Immunotherapy Combined With Chemotherapy for Pancreatic Cancer: A Game Changer?

Kara D. Forinash, MS, PA-C, Shari Pilon-Thomas, PhD, and Gregory M. Springett, MD, PhD | September 05, 2014

Abstract

Pancreatic cancer has one of the poorest prognoses out of all human malignancies. Only 20% of patients who present with this disease have surgically resectable tumors at the time of diagnosis, and of these 20% of patients, the vast majority will experience recurrence within the first 2 years. Chemotherapy is the mainstay of treatment. Unfortunately, little improvement has been made in the past few decades with regard to overall survival (OS) with chemotherapy alone. Of note, the immune system’s involvement in cancer development and progression has sparked much interest in recent years. The model of the cancer-immunity cycle suggests an interplay of immune-suppression and immune-stimulation. In normal individuals, a state of immunosurveillance is in place. However, within the tumor microenvironment, inhibitory signals and immunosuppressive cells are present and tip the scale in favor of immune suppression. This enables cancer cells to evade the immune system and allows tumors to grow. Studies in a variety of solid tumors have shown that many chemotherapies, including those used as standards of care in pancreatic cancer, have immune-modulating functions, including inhibition of immune suppression and stimulation of immune function. This article reviews up-to-date clinical studies combining chemotherapy with immunotherapy; it also explains the rationale for this combination in treatment of pancreatic cancer.
Pancreas

Introduction

Pancreatic ductal adenocarcinoma (PDA) has one of the most dismal prognoses out of all human malignancies, currently ranking as the fourth most common cause of cancer-related death in the United States.1 Although advances have been made in both understanding the molecular biology of the disease as well as its imaging, the current 5-year survival rate for all stages combined is only 6%, which is one of the lowest out of all cancer diagnoses.1-2 Currently, the only hope of cure for PDA is surgical resection.

However, even after an R0 resection with node-negative disease, the long-term survival rate is lower than 10%.2 This is due to a high recurrence rate, with 80% of those patients experiencing recurrence within 2 years of surgical resection. Over the last few decades, new chemotherapies have been discovered; still however, the effect on OS in patients with metastatic tumors has been minimal. For example, in 1997 gemcitabine was shown to improve the median OS by 1.2 months when compared with fluorouracil.3 More recently, 2 sets of chemotherapy combinations have also been shown to improve OS in this disease. The chemotherapy cocktail of fluorouracil, oxaliplatin, irinotecan and the vitamin leucovorin (FOLFIRINOX) used in the first-line setting was shown to improve OS to 11.1 months when compared with gemcitabine alone.4

In October 2013, nab-paclitaxel was shown to achieve an OS of 8.5 months compared with 6.7 months achieved with gemcitabine alone.5 The fact remains that, although we have seen advances in the treatment of this disease, the clinical effect on the overall prognosis has been slight, with 5-year survival essentially unaffected. In addition, the trial that achieved the greatest improvement in OS with FOLFIRINOX was accompanied by substantial toxicities and, therefore, is only recommended for robust patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.4 The meager improvement in OS is thought to be due to the disease’s resistance to both chemotherapy and targeted therapy.6

Today, many studies have focused on the immune system’s role in cancer and how it can recognize both cancer cells and tumor-associated antigens. Therefore, many investigators have turned their focus to immunotherapy as a potential treatment for PDA.

The Cancer-Immunity Cycle

Chen and Mellman have delineated the cancer-immunity cycle, which depicts the immune system’s role in controlling tumor growth in normal individuals. Understanding this cycle provides insight into how tumors can evade it. As cancer develops, oncogenic proteins are produced. In the normal individual, these cancer-associated antigens are released into the microenvironment during necrotic or immunogenic cell death. The antigens are captured by antigen-presenting cells (APCs), such as dendritic cells, processed into peptides, and presented on the cell surface bound to major histocompatibility complex I (MHCI) molecules.


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