T cells will now be able to kill the cancer cells carrying the specific H3.3K27M mutation.

Within this project, we will assess if such a therapy approach is feasible and safe. Precisely, we will test how many of these specifically modified T cells are able to be given back to participants without causing too many side effects. Further, we will perform specific tests from blood samples from trial participants to assess how long these modified T cells survive. To better understand responses, we will use advanced molecular technologies to assess the blood of participants. This information will help us to improve our ability to assign patients to the right therapies and make even more effective tumor-targeting T cells in the future.

This project has the potential to significantly impact the treatment approach for a disease for which we have not achieved any improvement for the last several decades and is the first of its kind for this devastating disease.

Pancreatic cancer is a major public health problem with approximately 57,600 new cases in 2020. Five-year survival is less than 9% for all stages, with surgical resection the only potentially curative therapy. Nonetheless, a clear majority of patients are not candidates for surgery due to locally advanced disease or metastatic spread, and ultimately derive little to no survival benefit from radiation or chemotherapy.  

Advances in cancer immunotherapy have revolutionized cancer care, providing hope in the form of durable cancer regression and long-term survival. In patients with treatment refractory metastatic melanoma, immunotherapy in the form of adoptive transfer with tumor infiltrating immune cells (TIL therapy) has yielded practice changing response rates, with complete remission in 10-20% of patients.  

Unfortunately, an immune response to pancreatic cancer has been elusive in most clinical trials, and thus identifying methods to enhance the immune response to cancer has been the focus of our research program in the last two decades. Recent transient responses to TIL therapy in pancreatic cancer obtained at the NCI Surgery Branch and our institution have revitalized our interest in improving TIL therapy outcomes.

A tumor’s ability to evade the immune system can be attributed to an immunosuppressive tumor microenvironment and downregulation or loss of the major histocompatibility complex (MHC), which is required by immune cells to recognize malignant cells. Conventional immunotherapy approaches, including TIL therapy, rely on activation and tumor specific recognition of T cells with alpha-beta T cell receptors that require intact MHC expression. However, with 60% of primary and 90% of metastatic pancreatic tumors exhibiting mutated or reduced expression of MHC molecules, new immunotherapy approaches are necessary to elicit improved treatment responses. Gamma Delta (gd) T cells are an understudied tissue resident immune subset that can recognize a broad range of antigens without the presence of MHC molecules.  

Gamma Delta T cells comprise as much as 40% of tumor infiltrating lymphocytes in pancreatic cancer and display potent antitumor immunity. Utilizing the resources of our world-renowned pancreatic cancer treatment center and established cell therapy production facility, we aim to evaluate the efficacy of gd TIL therapy for patients with metastatic pancreatic cancer. After developing a clinical grade cell manufacturing protocol to grow gd TIL and compare tumor specific reactivity with alpha beta TIL, we aim to conduct a pilot Phase I/II clinical trial assessing the safety and preliminary treatment efficacy of gd TIL therapy. We will also identify MHC independent TCRs from gd TIL for further development as universal gene therapies.  

Ultimately, this study will define the therapeutic potential of tumor infiltrating gd T cells, helping to advance pancreatic cancer into a disease that our own immune system, ‘the best doctor’ can control.