Intratumoral delivery of a novel oncolytic adenovirus encoding human antibody against PD-1 elicits enhanced antitumor efficacy

Abstract

To date, diverse combination therapies with immune checkpoint inhibitors (ICIs), particularly oncolytic virotherapy, have demonstrated enhanced therapeutic outcomes in cancer treatment. However, high pre-existing immunity against the widely used adenovirus human serotype 5 (AdHu5) limits its extensive clinical application. In this study, we constructed an innovative oncolytic virus (OV) based on a chimpanzee adenoviral vector with low seropositivity in the human population, named AdC68-spE1A-αPD-1, which endows the parental OV (AdC68-spE1A-ΔE3) with the ability to express full-length anti-human programmed cell death-1 monoclonal antibody (αPD-1). In vitro studies indicated that the AdC68-spE1A-αPD-1 retained parental oncolytic capacity, and αPD-1 was efficiently secreted from the infected tumor cells and bound exclusively to human PD-1 (hPD-1) protein. In vivo, intratumoral treatment with AdC68-spE1A-αPD-1 resulted in significant tumor suppression, prolonged overall survival, and enhanced systemic antitumor memory response in an hPD-1 knockin mouse tumor model. This strategy outperformed the unarmed OV and was comparable with combination therapy with intratumoral injection of AdC68-spE1A-ΔE3 and systemic administration of commercial αPD-1. In summary, AdC68-spE1A-αPD-1 is a cost-effective approach with potential clinical applications. ‬‬‬‬ To date, diverse combination therapies with immune checkpoint inhibitors (ICIs), particularly oncolytic virotherapy, have demonstrated enhanced therapeutic outcomes in cancer treatment. However, high pre-existing immunity against the widely used adenovirus human serotype 5 (AdHu5) limits its extensive clinical application. In this study, we constructed an innovative oncolytic virus (OV) based on a chimpanzee adenoviral vector with low seropositivity in the human population, named AdC68-spE1A-αPD-1, which endows the parental OV (AdC68-spE1A-ΔE3) with the ability to express full-length anti-human programmed cell death-1 monoclonal antibody (αPD-1). In vitro studies indicated that the AdC68-spE1A-αPD-1 retained parental oncolytic capacity, and αPD-1 was efficiently secreted from the infected tumor cells and bound exclusively to human PD-1 (hPD-1) protein. In vivo, intratumoral treatment with AdC68-spE1A-αPD-1 resulted in significant tumor suppression, prolonged overall survival, and enhanced systemic antitumor memory response in an hPD-1 knockin mouse tumor model. This strategy outperformed the unarmed OV and was comparable with combination therapy with intratumoral injection of AdC68-spE1A-ΔE3 and systemic administration of commercial αPD-1. In summary, AdC68-spE1A-αPD-1 is a cost-effective approach with potential clinical applications. ‬‬‬‬ IntroductionIn recent years, with the approval of immune checkpoint inhibitors (ICIs) by the US Food and Drug Administration (FDA), cancer immunotherapy has made great progress in clinical applications.1Xu W. Atkins M.B. McDermott D.F. Checkpoint inhibitor immunotherapy in kidney cancer.Nat. Rev. Urol. 2020; 17: 137-150https://doi.org/10.1038/s41585-020-0282-3Google Scholar Ipilimumab, the first FDA-approved monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA4), represents a milestone for ICI therapy.2Bagchi S. Yuan R. Engleman E.G. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance.Annu. Rev. Pathol. 2021; 16: 223-249https://doi.org/10.1146/annurev-pathol-042020-042741Google Scholar Notably, novel therapeutic antibodies targeting programmed cell death-1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) exhibit fewer side effects compared with that of the anti-CTLA4 antibody and have been developed as a powerful strategy in the clinical treatment of multiple types of cancer.3Sharma P. Allison J.P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.Cell. 2015; 161: 205-214https://doi.org/10.1016/j.cell.2015.03.030Google Scholar, 4Riley R.S. June C.H. Langer R. Mitchell M.J. Delivery technologies for cancer immunotherapy.Nat. Rev. Drug Discov. 2019; 18: 175-196https://doi.org/10.1038/s41573-018-0006-zGoogle Scholar, 5Alsaab H.O. Sau S. Alzhrani R. Tatiparti K. Bhise K. Kashaw S.K. Iyer A.K. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome.Front. Pharmacol. 2017; 8: 561https://doi.org/10.3389/fphar.2017.00561Google ScholarPD-1, also known as CD279, is mainly expressed on activated T cells and acts as a co-inhibitory molecule to regulate the extent of T cell activation.5Alsaab H.O. Sau S. Alzhrani R. Tatiparti K. Bhise K. Kashaw S.K. Iyer A.K. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome.Front. Pharmacol. 2017; 8: 561https://doi.org/10.3389/fphar.2017.00561Google Scholar,6Munn D.H. Bronte V. Immune suppressive mechanisms in the tumor microenvironment.Curr. Opin. Immunol. 