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Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo

Nature Medicine volume 11, pages 130–137 (2005)Cite this article

Abstract

Modest clinical outcomes of dendritic-cell (DC) vaccine trials call for the refinement of DC vaccine design. Although many potential antigens have been identified, development of methods to enhance antigen presentation by DCs has lagged. We have engineered a potent, drug-inducible CD40 (iCD40) receptor that permits temporally controlled, lymphoid-localized, DC-specific activation. iCD40 is comprised of a membrane-localized cytoplasmic domain of CD40 fused to drug-binding domains. This allows it to respond to a lipid-permeable, high-affinity dimerizer drug while circumventing ectodomain-dependent negative-feedback mechanisms. These modifications permit prolonged activation of iCD40-expressing DCs in vivo, resulting in more potent CD8+ T-cell effector responses, including the eradication of previously established solid tumors, relative to activation of DCs ex vivo (P < 0.01), typical of most clinical DC protocols. In addition, iCD40-mediated DC activation exceeded that achieved by stimulating the full-length, endogenous CD40 receptor both in vitro and in vivo. Because iCD40 is insulated from the extracellular environment and can be activated within the context of an immunological synapse, iCD40-expressing DCs have a prolonged lifespan and should lead to more potent vaccines, perhaps even in immune-compromised patients.

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Figure 1: Engineering an insulated, CID-inducible CD40 receptor.
Figure 2: Activation of iCD40 initiates potent, durable NF-κB.
Figure 3: iCD40-mediated activation of DC lines in vitro and in vivo.
Figure 4: Drug-dependent activation of iCD40-expressing primary BMDCs in vitro and in vivo.
Figure 5: iCD40, but not full-length CD40, augments the immunogenicity of DNA-based vaccines independent of CD4+ T cells.
Figure 6: iCD40 enhances the efficacy of DC-based tumor vaccines and the potency of DC-mediated tumor immunosurveillance.

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Acknowledgements

We thank M. Brenner, C. Rooney and D. Lewis for reviewing drafts of this manuscript; K. Freeman for discussions; and E. Nikitina and T-A. Nguyen for technical assistance. This work was supported by a Robert C. and Janice McNair MD/PhD Training Fellowship at Baylor College of Medicine (to B.A.H.) and Department of Defense grant PC010463 (to D.M.S., K.M.S. and B.A.H.) and a Prostate Cancer Research Initiative grant (to D.M.S. and J.J.).

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Authors and Affiliations

  1. Department of Immunology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Brent A Hanks, Jianghong Jiang, Rana A K Singh, Michael Barry & David M Spencer

  2. Medical Scientist Training Program, Baylor College of Medicine, Houston, 77030, Texas, USA

    Brent A Hanks

  3. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, 77030, Texas, USA

    Rana A K Singh, Michael Barry & Mary H Huls

  4. Scott Department of Urology, The Methodist Hospital, Houston, 77030, Texas, USA

    Weitao Song & Kevin M Slawin

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Correspondence to David M Spencer.

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Supplementary information

Supplementary Fig. 1

Supportive data for iCD40-mediated activation of DC lines. (PDF 20 kb)

Supplementary Fig. 2

Generation of a stable LLO91–99-expressing A20 tumor cell line. (PDF 16 kb)

Supplementary Fig. 3

The iCD40 activation 'switch' is resistant to type II CD40 isoform regulation. (PDF 36 kb)

Supplementary Methods (PDF 49 kb)

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Hanks, B., Jiang, J., Singh, R. et al. Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo. Nat Med 11, 130–137 (2005). https://doi.org/10.1038/nm1183

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