The Vaccine-site Microenvironment Induced by Injection of Incomplete Freund's Adjuvant, With or Without Melanoma Peptides

Abstract

Cancer vaccines have not been optimized. They depend on adjuvants to create an immunogenic microenvironment for antigen presentation. However, remarkably little is understood about cellular and molecular changes induced by these adjuvants in the vaccine microenvironment. We hypothesized that vaccination induces dendritic cell activation in the dermal vaccination microenvironment but that regulatory processes may also limit the effectiveness of repeated vaccination. We evaluated biopsies from immunization sites in two clinical trials of melanoma patients. In one study (Mel38), patients received one injection with an adjuvant mixture alone, comprised of incomplete Freund's adjuvant (IFA) plus granulocyte-macrophage colony stimulating factor (GM-CSF). In a second study, patients received multiple vaccinations with melanoma peptide antigens plus IFA. Single injections with adjuvant alone induced dermal inflammatory infiltrates consisting of B cells, T cells, mature dendritic cells (DC) and vessels resembling high endothelial venules (HEV). These cellular aggregates usually lacked organization and were transient. In contrast, multiple repeated vaccinations with peptides in adjuvant induced more organized and persistent lymphoid aggregates containing separate B and T cell areas, mature DC, HEV-like vessels, and lymphoid chemokines. Within these structures, there are proliferating CD4+ and CD8+ T lymphocytes, as well as FoxP3+CD4+ lymphocytes, suggesting a complex interplay of lymphoid expansion and regulation within the dermal immunization microenvironment. Further study of the physiology of the vaccine site microenvironment promises to identify opportunities for enhancing cancer vaccine efficacy by modulating immune activation and regulation at the site of vaccination.

Safety and tolerability evaluation of the use of Montanide ISA™51 as vaccine adjuvant: A systematic review

“…After removing duplicate entries, 462 studies were evaluated for inclusion based on the title and/or abstract, after which 114 potentially relevant studies were included for full-text examination; the majority of excluded studies were reviews or animal studies and 6 studies were not reported in English. From the 114 studies, full-text was unavailable for one study 13 , 2 studies were duplicates published under different titles 14,15 , one study only described the study design 16 and 6 studies did not report safety, tolerability and/or toxicity results 7,[17][18][19][20][21] . These together with 11 case reports [22][23][24][25][26][27][28][29][30][31][32] and 2 letters to the editor were excluded 33,34 .…”

Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials’ experience

“…For the Mel48 trial (NCT00705640), all patients received the same vaccine of 12MP plus tetanus helper peptide (MELITAC 12.1), but differed in whether the vaccine peptides were administered at one or two sites [26-27]. …”

Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase

“…The vaccine was well tolerated with manageable side effects and no CTCAE grade 3/4 toxicities. Only local reactions at the vaccine site were frequently induced (90% of patients) most likely due to Montanide (20) and imiquimod (21).…”