The Therapeutic Vaccine Potential of MIS416 Adjuvant - Linking innate and adaptive immunity through the activation of multiple innate host defenses. - BioPharm International

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The Therapeutic Vaccine Potential of MIS416 Adjuvant
Linking innate and adaptive immunity through the activation of multiple innate host defenses.


BioPharm International Supplements



Figure 7. Induction of FAS L secretion by MIS416 stimulated NK/NKT cells. Human NK and NKT cells were purified from whole blood to 99% and cultured for 24 hours with no stimulus, known NK/NKT activating agents IL-2 (500 U/mL) and IL-12 (50 ng/mL), or with MIS416 (20, 10, 5, and 1 g/mL). Cell-free supernatants were assayed for FAS L content using flow cytometric bead array technology.

Figure 8. MIS416 activates PBMC NK granule and FAS L cytotoxicity. MIS416-activated PBMC were cultured with MIS416 at 20 and 5 g/ml. Known NK cell-activating agents, IL-2 (500 U/ml), IL-12 (50 ng/mL), and TLR3 ligand, poly I:C (50 g/ml) served as assay positive controls. Following a 46-hour culture, activated PBMCs were then washed into fresh medium and tested for cytotoxicity against fluorescently labelled tumor target cells at an effector:target ratio of 100:1. Tumor cell killing was determined after four hours by flow cytometric determination of viability dye uptake live/dead discrimination of gated, fluorescent tumor targets. It can be seen that MIS416 microparticle enhances human PBMC spontaneous killing activity against NK sensitive K562 (erythroleukemia) and DU-145 (prostate), as well as FAS L sensitive Daudi (Burkitt lymphoma) and T47D (breast) tumor cell targets.
Tumor-specific killing that results in the induction of apoptosis leads to clearance of these cells through the phagocytic pathway, resulting in uptake and cross-presentation of apoptotic tumor cell antigens by dendritic cells, which is required for the development of cytotoxic CD8+ antitumor responses. The induction of antitumor activity by immunostimulatory compounds is a clinically relevant therapeutic approach to treating neoplastic disease, as is demonstrated by the usefulness of BCG in preventing recurrence of bladder cancer that has been surgically removed at early stages of cancer development. Although natural killer (NK) cells play a central role in tumor cell surveillance and destruction, NKTs and monocytes or macrophages represent additional nonredundant arms of innate antitumor responses. Together these cell subsets are known to kill tumour targets by several mechanisms including, but not limited to, granule, FAS L and tumor necrosis factor-alpha (TNFα)-mediated pathways. MIS416 activates both NK cell granule-mediated cytotoxicity (Figure 6) and the secretion of cytotoxic soluble factors such as FAS L (Figure 7). When MIS416-stimulated pooled NK/NKT cells are tested against a range of tumors that have known differential sensitivity to these mechanisms, reliable killing is detected (Figure 8).

Summary

The molecular and cellular basis for adjuvancy and immune-boosting therapeutics is overlapping. There is accelerating interest in the use of nonspecific immunostimulants or adjuvants as a means of enhancing or inducing nonspecific immunity, which is a key to successful therapeutic vaccine development. The rationale behind this approach exploits several aspects associated with the innate immune system such as its rapid activation, the diverse activated array of broad-spectrum innate defenses are less likely to suffer the development of resistance, and the coherent activation of innate immune responses promotes normal activation of adaptive immune responses, which prevents or limits recurrent or progressive infections. The potential of the innate immune system as a therapeutic target has been demonstrated in several infectious and cancer models using TLR based and nonTLR-based approaches of selectively boosting the innate antiviral and antibacterial immune responses1 . As such, incorporation of this activity into vaccine designs is highly desirable from a therapeutic vaccine standpoint, and MIS416 is well placed to fulfill this role.

Gill A. Webster, PhD, is chief scientific officer and Frank B. Gelder, PhD, is founding scientist at Virionyx Corporation Ltd., Auckland, New Zealand, +64 (9) 6362500,

REFERENCES

1. Brown KL, Cosseau C, Gardy JL, Hancock REW. Complexities of Targeting Innate Immunity to Treat Infection. Trends in Immun. 2007;28:6.


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