Using the NCDB, this study examined the impact of immunotherapy in combination with chemotherapy and chemoradiation on the OS of PDAC patients who received definitive surgery of the tumor. Chemoradiation but not chemotherapy alone plus immunotherapy was associated with significantly improved OS in the univariate and multivariable Cox Proportional analysis adjusted for age of diagnosis, gender, race, income, education treatment facility type, Charlson/Deyo score, place of living, year of diagnosis, and insurance status.
The tumor microenvironment of PDAC is non-immunogenic and immunosuppressive19. Pancreatic cancer itself induces local and systemic immune dysfunction or immunosuppression to avoid being recognized and attacked by effector immune cells24,25. The tumor cells use mechanisms such as the up-regulation of immune checkpoint signaling program ( PD-L1, CTLA-4), the blockage of co-stimulation to activate T cells, and the recruitment of MDSCs, and tumor-associated macrophages to achieve immune suppression26–28. The tumor microenvironment reflects a lack of tumor-infiltrating lymphocytes and dendritic cells and plenty of suppressor T cells29,30. Various rational combination treatment strategies have been proposed to overcome the resistance of PDAC to immunotherapy, including the combination of immunotherapies with chemotherapy and chemoradiation31,32.
Chemoradiation can work synergistically with immunotherapy and improve OS compared to chemoradiation alone. Chemotherapy and RT cause the release of neoantigens and upregulation of inflammatory cytokines, which promote the presentation of the neoantigens in the tumor microenvironment and thereby increase the immunogenicity of the tumor cells making them better targets for immunotherapy33–35.
Checkpoint blockade immunotherapy has resulted in impressive responses in the metastatic setting of various tumors and, more recently, has been tested in the adjuvant setting after surgery29,30. FDA has approved a couple of checkpoint inhibitors for adjuvant use in advanced melanoma, cervical cancer, bladder cancer, and renal cancer30,36. Various types of immunotherapies, including checkpoint inhibitors and vaccines therapies in combination with chemotherapy and chemoradiation, have been studied in early-stage and metastatic PDAC but have not led to the FDA approval of immunotherapy for pancreatic cancer37. The use of immunotherapy in neoadjuvant or adjuvant setting combined with chemoradiation in PDAC has been limited. Some clinical trials studying the efficacy of immunotherapy in resectable PDAC combined with chemoradiation therapy have shown positive response and measurable activity38–41. The immunotherapy group represents only 1.01% of patients who received definitive surgery of the pancreatic tumor, indicating that this is a very highly select group of patients, and many of these patients might have been enrolled in clinical trials.
Nonetheless, the findings of the current study are consistent with the results of a few other clinical trials and retrospectives studies. A phase II trial involving 60 patients with resected PDAC, investigated the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) with chemoradiation reported a median survival of 24.8 months (95% CI, 21.2–31.6)39. A dose-escalating study with 24 patients evaluated Gene-mediated cytotoxic immunotherapy (GMCI™) in combination with chemoradiation therapy for resected PDAC in adjuvant setting reported a median OS of 12 months and a 1-year OS of 50%40. A multi-institutional open-label phase II study evaluated algenpantucel-L in combination with chemoradiation therapy in 70 patients with resectable PDAC and reported the 12-months OS rate of 86%41. In the current study, we found a median OS of 26.2 months, a 12-months OS rate of 88%, and a 24-months OS rate of 60% comparable to these studies.
To our knowledge, the current study is the first to use an extensive database such as NCDB and investigate the impact of immunotherapy on the OS of PAD patients who receive definitive surgery. In this study combining immunotherapy with chemoradiation was associated with significantly improved OS. The results stayed the same when patients who received immunotherapy more than six months before or after chemoradiation were excluded. The findings of our study, together with early findings of some clinical trials, warrant future clinical trials of immunotherapy combined with chemoradiation in PAD patients. Chemotherapy and immunotherapy both induce a systemic immune response, and the addition of RT to chemotherapy and immunotherapy may be required to overcome the local and systemic immune suppression.
The negative results of chemotherapy plus immunotherapy compared to chemotherapy indicates that both systemic and local immune response is necessary to overcome the immune evasion of pancreatic cancer cells. The immunostimulatory effect of chemotherapy, especially in the adjuvant setting is through the inhibition of T regulatory cell and MDSCs rather than the stimulation and increase of T cells42–44. The significant improved OS associated with chemoradiation and immunotherapy is biologically justified. Evidence indicates that chemoradiation, especially after surgery, can significantly increase the number and function of dendritic cells by reducing immunosuppressive cytokines45. Dendritic cells are an essential part of the immune system and play a critical role in tumor cell recognition and T cells stimulation46. Chemoradiation is also capable of producing humoral or cellular immune responses, and its combination with immunotherapy has shown to mount long-term T cell reactivity47–49.
No difference in the OS of patients who received neoadjuvant chemoradiation plus immunotherapy (N = 48) vs. chemoradiation alone (N = 3,669) and neoadjuvant chemoradiation plus immunotherapy vs. adjuvant chemoradiation plus immunotherapy (N = 205) is likely to be due to the small sample size of neoadjuvant chemoradiation plus immunotherapy. Not Seeing a difference in OS between patients who received neoadjuvant chemotherapy plus immunotherapy (N = 19) vs patients who received only neoadjuvant chemotherapy (N = 2,336) and neoadjuvant chemotherapy plus immunotherapy vs neoadjuvant chemotherapy plus immunotherapy (N = 92) is likely to be due to the small sample size of the neoadjuvant chemotherapy plus immunotherapy group.