Abstract and Introduction
Background and Objective: Immunotherapy is the fastest growing branch in oncology that have already revolutionized the treatment of few solid cancers. The number of immunotherapy trials for pancreatic cancer (PC) is growing but the vast number of different agents used make it difficult to comprehend a possible success trait of a certain type of immunotherapy. The aim of this review is to summarize and critically evaluate the outcome of immunotherapy trials for PC intended to aid the comprehensiveness for the treating physicians.
Methods: A PubMed search was performed to identify clinical trials in patients with PC, published in English from year 2000 to June 2021 and using combination of the terms immunotherapy, PC, and cross-checked the bibliography of the revised literature as the dublettes have been removed. Studies were divided into three groups depending on what immune components have been applied: passive products (peptides, antibodies, etc.), antigen-presenting cells, and adoptive cell transfer trials.
Key Content and Findings: The vast majority of trials, including those from most recent years, used passive products of the immune system—peptide vaccines and antibodies. The administration was often parallel to chemotherapy that was prevalently gemcitabine-based. Although immunological responses have been detected, the clinical efficacy was very limited. Trials with check point inhibitors did not show survival advantage. Dendritic cell (DC) vaccines have been associated with some clinical objective response and prolonged survival in few patients with delayed type hypersensitivity reactions. Trials with adoptive transfer therapy are lacking. The very few trials with lymphokine-activated killer (LAK)/cytokine-induced killer (CIK) cells tested only in Asian population have resulted in some clinical effects with prolonged survival. In none of the trials have the patients been preconditioned before receiving immunotherapy.
Conclusions: Although the clinical effectiveness in the majority of the reported trials has been limited, the immunological effects observed in almost all trials show a proof of concept—that immunotherapy can work. Careful re-evaluation of the clinical premises and focus on combination and cell therapy may be the way to achieve improved survival by immunotherapy in PC.
Pancreatic cancer (PC) is one among very few cancer types for which the prognosis has not improved much over the past decades. While the 5-year survival for all cancers altogether is above 60%, the survival of all-stage PC remains below 10%.[1,2] Three major features of PC make it particularly difficult to treat and roadmap its dismal prognosis. The tricky anatomic location not only predefines the limitation to extend surgical resection margins, resulting in about 80% R1 resections, but is also the reason why about 30% of patients present with locally advanced disease with tumor advancement along major abdominal vessels and propagation along the rich neural routes in the area.[2–4] Second, PC is prone to give early rise of metastases that can occur even before the primary tumor becomes visible to the clinician. This is one of the explanations why even smaller primary resectable tumors tend to recur in the majority of cases even following curative resection, leaving a 5-year chance of survival of only about 20%. These two major characteristics of PC are the reason why systemic oncologic treatment is making its way as the new standard in the neoadjuvant setting. Its purpose is to combat occult distant spread and/or consolidate the advanced tumor in order to select who would benefit the most from surgical resection. However, as potent and promising the new combination regimens like FOLFIRINOX or gemcitabine-nab-paclitaxel might be in prolonging life, used alone they basically never lead to cure due to the microenvironment architecture of PC.
The third unfortunate characteristic of PC is the abundant stroma that shields the tumors cells and defines its chemoresistance.[6,7] The poor vascular tumor network is responsible for the ineffective drug delivery and is the driver of hypoxia which enhances endothelial-mesenchymal transformation and invasiveness of PC cells. The thick fibrotic stroma increases the distance between the vessels and the tumor cells and mechanically hampers the diffusion of the infused drugs, which cannot reach the cancer cells in therapeutic concentrations. Thus, theoretically any passively infused treatment would be doomed to failure.
The tumor microenvironment also plays an active role in carcinogenesis and tumor progression. The components of the immune system are part of this environment and depending on the immune cell composition and its balance, it can either tip over the response toward tumor antigen recognition and appropriate adoptive anti-tumoral response or aid in escaping effective tumor recognition and elimination. Manipulating the immune response towards continuous activation and tumor recognition is the basis of immunotherapy—the fastest growing branch of oncology. Immunotherapy has already revolutionized the treatment of some dismal cancer types, such as malignant melanoma or lung cancer.[10,11] In particular, treatment with check point inhibitors has led to long-term survival in patients with melanoma and renal cancer.[10,12,13] Inevitably, there is hope that immunotherapy may have similar significant impact on the prognosis of PC. The theoretical advantage of immunotherapy compared to cytotoxic drugs is that it will not only "work" during the treatment occasion but can perpetuate itself and be able to augment and persist during cancer recognition and elimination.
The purpose of this review is to give a comprehensive overview of the role and current attempts of immunotherapy for PC from the clinician's perspective of possible integration in treatment, to map the problematic areas and to highlight what might be opportunities for successful implementation. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-21-174/rc).
Chin Clin Oncol. 2022;11(1):4 © 2022 AME Publishing Company