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Vaccine May Cause Pancreatic Cancer to Respond to Immunotherapy

Scientists reprogram tumor cells to become immunogenic

Pancreatic ductal adenocarcinomas (PDACs) do not typically respond to immunotherapy, which limits treatment options for this type of cancer. By priming with a therapeutic vaccine and a low-dose chemotherapy combination before surgery, researchers converted PDACs into immunogenic cancers that may respond to immunotherapy, according to a study published in Cancer Immunology Research.

In the clinical study, pretreatment of PDAC patients with the vaccine GVAX and low doses of the chemotherapy cyclophosphamide caused the aggregation of immune cells inside the patients’ tumors, and many of these immune cells expressed proteins that may make these cancers amenable to immunotherapies, such as programmed cell death protein-1 (PD-1) inhibitors.

“Our study shows for the first time that treatment with a vaccine-based therapy directly reprograms the pancreatic cancer microenvironment, allowing the formation of lymphoid aggregates, which are organized, lymph node-like, functional immune structures, and which convert an immunologically quiescent tumor into an immunologically active tumor,” said lead investigator Lei Zheng, MD, PhD, of the Johns Hopkins University School of Medicine.

Between 2008 and 2012, Zheng and his colleagues randomly assigned 59 patients with PDAC into three treatment arms. Patients in arm A received GVAX alone; patients in arm B received GVAX plus a single intravenous dose of cyclophosphamide (200 mg/m2); and patients in arm C received GVAX plus 100-mg oral doses of cyclophosphamide once daily on alternate weeks.

Approximately 2 weeks after vaccination, all of the patients underwent surgery to remove their pancreatic tumors. Of the 59 patients, 39 remained grossly free of disease after surgery and underwent further treatment with chemotherapy and radiotherapy. These patients’ tumors were analyzed in the study.

In addition to tumor samples from the 39 patients, the researchers used, for the comparative analyses, tumor samples from 58 patients from other studies. Four patients were unvaccinated, and 54 were patients whose tumor samples were collected before vaccination.

The researchers found that the vaccine-chemotherapy combination resulted in the formation of lymphoid aggregates within the tumors in 33 (85%) of the 39 patients within 2 weeks of vaccination.

Analysis of the various immune cell types found in the tumors after vaccination showed an increase in the ratio of effector T cells to regulatory T cells. According to Zheng, this meant that the tumors had become immunogenic and that the immune cells in the tumor area were capable of fighting the cancer cells. An increase in the ratio was associated with better survival.

The researchers also found that the tumors from patients who survived for more than 3 years after vaccine therapy had enhanced signaling pathways that promoted immune responses compared with patients who survived for fewer than 1.5 years after vaccination.

“Our study has suggested a new model for developing more effective immunotherapy for traditionally nonimmunogenic tumors, like pancreatic cancer,” Zheng said. “We will next investigate immunotherapies that include both cancer vaccines and treatments that boost the ‘good’ immune-regulatory signals or block the ‘bad’ immune-regulatory signals.”

Source: AACR; June 18, 2014.

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