Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive pancreatic cancer with limited treatment options. PDAC is the most common pancreatic malignancy accounting for over 90% of pancreatic cancer cases. Due in part to typically late diagnoses, five-year survival for those diagnosed with PDAC is less than 9%. Further, the therapeutic advances made over the past two decades have resulted in a mere three-week survival benefit.
Despite the dreary outlook on this awful disease, a promising study published last week in the New England Journal of Medicine describes a therapeutic option that produced disease regression.
The brief report describes the case of a 71-year-old woman with progressive metastatic pancreatic cancer. The patient had a long history of pancreatitis and biliary stricture, and she had received a cancer diagnosis at age 67. She first received chemotherapy followed by tumor resection. Following surgery, the patient received additional chemotherapy along with radiation therapy.
While briefly becoming disease-free, the cancer metastasized to the lung about a year later. She then entered a clinical trial (NCT03935893, receiving an infusion of ex vivo expanded tumor-infiltrating lymphocyte (TIL) therapy and high-dose interleukin-2 (IL-2). This therapy involves removing TILs from the patient, and subsequently, the cells are grown in a laboratory. Doctors will then administer the expanded pool of cells back to the patient. IL-2 is a cellular signaling mediator known as a cytokine. This specific cytokine is integral to cell growth and survival, and thus, it is provided to help the recently transferred cells continue to grow and increase. Within six months of this treatment regimen, the patient’s lung metastasis grew larger.
The next therapy, approved by the FDA through a single-patient investigational new drug application, involved some additional engineering of the T cells before returning them to the patient. T cells extracted from the blood underwent a retroviral transduction, a laboratory procedure that integrates DNA into the genome of a dividing cell. The engineering resulted in two T cell receptors (TCRs) activated to target an oncogene (KRAS G12D) highly expressed on the tumor cells but not on healthy cells. The TCR, located on T cells, binds antigens on cancer cells, thus activating an anti-tumor immune response, killing the cancer cells. Inserting the TCRs primed to discover the protein expressed on tumor cells increases the odds that TILs will find cancer cells and eventually kill them.
Following the treatment, the metastases regressed significantly. The patient’s tumors shrunk by 72% according to the Response Evaluation Criteria in Solid Tumors (RECIST), a systemic method to evaluate therapeutic efficacy. There was no regrowth of the metastasis six months following treatment at which time the specially engineered T cells made up more than 2% of the T cells circulating in the blood.
This approach reprograms a patient’s own cells so they can find and destroy cancer cells, without damaging healthy cells. While the publication described a case study in a single patient, the strong efficacy demonstrated in this aggressive and virtually untreatable form of cancer shows excellent progress in the fight against PDAC.
Sources: World J Gastrointest Oncol, Eu J Cancer, Curr Protoc Mol Biol, NCI Visuals Online