2016; 39: 1-6https://doi.org/10.1016/j.coi.2015.10.009Google Scholar To obviate the recognition and elimination by cytotoxic T cells, the majority of tumor cells overexpress PD-L1 to yield downstream inhibitory signals and result in T cell dysfunction by interacting with PD-1.7Mahoney K.M. Rennert P.D. Freeman G.J. Combination cancer immunotherapy and new immunomodulatory targets.Nat. Rev. Drug Discov. 2015; 14: 561-584https://doi.org/10.1038/nrd4591Google Scholar Thus, blocking the PD-1 and PD-L1 interaction with the responsible antibodies could rescue the T cell-mediated antitumor immune response.8Topalian S.L. Drake C.G. Pardoll D.M. Immune checkpoint blockade: a common denominator approach to cancer therapy.Cancer Cell. 2015; 27: 450-461https://doi.org/10.1016/j.ccell.2015.03.001Google Scholar In general, ICI monotherapy fails to solve the “cold tumors” problem, which is often characterized by insufficient T cell infiltration, low PD-L1 expression, and defective antigen processing and presentation.9Galon J. Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies.Nat. Rev. Drug Discov. 2019; 18: 197-218https://doi.org/10.1038/s41573-018-0007-yGoogle Scholar According to previous studies, only approximately 10%–40% of patients with certain tumors could generate an inspiring response to ICI.10Weber J. Thompson J.A. Hamid O. Minor D. Amin A. Ron I. Ridolfi R. Assi H. Maraveyas A. Berman D. et al.A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab with in patients with J. K. McDermott D. et and ipilimumab ipilimumab in J. 2015; Scholar the years, the ICI monotherapy has been toward combination in which effects therapeutic the PD-1 and PD-L1 and in combination with oncolytic virotherapy, in and clinical P. Allison J.P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.Cell. 2015; 161: 205-214https://doi.org/10.1016/j.cell.2015.03.030Google and PD-1 blockade: in the 2015; J. A. with in the of immune checkpoint Rev. 2020; 17: combination oncolytic virus (OV) represents a new of therapeutic its in tumor cells targeting J. oncolytic with cancer immunotherapy: a new of cancer Immunol. 2020; Scholar This PD-L1 in tumor cells and antigen which to extensive T cell in the tumor S. oncolytic to antitumor progress and 2020; R. P. combination of oncolytic virus and PD-L1 to therapeutic 2017; 8: Scholar the suppressive tumor from T cells and cells by OV on the tumor 2015; H. J. et by intratumoral oncolytic virus the efficacy of 2019; of have been developed as virus and and have been developed as of the used of its and in and clinical D.M. to oncolytic for of Combination of oncolytic adenovirus with antitumor in mouse 2019; 8: Scholar oncolytic from that Combination of oncolytic adenovirus with antitumor in mouse 2019; 8: S. R. A. A. D. and of injection with an adenovirus of the a phase 8: Scholar the of has a high for which to of by D. K. H. R. J.A. et serotype 5 Scholar In the majority of have antibodies against of which the antitumor effects in clinical of novel based on is an for this the therapeutic efficacy of the combination of OV and the clinical the of the and the on antibodies that in the To a we an innovative oncolytic chimpanzee adenovirus with αPD-1 and its efficacy in cancer cell and a human PD-1 (hPD-1) knockin mouse tumor and was from and is to the of human and adenovirus for virus adenovirus as a vector with the and adenovirus Scholar However, is a serotype with a low in the human and by antibodies against common human adenovirus of the of J. vector based on a chimpanzee Scholar Thus, we to a oncolytic adenovirus for cancer the of the oncolytic adenovirus in tumor cells, we the S. S. H. K. adenovirus and Scholar which is in tumor cells, to the adenoviral To the OV vector we the by to the of adenovirus vector which the and to generate OV we the full-length antibody of αPD-1 the of the parental OV vector adenovirus was constructed as a antibody by the αPD-1 the of the in a of cells, the human cell human tumor cell and and tumor cell and to in and that in cells, which result from of in To the of the cells infected with the and of and in in cells infected with OV AdC68-spE1A-αPD-1 in and in and and in Thus, the was activated efficiently in tumor cells in oncolytic efficiently in tumor cell we the of and by in and efficiently in and cells and in cells, which was in However, and also in and and we the in cells, which to of as by et K.M. A. K. S.L. of of human adenovirus in cancer cells by in vitro and in Scholar that the mechanisms that to that the efficiently adenovirus in certain types of tumor cell Notably, in cell was significant AdC68-spE1A-αPD-1 and that the of αPD-1 the of of αPD-1 from tumor cells infected with of αPD-1 from the tumor cells