Adenovirus-based viral vectors have been extensively studied in clinical trials. We and others have shown previously that oncolytic adenoviruses (OAds) represent an excellent platform for cancer immunotherapy due to their ability to stimulate the immune system. In fact, they are named nowadays as oncolytic vaccines. However, pre-existing immunity (PEI) in patients represents a recurrent concern, since a large part of the population has been pre-exposed to adenoviruses. Despite this high prevalence, the effect of pre-existing immunity on the efficacy of oncolytic vaccines in the context of cancer immunotherapy, has not been clearly elucidated given the pre-assumption that PEI is hindering the viral therapy. We challenged this assumption and investigated whether pre-existing immunity against adenoviral vectors would have a positive or a negative effect on OAd-based immunotherapy. In particular we studied the combination of immune checkpoint inhibitors with a novel oncolytic vaccine platform (PeptiCRAd). PeptiCRAd is based on OAds which are coated with tumor-derived peptides in order to redirect the immune system towards tumor antigens. In mice, the combination of PeptiCRAd and anti-PDL1 therapy significantly increased the median survival of B16 melanoma bearing mice (43 days for Combo therapy versus 35 and 27.5 days for the anti-PDL1 and PeptiCRAd monotherapies, respectively). On day 28 all mice were subjected to tumor re-challenge and tumor emergence and growth was followed. Mice treated with PeptiCRAd and anti-PDL1 combination showed a significantly slower tumor growth rate compared to mice treated with anti-PDL1 monotherapy (p=0.0248), highlighting that immunological memory was induced. Next, we sought to investigate the effect of a second round of treatment with PeptiCRAd oncolytic vaccine on primary tumors. To this end, we treated all the mice intratumorally with a PeptiCRAd targeting TRP2 and gp100 tumor antigens. Interestingly, mice with an anti-adenovirus PEI (mice previously treated with Combo therapy) showed a reduction in tumor growth compared to mice näive to Adenovirus (anti-PDL1 monotherapy mice). This finding suggested that pre-existing immunity to adenoviral vector might play a positive role in anti-cancer immunotherapy. In fact, in an independent experiment we observed a positive correlation between the degree of anti-adenoviral and anti-tumor T-cell responses, measured by an ELISPOT assay. To validate our previous findings, we performed an additional experiment where we induced anti-adenovirus-PEI by subcutaneous injections of OAds. Then, 14 days after the first immunization, we implanted B16 melanomas and once tumors developed, we started to treat these mice with the combination of PeptiCRAd and anti-PDL1. The results of the comparison between pre-immunized and non-pre-immunized mice will be presented in the ESGCT meeting.

Re-thinking the role of pre-existing anti-adenoviral immunity in cancer immunotherapy

CARPI, SARA;
2016-01-01

Abstract

Adenovirus-based viral vectors have been extensively studied in clinical trials. We and others have shown previously that oncolytic adenoviruses (OAds) represent an excellent platform for cancer immunotherapy due to their ability to stimulate the immune system. In fact, they are named nowadays as oncolytic vaccines. However, pre-existing immunity (PEI) in patients represents a recurrent concern, since a large part of the population has been pre-exposed to adenoviruses. Despite this high prevalence, the effect of pre-existing immunity on the efficacy of oncolytic vaccines in the context of cancer immunotherapy, has not been clearly elucidated given the pre-assumption that PEI is hindering the viral therapy. We challenged this assumption and investigated whether pre-existing immunity against adenoviral vectors would have a positive or a negative effect on OAd-based immunotherapy. In particular we studied the combination of immune checkpoint inhibitors with a novel oncolytic vaccine platform (PeptiCRAd). PeptiCRAd is based on OAds which are coated with tumor-derived peptides in order to redirect the immune system towards tumor antigens. In mice, the combination of PeptiCRAd and anti-PDL1 therapy significantly increased the median survival of B16 melanoma bearing mice (43 days for Combo therapy versus 35 and 27.5 days for the anti-PDL1 and PeptiCRAd monotherapies, respectively). On day 28 all mice were subjected to tumor re-challenge and tumor emergence and growth was followed. Mice treated with PeptiCRAd and anti-PDL1 combination showed a significantly slower tumor growth rate compared to mice treated with anti-PDL1 monotherapy (p=0.0248), highlighting that immunological memory was induced. Next, we sought to investigate the effect of a second round of treatment with PeptiCRAd oncolytic vaccine on primary tumors. To this end, we treated all the mice intratumorally with a PeptiCRAd targeting TRP2 and gp100 tumor antigens. Interestingly, mice with an anti-adenovirus PEI (mice previously treated with Combo therapy) showed a reduction in tumor growth compared to mice näive to Adenovirus (anti-PDL1 monotherapy mice). This finding suggested that pre-existing immunity to adenoviral vector might play a positive role in anti-cancer immunotherapy. In fact, in an independent experiment we observed a positive correlation between the degree of anti-adenoviral and anti-tumor T-cell responses, measured by an ELISPOT assay. To validate our previous findings, we performed an additional experiment where we induced anti-adenovirus-PEI by subcutaneous injections of OAds. Then, 14 days after the first immunization, we implanted B16 melanomas and once tumors developed, we started to treat these mice with the combination of PeptiCRAd and anti-PDL1. The results of the comparison between pre-immunized and non-pre-immunized mice will be presented in the ESGCT meeting.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/854059
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