Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer in the United States by 2025, with 5-year survival at less than 10%. In other recalcitrant cancers, immunotherapy has shown unprecedented response rates, including durable remissions after drug discontinuation. However, responses to immunotherapy in PDAC are rare. Accumulating evidence in mice and humans suggests that this remarkable resistance is linked to the complex, dueling role of the immune system in simultaneously promoting and restraining PDAC. In this review, we highlight the rationale that supports pursuing immunotherapy in PDAC, outline the key barriers that limit immunotherapy efficacy, and summarize the primary preclinical and clinical efforts to sensitize PDAC to immunotherapy.

Keywords: Clinical Trials; Immunity; Immunotherapy; PDAC; Pancreatic Cancer.

Figure 1.. The pancreatic tumor microenvironment is highly immunosuppressive

Malignant cells (purple), fibroblasts, and myeloid cells in the tumor microenvironment secrete a variety of immunosuppressive cytokines and chemokines (pink) that prevent effective anti-tumor CD8 T cell responses. TAM, tumor-associated macrophage; Treg, Foxp3+ regulatory T cell; MoMDSC, monocytic myeloid-derived suppressor cell; GrMDSC, granulocytic myeloid-derived suppressor cell; iCAF, inflammatory cancer-associated fibroblast; myCAF, myofibroblastic cancer-associated fibroblasts.

Figure 2.. Therapeutic sequencing versus treat-to-progression for PDAC

(A) Conceptual model showing treatment-naïve PDAC responding initially to first-line (1L) chemotherapy but then acquiring resistance on continued (cont’d) chemotherapy and ultimately manifesting as tumor progression. (B) Conceptual model showing treatment-naïve PDAC responding initially to 1L chemotherapy; chemotherapy is then discontinued prior to tumor progression. A series of sequential treatments (i.e., A, B, and C) are then initiated to coax the tumor into remission. Each treatment is designed to anticipate mechanisms of acquired resistance that emerge from the prior treatment.

Figure 3.. Workflow for advancing therapeutic strategies in PDAC

Patients enrolled in a clinical study are monitored with repeat liquid and tissue biopsies beginning at baseline prior to treatment and at defined time points on-treatment. Responders (partial or complete response) and non-responders (stable or progressive disease) are defined early after treatment (within 2–4 cycles) based on radiologic imaging (CT, MRI, or PET/CT). Sample biopsies are interrogated in the laboratory to assess pre-defined biomarkers of biological response and their relationship to clinical response. Pharmacodynamic markers in blood and tissue that are defined a priori are used to understand mechanisms of response and resistance to therapy. Findings are then used to inform development of new preclinical data and scientific rationale for the conduct of subsequent clinical studies.