Vaccine-chemo combination boosts immunotherapy in pancreatic cancer

A therapeutic vaccine combined with low-dose chemotherapy primed almost 85% of pancreatic ductal adenocarcinomas to potentially respond to immunotherapy, according to researchers.

The report was published online June 17 in Cancer Immunology Research.

The small trial "provides the strongest rationale so far for combining immune-modulating agents with vaccination in patients whose tumors do not naturally contain abundant effector T cells," said Dr. Eric Lutz of Johns Hopkins University, Baltimore, and his associates. "Here, we report the first description of tertiary lymphoid aggregates infiltrating human PDAC [pancreatic cell adenocarcinomas]. These aggregates develop 2 weeks after a single treatment with a PDAC vaccine," they added.

The researchers randomized 39 patients with resectable pancreatic cell adenocarcinomas to receive irradiated, granulocyte-macrophage colony-stimulating factor–secreting , allogeneic vaccine (GVAX) alone, GVAX plus a single intravenous dose of cyclophosphamide at 200 mg/m² 1 day before each vaccination, or GVAX plus oral cyclophosphamide 100 mg once daily for 1 week on and 1 week off. Two weeks after vaccination, all patients underwent tumor resection surgery (Cancer Immunol. Res. 2014 June 17 [doi: 10.1158/2326-6066.CIR-14-0027].

Histologic analysis showed that tumors from 33 of the 39 patients (84.6%) had formed vaccine-induced intratumoral tertiary lymphoid aggregates, the researchers said. "Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity," they added, noting that after vaccination, the ratio of effector T cells to regulatory T cells increased, indicating immunogenicity.

Furthermore, the researchers found that lymphoid aggregates in tumors from patients who survived more than 3 years after vaccine therapy had significantly greater IL17A protein expression compared with patients who survived for less than 1.5 years after vaccination (P = .02).

"On the basis of the evidence available, this model explains why vaccination and immune modulation as single-agent therapies have failed in patients with PDAC," the investigators said. They cited their prior study, which showed objective responses when patients received a combination of GVAX and ipilimumab but not when they received ipilimumab alone (J. Immunother. 2013;36:382-9).

Researchers estimate that pancreatic ductal adenocarcinoma kills 95% of patients within 5 years of diagnosis.

The National Institutes of Health, Johns Hopkins School of Medicine Clinical Scientist Award, American Society of Clinical Oncology Young Investigator Award, Viragh Foundation and Skip Viragh Pancreatic Cancer Center at Johns Hopkins, National Pancreas Foundation, Lefkofsky Family Foundation, Lustgarten Foundation, Sol Goldman Pancreatic Cancer Center, and AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award funded the study. A coauthor disclosed ties to Bristol-Myers Squibb; the others declared no conflicts of interest.

A therapeutic vaccine combined with low-dose chemotherapy primed almost 85% of pancreatic ductal adenocarcinomas to potentially respond to immunotherapy, according to researchers.

The report was published online June 17 in Cancer Immunology Research.

The small trial "provides the strongest rationale so far for combining immune-modulating agents with vaccination in patients whose tumors do not naturally contain abundant effector T cells," said Dr. Eric Lutz of Johns Hopkins University, Baltimore, and his associates. "Here, we report the first description of tertiary lymphoid aggregates infiltrating human PDAC [pancreatic cell adenocarcinomas]. These aggregates develop 2 weeks after a single treatment with a PDAC vaccine," they added.

The researchers randomized 39 patients with resectable pancreatic cell adenocarcinomas to receive irradiated, granulocyte-macrophage colony-stimulating factor–secreting , allogeneic vaccine (GVAX) alone, GVAX plus a single intravenous dose of cyclophosphamide at 200 mg/m² 1 day before each vaccination, or GVAX plus oral cyclophosphamide 100 mg once daily for 1 week on and 1 week off. Two weeks after vaccination, all patients underwent tumor resection surgery (Cancer Immunol. Res. 2014 June 17 [doi: 10.1158/2326-6066.CIR-14-0027].

