Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates

Abstract

Non-live vaccine platforms that induce potent cellular immune responses in mucosal tissue would have broad application for vaccines against infectious diseases and tumors. Induction of cellular immunity could be optimized by targeted activation of multiple innate and co-stimulatory signaling pathways, such as CD40 or toll-like receptors (TLRs). In this study, we evaluated immune activation and elicitation of T cell responses in non-human primates (NHPs) after immunization with peptide antigens adjuvanted with an agonistic αCD40Ab, with or without the TLR3 ligand poly IC:LC. We found that intravenous administration of the αCD40Ab induced rapid and transient innate activation characterized by IL-12 production and upregulated co-stimulatory and lymph node homing molecules on dendritic cells. Using fluorescently-labeled Abs for in vivo tracking, the αCD40Ab bound to all leucocytes, except T cells, and disseminated to multiple organs. CD4+ and CD8+ T cell responses were significantly enhanced when the αCD40Ab was co-administered with poly IC:LC compared to either adjuvant given alone and were almost exclusively compartmentalized to the lung. Notably, antigen-specific T cells in the bronchoalveolar lavage were sustained at ~5–10%. These data indicate that systemic administration of αCD40Ab may be particularly advantageous for vaccines and/or therapies requiring T cell immunity in the lung.

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

“…However, only the TLR3 agonist with peptide and anti-CD40 effectively boosted tumor-specific CD8 T cell immunity which occurred independently of CD4+ T cells [55,56]. In nonhuman primates, the combination of a human anti-CD40 antibody and a TLR3 agonist (Poly IC:LC) with a peptide antigen also produced potent antigen-specific T cell activation particularly within the lung [57]. …”

T Cell Vaccinology: Beyond the Reflection of Infectious Responses

“…In contrast, after a single exposure, the combined innate/CD40 adjuvant can produce a similar number of antigen specific T cells (~1–3 million antigen specific T cells), and in the same time frame (7 days), as the infectious challenge [2, 10, 13, 44, 45]. As a result of the potency of this vaccine adjuvant, we and others [46–48] have spent years studying its underlying mechanisms in mice and have recently shown its capacity to produce robust CD8 and CD4 responses in non-human primates [49]. …”

Cross-Presenting XCR1+ Dendritic Cells as Targets for Cancer Immunotherapy

“…Engagement of CD40 on DCs, typically via interaction with CD40L on helper CD4 + T cells, is essential for successful T cell priming [161,179]. Promising studies in both mice and humans indicate delivery of agonistic antibodies to CD40 activates DCs both in vivo and ex vivo to induce tumor-specific CD8 + T cell responses [152,153,155], and synergize with poly I:C treatment [180] independent of CD4 + T cell help. However, therapeutic use is limited due to severe toxicities associated with anti-CD40 treatment in the clinic, primarily cytokine release syndrome [155].…”