Accumulation of Memory Precursor CD8 T Cells in Regressing Tumors following Combination Therapy with Vaccine and Anti-PD-1 Antibody

Abstract

Immunosuppression in the tumor microenvironment blunts vaccine induced immune effectors. PD-1/B7-H1 is an important inhibitory axis in the tumor microenvironment. Our goal in this study was to determine the effect of blocking this inhibitory axis during and following vaccination against breast cancer. We observed that using anti-PD-1 antibody and a multi-peptide vaccine (consisting of immunogenic peptides derived from breast cancer antigens, neu, legumain and β-catenin) as a combination therapy regimen for the treatment of breast cancer bearing mice prolonged the vaccine-induced progression-free survival period. This prolonged survival was associated with increase in number of Tc1 and Tc2 CD8 T cells with memory precursor phenotype, CD27+IL-7RhiT-betlo and decrease in number of PD-1+ dendritic cells (DCs) in regressing tumors and enhanced antigen reactivity of tumor-infiltrating CD8 T cells. It was also observed that blockade of PD-1 on tumor DCs enhanced IL-7R expression on CD8 T cells. Taken together, our results suggest that PD-1 blockade enhances breast cancer vaccine efficacy by altering both CD8 T cell and DC components of the tumor microenvironment. Given the recent success of anti-PD-1 monotherapy, our results are encouraging for developing combination therapies for the treatment of cancer patients in which anti-PD-1 monotherapy alone may be ineffective (i.e. PD-L1-negative tumors).

IMA901: A multi-peptide cancer vaccine for treatment of renal cell cancer

“…Preclinical findings [74][75][76][77] as well as early clinical data in pancreatic, melanoma and prostate cancer [78][79][80] suggest synergistic effects between cancer vaccines and immune checkpoint blockade. Nivolumab, a programmed death-1 (PD-1) inhibitor blocking the PD-1 co-inhibitory receptor on activated T-cells is a promising and in RCC well advanced checkpoint inhibitor, currently being investigated in a phase III trial to assess whether it prolongs survival of second-or third-line RCC patients compared with everolimus.…”

Metabolic regulation of immune responses: therapeutic opportunities

“…This notion is supported by numerous preclinical studies investigating combinations of strategies, though the importance of the tumor microenvironment and immune cell metabolism was largely unappreciated at the time. For instance, cancer vaccinations have been combined with checkpoint blockade antibodies, now known to enhance glucose availability and T cell glycolysis, to improve antitumor responses (52)(53)(54)(55). Clinical trials have now been initiated to test the combination of a pancreatic cancer vaccine and an anti-PD-1 antibody, nivolumab (ClinicalTrials.gov identifier NCT02243371 and NCT02451982).…”

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).…”