Peptide emulsions in incomplete Freund’s adjuvant create effective nurseries promoting egress of systemic CD4⁺and CD8⁺T cells for immunotherapy of cancer

Abstract

Water-in-oil emulsion incomplete Freund’s adjuvant (IFA) has been used as an adjuvant in preventive and therapeutic vaccines since its development. New generation, highly purified modulations of the adjuvant, Montanide incomplete seppic adjuvant (ISA)-51 and Montanide ISA-720, were developed to reduce toxicity. Montanide adjuvants are generally considered to be safe, with adverse events largely consisting of antigen and adjuvant dose-dependent injection site reactions (ISRs). Peptide vaccines in Montanide ISA-51 or ISA-720 are capable of inducing both high antibody titers and durable effector T cell responses. However, an efficient T cell response depends on the affinity of the peptide to the presenting major histocompatibility complex class I molecule, CD4+ T cell help and/or the level of co-stimulation. In fact, in the therapeutic cancer vaccine setting, presence of a CD4+ T cell epitope seems crucial to elicit a robust and durable systemic T cell response. Additional inclusion of a Toll-like receptor ligand can further increase the magnitude and durability of the response. Use of extended peptides that need a processing step only accomplished effectively by dendritic cells (DCs) can help to avoid antigen presentation by nucleated cells other than DC. Based on recent clinical trial results, therapeutic peptide-based cancer vaccines using emulsions in adjuvant Montanide ISA-51 can elicit robust antitumor immune responses, provided that sufficient tumor-specific CD4+ T cell help is given in addition to CD8+ T cell epitopes. Co-treatment with PD-1 T cell checkpoint inhibitor, chemotherapy or other immunomodulatory drugs may address local and systemic immunosuppressive mechanisms, and further enhance efficacy of therapeutic cancer peptide vaccines in IFA and its modern variants. Blinded randomized placebo-controlled trials are critical to definitively prove clinical efficacy. Mineral oil-based adjuvants for preventive vaccines, to tackle spread and severity of infectious disease, induce immune responses, but require more studies to reduce toxicity.

Tertiary lymphoid structures in cancer: maturation and induction

“…Similarly, intratumoral TLS was formed in 85% of patients with pancreatic cancer after administering an irradiated allogeneic vaccine secreted by granulocyte-macrophage colony-stimulating factor for pancreatic ductal adenocarcinoma (PDAC) and its presence improved the immunosuppressive state characteristic of PDAC ( 15 ). Incomplete Freund’s adjuvant, a commonly used adjuvant, was employed to amplify the immune response elicited by vaccines ( 73 ). Repeated administration of peptide vaccines formulated with incomplete Freund’s adjuvant could enhance the Th1-dominated immune response and improve immunogenicity.…”

Current status of immunological therapies for rheumatoid arthritis with a focus on antigen-specific therapeutic vaccines

“…Although the adjuvant (manufactured by Seppic and called ISA51vg or Montanide) used in our LEAPS vaccine formulations has proven safe in numerous human trials for cancer vaccines (including the ones using peptides similar to CEL-4000) for many years (see recent review by Melssen et al. ( 84 )), it may also be necessary to evaluate the adjuvant’s safety separately.…”

Synthesis and Biological Evaluation of Peptide-Adjuvant Conjugate Vaccines with Increasing Antigen Content

“…However, peptide epitopes are poorly immunogenic when administered as single agents and require coadministration with an immune stimulant (adjuvant) to support acquisition and/or presentation by appropriately activated antigen presenting cells (APCs) in vivo. Strategies to achieve this include oil-in-water emulsions that aid in delivery, cytokines that support the function of APCs, and chemical compounds that trigger APCs directly via pattern recognition receptors such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) . Alternatively, APC activation can be achieved through direct interaction with other immune cells, notably those capable of producing licensing signals, typified by the stimulation of CD40. , This includes “unconventional” T cells like type I natural killer T (NKT) cells, which are found in high numbers in lymphoid tissues and respond rapidly to stimulation with specific agonistic antigens .…”