Oncolytic adenovirus research evolution: from cell-cycle checkpoints to immune checkpoints - PubMed (original) (raw)

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Oncolytic adenovirus research evolution: from cell-cycle checkpoints to immune checkpoints

Hong Jiang et al. Curr Opin Virol. 2015 Aug.

Abstract

Oncolytic adenoviruses are modified to exploit the aberrant expression of proteins in cancer cells to obtain cancer-selective replication. Moreover, the natural tropism of oncolytic adenoviruses can be redirected to tumor cells. Clinical trials revealed that oncolytic viruses showed poor replication in the tumor that is due in part to the immune response against the virus. More recent data demonstrated that tumor infection might subvert the tumor immune system and lead to an anti-tumor immune response. In the next few years, combination of adenoviruses with immune checkpoint antibodies and other immune modulators will be tested in clinical trials.

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Figures

Figure 1

Figure 1. Dual mechanism of cancer virotherapy

Viral-mediated anticancer effect in vivo would depend on success of the two stages: viral replication with the effect of viral-induced oncolysis and the subsequent immune response. The first stage, viral-induced oncolysis, should probably be 1) enhanced by directing the tropism of the adenovirus to cancer cells, per instance with the insertion of an RGD-motif peptide sequence in the viral fiber knob; 2) restricted to cancer cells, and this can be achieved by modifying the viral proteins that interact with cellular proteins, per instance, via mutations of the early viral proteins E1A or E1B; and 3) modified by accelerating the lysis process, per instance by increasing autophagy with autophagy regulators. The anti-virus and anti-tumor immune responses are elicited by the accumulation of pathogen-associated molecular patterns (PAMPs), which reflect conserved components of microbes and viruses, per instance the adenovirus capsid proteins, together with the release to the tumor milieu of danger-associated molecular patterns (DAMPs), which are responsible for the attraction of innate immune cells and eventually for T cell priming. It is possible that tumor regression after adenoviral infection would exclusively occur if the anti-tumor immune response is elicited and maintained.

Figure 2

Figure 2. Rationale for the combination of oncolytic adenoviruses with immune checkpoint modulators

Future personalized medicine in the field of oncolytic virotherapy might depend on the degree of tumor immunogenicity, the status of the host immune response with respect to tumor cells, and the levels of expression of immune checkpoints and other positive and negative regulators of anergy. Combination therapy might be required particularly for patients with weak Th1 primed lymphocytes, and high levels of expression of immune checkpoints in the tumor infiltrative T cells, and with a low degree of immunogenicity. Further preclinical studies would be necessary to buttress these algorithms.

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