PD-1/PD-L1 Blockade Together With Vaccine Therapy Facilitates Effector T-Cell Infiltration Into Pancreatic Tumors

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment (TME) is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death 1 (PD-1) and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a GM-CSF secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared to PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8+ T lymphocytes and tumor-specific interferon-γ production of CD8+ T cells in the TME. Immunosuppressive pathways, including regulatory T cells (Tregs) and CTLA-4 expression on T cells were overcome by the addition of vaccine and low dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.

Twelve-year survival and immune correlates in dendritic cell–vaccinated melanoma patients

“…Cancer vaccines aim at inducing or restimulating tumor-specific T cell responses. Based on preclinical (1)(2)(3)(4)(5)(6)(7)(8)(9) and initial clinical reports (10)(11)(12), they could be instrumental in breaking primary resistance to checkpoint blockade of tumors with low mutational load (13)(14)(15) and in increasing response rates of highly mutated tumors, such as melanoma (11).…”

Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy

“…Anti-PD1 or anti-CTLA4 therapy substantially enhanced the vaccine-induced antitumor effects on several low immunogenic cancers. [24][25][26][27] Despite the striking clinical benefits observed from the use of immune checkpoint inhibitors to block PD-1 or CTL-4 and restrain T-cell-mediated antitumor immunity, a large proportion of patients with advanced cancer failed to respond to these immunotherapeutics. 28,29 Thus, immune checkpoint blockade requires additional treatment modalities to improve antitumor efficacy.…”

Prospective immunotherapies in childhood sarcomas: PD1/PDL1 blockade in combination with tumor vaccines

“…Moreover, coadministration of a PD1-blocking mAb caused a complete regression of established tumors in a mouse model of melanoma. Several other preclinical mouse models combining various tumor vaccines with anti-PD1/PDL1 antibodies have also demonstrated similarly enhanced CD8+ T-cell activity against a variety of solid tumors, including mouse models of sarcoma, pancreatic ductal adenocarcinoma, ovarian, breast, colon, and hepatocellular carcinoma (74)(75)(76)(77)(78). Given the wide variety of subtypes of tumor vaccines used in these studies (DNA vaccines, DC vaccines, peptide vaccines), it may be that any or all of them may prove useful for potential clinical trials.…”