Harnessing the Immune System in Pancreatic Cancer

Abstract

Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma

“…PDAC, one of the most immunosuppressive tumors, educates resident and infiltrating immune cells towards this immunosuppressive state [ 59 ]. The immune cell compartment of the pancreatic TME mainly consists of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and few activated cytotoxic effector T cells (CD8 + ) [ 60 ].…”

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

“…Therefore, along with the recent development in sequencing technology, a personalized, molecular-targeted approach for PDAC is becoming an active area of research [9]. Several case studies showed a benefit of platinum-based chemotherapies or poly ADPribose polymerase (PARP) inhibitors for PDAC patients with BRCA1/2 abnormalities, and the NCCN guidelines suggest consideration of platinum-based regimen as a first-line therapy for advanced-stage pancreatic cancer patients with BRCA gene mutations [10][11][12][13][14].…”

Immune-Based Therapies and the Role of Microsatellite Instability in Pancreatic Cancer

“…The CSF-1 receptor (CSF-1R) inhibitor cabiralizumab was administered together with nivolumab in a phase I study for pretreated advanced pancreatic cancer patients. Four out of 31 patients had an ORR of 13% and of special interest all belong to the MSS subgroup [ 136 ]. Another phase I/II trial tested the combination of lacnotuzumab (anti-CSF-1 monoclonal antibody) with spartalizumab (PD-1 inhibitor).…”

“…Another phase I/II trial tested the combination of lacnotuzumab (anti-CSF-1 monoclonal antibody) with spartalizumab (PD-1 inhibitor). From the 13 patients with advanced pancreatic cancer, six patients had disease control with this combination and three of six had a disease control superior to 300 d [ 136 , 137 ].…”