Immunotherapy Combined With Radiation and Influenza Vaccine for Pancreatic Cancer.

Pancreatic cancer (PC) is the fourth leading cause of cancer death, and each year 1000 Danes are diagnosed with PC, 80% of which are advanced stage. Survival rates are meager, currently approaching 10% at 5 years postdiagnosis, and have scarcely improved over the last 50 years. PC is highly resistant to conventional treatments, and nearly all patients develop metastases and die. As the incidence of PC continuously rises while treatment response rates remain incredibly low, a lack of effective therapy options and accurate predictive biomarkers is a real cause for concern and underlines the need for further research in this area. Immunotherapy has not been successful in PC patients primarily due to a lack of pre-existing T-cell immunity and/or a highly immunosuppressive tumor microenvironment. "Non-immunogenicity" of PC with high prevalence of immunosuppressive cells and typically a scarcity of tumor-infiltrating effector lymphocytes is considered as one of the reasons for lacking responsiveness to single-agent immunotherapies. Considering the emerging role of the tumor microenvironment, the combination of checkpoint blocking antibodies with immunomodulation of the tumor microenvironment could lead to better responses in tumor historically resistant to radiation and checkpoint blocking antibody approaches as single modalities. Preliminary data from the phase 2 study CHECKPAC (NCT02866383) showed durable clinical benefit in a small subgroup of patients after the addition of stereotactic body radiation therapy (SBRT) of 15 Gy to the combination of nivolumab and ipilimumab (Herlev internal data) in patients with resistant metastatic PC. Influenza vaccination in cancer patients receiving immune checkpoint inhibitors inexplicably was associated with a better survival, irrespective of the anticancer treatment outcome. Influenza vaccine facilitates both T- and B cell activation and drives interferon-gamma response, supporting the rationale for combining of influenza vaccine with CHECKPAC strategy. Based on these considerations, the proposed treatment with nivolumab, ipilimumab and radiation in combination with influenza vaccine may potentially provide meaningful clinical benefit by generating durable clinical responses, thereby improving quality of life (QoL) and potentially extending survival.