Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T cell anergy and promotes survival in tumor-bearing mice

Restoring Anti-Oncodriver Th1 Responses with Dendritic Cell Vaccines in HER2/ neu -Positive Breast Cancer: Progress and Potential

“…In a murine breast cancer model, administration of a monoclonal antibody against PD-L1 in combination with DC vaccination induced more potent protective immunity than just DC vaccination alone [52]. Anti-HER2 DC vaccination combined with anti-CTLA4 therapy in a murine mammary carcinoma model also exhibited a significant increase in the frequency of tumor infiltrating CD4 pos and CD8 pos T cells [62]. A probable mechanism for the success in this therapeutic combination is the restoration and promotion of a robust Th1 response, encouraging cytotoxic CD8 pos T-cell response and infiltration into the tumor [62].…”

Combination Strategies to Enhance the Potency of Monocyte-Derived Dendritic Cell-Based Cancer Vaccines

“…Furthermore, results from a Phase II study (NCT01302496) of vaccination with autologous monocyte-derived DCs electroporated to express melanoma-associated antigens (TirMixDC-Mel) [6,14] in combination with anti-CTLA-4 therapy show highly durable antitumor responses in the peripheral blood of advanced-stage melanoma patients, with 38% of vaccinated patients achieving objective clinical response, including 20% with complete responses [15]. In murine models, increased tumor-infiltrating Te activity and improved Strategies to enhance potency of monocyte-derived DC-based cancer vaccines Review overall survival rates were observed in tumor-bearing animals treated with immature DC and radiation plus anti-CTLA-4 antibody [16] or those treated with anti-CTLA-4 and anti-CD134 (OX40) in combination with anti-DEC205/HER2 monoclonal antibody that specifically targets the HER2 TAA into crosspresenting DCs [17]. Additionally, combination anti-PD-1 antibody plus DC-based vaccines are being actively explored by a number of groups, with early-phase clinical trials underway.…”

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

“…Similarly, KRAS-mutant lung tumors develop resistance to MEK inhibition via compensatory mitogenic signals received through FGFR1 and thus become susceptible to FGFR1 inhibition [97]. Given the reciprocal effects, checkpoint inhibitors and costimulatory agonists have in regulating T-cell responsiveness by relieving negative and potentiating positive signals, respectively, it was perhaps logical that combining biologics from each class do enhance therapeutic efficacy [82][83][84]. Nevertheless, even though nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) are both checkpoint inhibitors, combination therapy is clinically superior compared with the monotherapies [98].…”

“…The ligands for these receptors are typically expressed on PAMP-activated dendritic cells, and agonists to these costimulatory receptors thus provide critical signals for programming T-cell effector functionality that are otherwise lacking during steady-state antigen presentation [81]. Costimulatory agonists and checkpoint inhibitors thus act in reciprocal, but potentially synergistic manners [82][83][84]. Currently, agonists to the TNFR family members CD134 (OX40) [85], CD137 (4-1BB) [86], GITR [87] and CD27 [88] have demonstrated therapeutic activity in preclinical mouse models and are at various stages of clinical testing.…”

“…For instance, certain checkpoint inhibitor plus costimulatory agonist combinations have already been shown to have synergistic efficacy [82][83][84].…”