Zureikat

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. 

Glorioso

Significant strides have been made in the treatment of solid tumors using viruses designed to attack and kill tumors (Oncolytic Viruses: OV) following direct injection into a detectable tumor mass. Tumor cell killing releases tumor-related proteins capable of inducing anti-tumor immunity, potentially eliminating similar tumor masses throughout the body.  

The first OV to achieve FDA approval is an oncolytic herpes simplex virus (oHSV) whose use in treatment of late-stage melanoma achieved a significant “cure” rate (~50%) when administered in combination with antibodies that enhance tumor rejection. Here we propose to create substantially improved oHSV vectors that will be extraordinarily safe (tumor targeted) and highly resistant to pre-existing anti-HSV immunity common in the human population. The advanced vector design will allow intravenous administration of a “heat-seeking missile” that targets metastatic cancer for destruction and consequently induces protective immunity against relapse.

Delgoffe

Recent clinical successes have revealed that the immune system can be successfully harnessed to fight cancer. Various strategies are utilized, including enhancing a patient’s ‘natural’ response to cancer as well as ‘redirecting’ a patient’s immune cells (‘T cells’) to the tumor using genetic engineering. While these T cell therapies have had major success in leukemias, they have not yet shown promise in the treatment of solid tumors.  

T cells require an enormous amount of fuel to perform their tumor-killing functions. However, we have recently shown that in solid tumors, cancer cells evade immune responses in part by depriving the T cell of the ability to generate energy and depleting the local environment of nutrients.  

In this Alliance for Cancer Gene Therapy funded research program, we will utilize genetic engineering to metabolically ‘reprogram’ tumor-specific T cells. Using this technology, they will become more fit to fight cancer for an extended period of time. We will test these T cells in animal models and translate these findings into human T cells as well. The goal is to generate super-soldier type T cells, those that can be both redirected to the tumor site, but also bolstered metabolically to support long-term and durable responses.  

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.