Abstract
Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune-oncology were addressed.
Highlights
Pancreatic cancer is the fourth leading cause of cancer death for both men and women, with an annual incidence of approximately 53,000 new cases in the United States, of whom 43,000 are expected to die [1]
For tumors reported with clinical response to the anti-PD-1/PD-L1 therapies including melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and bladder cancer, the range of PD-L1 expression falls from 14% to 100% [11,12,13]
CD8+ PD-1+ neoantigen-specific lymphocytes detected in the peripheral blood in melanoma patients resembled infiltrating CD8+ PD-1+. Cells in their tumors, implying that vaccine-induced CD8+ PD-1+ lymphocytes could traffic into the tumors [74]. These results provide evidence for the rationale to develop personalized therapies using neoantigen-reactive lymphocytes or T cell receptor (TCR) engineered T cells to treat cancer [75]
Summary
Pancreatic cancer is the fourth leading cause of cancer death for both men and women, with an annual incidence of approximately 53,000 new cases in the United States, of whom 43,000 are expected to die [1]. Despite a better understanding of tumor biology and optimization of current treatment modalities, 5-year survival rate of pancreatic cancer is only 5–6% [2]. These sobering results have spawned the efforts spent on developing novel therapies to improve the treatment outcomes. There is a growing need for individualized medicine solutions to guide patient selection by predicting treatment response, to spare patients from ineffective treatment, and to avoid toxicity associated with immunotherapy. With rapid advancement in the technology of generation sequencing and novel bioinformatics platforms, molecular and genetic profiling of tumors has become an integral venue to guide personalized cancer cares. Particular opportunities and challenges of personalized immunotherapy exist for pancreatic cancers
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