Combination Therapy May Make Pancreatic Cancer Responsive to Immunotherapy

Priming pancreatic ductal adenocarcinoma (PDAC) with a combination of a vaccine and low-dose chemotherapy before surgery resulted in an immune response, including an increase in immune cells that express key immunogenic proteins within patients’ tumors, according to a study published in Cancer Immunology Research, a journal of the American Association for Cancer Research (AACR).

PDAC is not typically responsive to immunotherapy and has few treatment options besides surgical resection, which is only curative for a minority of patients.

According to the study authors, this is the first instance of the ability of an immune-based therapy to convert a so-called non-immunogenic tumor into an immunogenic one. This is done by stimulating the infiltration of T-cells and facilitating the development of lymphoid structures within the tumor microenvironment.

Lei Zheng, MD, PhD, assistant professor of oncology and surgery at the Sidney Kimmel Comprehensive Cancer Center, and colleagues compared neoadjuvant therapy with an irradiated, granulocyte macrophage colony-stimulating factor (GMC-SF) secreting, allogeneic PDAC (GVAX) vaccine as a monotherapy to the combination of the GVAX vaccine with low-dose cyclophosphamide chemotherapy, in 39 PDCA patients, measuring alterations in the tumor microenvironment. Cyclophosphamide is known to deplete regulatory T-cells which are inhibitory to the immune stimulation process.

Two weeks after vaccination, patients underwent tumor resection. Analysis of the tumors showed that the vaccine induced intratumoral adaptive immunity in 33 of the 39 patients. The researchers also compared these treated tumor samples to samples from other studies, including four samples from unvaccinated patients and 54 patients prior to vaccination from a different vaccine clinical trial.

Few treatments exist for advanced PDAC and earlier stage disease is only curative with surgical resection. Even with surgery, about 80% of these patients relapse and die from the disease within 5 years, according to Zheng. PDAC typically lacks immune-cell infiltrates within the tumor, but this new approach suggests that there are ways to make this tumor type responsive to immunotherapy, which can offer a long-term remission for some patients.

Microarray analysis of the resected, treated tumors showed that the intratumoral lymphoid aggregates detected within tumors after the neoadjuvant treatment had a gene expression profile consisting of five signaling pathways involved both immune cell trafficking and activation-this gene signature was associated with better post-vaccine responses.

“Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1/PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naïve patients for immune checkpoint and other immunomodulatory therapies,” concluded the authors.

The clinical trial enrolled 59 patients between 2008 and 2012 into one of three trial arms-GVAX alone, GVAX plus a single IV dose of cyclophosphamide at 200 mg/m2, or GVAX plus oral doses of cyclophosphamide given once a day on alternative weeks. Of the 59 patients on the trial, 39 were free of detectable macro disease after surgery, had their tumors analyzed, and had further chemotherapy and radiotherapy.

Based on these study results, Zheng and colleagues proposed a model by which a systemic vaccine is needed to induce an immune response that allows the trafficking of immune cells to tumors, creating an inflammatory environment. Still, this immune-responsive environment contains immunosuppressive components that require additional suppressive therapy. This model, according to the authors, provides a strong rationale for combining immune-modulating therapies with vaccination for those patients who do not have immune infiltrates within their tumors.