Histologic analysis showed that tumors from 33 of the 39 patients (84.6%) had formed vaccine-induced intratumoral tertiary lymphoid aggregates, the researchers said. "Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity," they added, noting that after vaccination, the ratio of effector T cells to regulatory T cells increased, indicating immunogenicity.

Furthermore, the researchers found that lymphoid aggregates in tumors from patients who survived more than 3 years after vaccine therapy had significantly greater IL17A protein expression compared with patients who survived for less than 1.5 years after vaccination (P = .02).

"On the basis of the evidence available, this model explains why vaccination and immune modulation as single-agent therapies have failed in patients with PDAC," the investigators said. They cited their prior study, which showed objective responses when patients received a combination of GVAX and ipilimumab but not when they received ipilimumab alone (J. Immunother. 2013;36:382-9).

Researchers estimate that pancreatic ductal adenocarcinoma kills 95% of patients within 5 years of diagnosis.

The National Institutes of Health, Johns Hopkins School of Medicine Clinical Scientist Award, American Society of Clinical Oncology Young Investigator Award, Viragh Foundation and Skip Viragh Pancreatic Cancer Center at Johns Hopkins, National Pancreas Foundation, Lefkofsky Family Foundation, Lustgarten Foundation, Sol Goldman Pancreatic Cancer Center, and AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award funded the study. A coauthor disclosed ties to Bristol-Myers Squibb; the others declared no conflicts of interest.

A therapeutic vaccine combined with low-dose chemotherapy primed almost 85% of pancreatic ductal adenocarcinomas to potentially respond to immunotherapy, according to researchers.

The report was published online June 17 in Cancer Immunology Research.

The small trial "provides the strongest rationale so far for combining immune-modulating agents with vaccination in patients whose tumors do not naturally contain abundant effector T cells," said Dr. Eric Lutz of Johns Hopkins University, Baltimore, and his associates. "Here, we report the first description of tertiary lymphoid aggregates infiltrating human PDAC [pancreatic cell adenocarcinomas]. These aggregates develop 2 weeks after a single treatment with a PDAC vaccine," they added.

The researchers randomized 39 patients with resectable pancreatic cell adenocarcinomas to receive irradiated, granulocyte-macrophage colony-stimulating factor–secreting , allogeneic vaccine (GVAX) alone, GVAX plus a single intravenous dose of cyclophosphamide at 200 mg/m² 1 day before each vaccination, or GVAX plus oral cyclophosphamide 100 mg once daily for 1 week on and 1 week off. Two weeks after vaccination, all patients underwent tumor resection surgery (Cancer Immunol. Res. 2014 June 17 [doi: 10.1158/2326-6066.CIR-14-0027].

Histologic analysis showed that tumors from 33 of the 39 patients (84.6%) had formed vaccine-induced intratumoral tertiary lymphoid aggregates, the researchers said. "Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity," they added, noting that after vaccination, the ratio of effector T cells to regulatory T cells increased, indicating immunogenicity.

Furthermore, the researchers found that lymphoid aggregates in tumors from patients who survived more than 3 years after vaccine therapy had significantly greater IL17A protein expression compared with patients who survived for less than 1.5 years after vaccination (P = .02).

"On the basis of the evidence available, this model explains why vaccination and immune modulation as single-agent therapies have failed in patients with PDAC," the investigators said. They cited their prior study, which showed objective responses when patients received a combination of GVAX and ipilimumab but not when they received ipilimumab alone (J. Immunother. 2013;36:382-9).

Researchers estimate that pancreatic ductal adenocarcinoma kills 95% of patients within 5 years of diagnosis.

The National Institutes of Health, Johns Hopkins School of Medicine Clinical Scientist Award, American Society of Clinical Oncology Young Investigator Award, Viragh Foundation and Skip Viragh Pancreatic Cancer Center at Johns Hopkins, National Pancreas Foundation, Lefkofsky Family Foundation, Lustgarten Foundation, Sol Goldman Pancreatic Cancer Center, and AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award funded the study. A coauthor disclosed ties to Bristol-Myers Squibb; the others declared no conflicts of interest.