infected with AdC68-spE1A-αPD-1 was in the of αPD-1 was in cells infected with AdC68-spE1A-αPD-1 and Notably, the of αPD-1 in cells was that in which was to In the for to the antibody was secreted and full-length and and that αPD-1 was in and cells infected with of αPD-1 in the from from which resulted from of in cells of αPD-1 to PD-1 is for blocking the in compared with the commercial hPD-1 the expressed αPD-1 from cells infected with AdC68-spE1A-αPD-1 and to the hPD-1 bound to PD-1 αPD-1 was expressed in tumor cells and bound to hPD-1 αPD-1 was by and cells infected with the indicated in to and the of cells infected with was as indicated tumor cells infected with the of αPD-1 in the was and of the expressed αPD-1 to hPD-1 and protein. from cells infected with was used as a and the commercial hPD-1 antibody and antibody used as was by as summary, that αPD-1 was from tumor cells infected with AdC68-spE1A-αPD-1, which for the hPD-1 of AdC68-spE1A-αPD-1 in the antibody the oncolytic of AdC68-spE1A-αPD-1, we the cells with and from 1 to in the of cells was with a high of the tumor cells, compared with the and infected with AdC68-spE1A-ΔE3 AdC68-spE1A-αPD-1 and Notably, in cells, AdC68-spE1A-ΔE3 and AdC68-spE1A-αPD-1 oncolytic effects on cells an of In was in in human tumor cells, the could enhanced oncolytic effects was with the in and the oncolytic effects of AdC68-spE1A-ΔE3 and AdC68-spE1A-αPD-1 on cell an of and tumor cell death in and infected with indicated for of cells was by as compared with the parental OV AdC68-spE1A-αPD-1 comparable oncolytic in an tumor cell death and has that cell death by multiple P. J. P. et of cell of the on cell death 16: Scholar To the by which AdC68-spE1A-αPD-1 tumor cell we to and 4 that was and was in and cells with AdC68-spE1A-ΔE3 AdC68-spE1A-αPD-1 and that was by AdC68-spE1A-αPD-1, to of tumor H. H. S. A. K. et cell death of cells by a Scholar is an in a of as K. S. a of is a that the death the of J. Scholar of was in tumor cells infected with AdC68-spE1A-ΔE3 AdC68-spE1A-αPD-1 Notably, the of was AdC68-spE1A-αPD-1 in of and its downstream molecule in cells, in cells with AdC68-spE1A-ΔE3 cell 1 which to the cell as a by the of the of Scholar was in tumor cells treatment with AdC68-spE1A-ΔE3 a as that with was also in as and tumor cell death by and and cells infected with the indicated cells and to the and was used as a that AdC68-spE1A-αPD-1 tumor cell death by the and antitumor efficacy and a memory response in an hPD-1 mouse tumor the antitumor of AdC68-spE1A-αPD-1 in vivo, we an hPD-1 knockin mouse tumor in which the of the was by its human in downstream inhibitory signaling in this mouse was efficiently by and the αPD-1 expressed from cells in Thus, this mouse was for the of antitumor of AdC68-spE1A-αPD-1 treatment in with the the tumor the of AdC68-spE1A-αPD-1 for in In a combination therapy injection of AdC68-spE1A-ΔE3 with administration of the commercial was also in AdC68-spE1A-αPD-1 treatment was to combination tumor In in the tumor and the parental AdC68-spE1A-ΔE3 the antibody to only a in tumor tumor of in Notably, of in the AdC68-spE1A-αPD-1 of and in the combination therapy of tumor the in AdC68-spE1A-ΔE3 tumor of the also with the tumor inhibition to the tumor cells death was by AdC68-spE1A-αPD-1 we the and the on 5 the treatment to the in the tumor of the of the AdC68-spE1A-ΔE3 and comparable with of the combination treatment Notably, compared with the the in the was which was indicated by the of the of the of P. of tumor antitumor effects in an hPD-1 knockin mouse tumor of the treatment strategy in hPD-1 knockin mouse tumor model. with tumor the with of AdC68-spE1A-αPD-1 for a of combination therapy injection of AdC68-spE1A-ΔE3 with of commercial was also was overall was on 5 and the tumor was and tumors used to and the of cells was by in from the indicated with a of cells on in the tumor survival, and tumor by and as we AdC68-spE1A-αPD-1 treatment could memory from the indicated treatment combination with a of tumor cells in the on in tumors to in the in a tumors AdC68-spE1A-αPD-1 a significant antitumor and a antitumor response comparable with that of the combination enhanced the of immune cells studies have that combination therapy could immune and systemic immunity against Combination immunotherapy oncolytic virus for the treatment of J. 2020; A. R. I. A. O. J. J. et intratumoral T cell and 2017; Scholar we the in 5 and AdC68-spE1A-αPD-1 treatment could systemic from treatment on treatment to the of T cells by in was significant in the of T cells the Notably, T cell in the AdC68-spE1A-αPD-1 compared with of AdC68-spE1A-ΔE3 treatment compared with that of the combination therapy that the of the co-inhibitory molecule PD-1 a in T cell we the of in the T cells and that AdC68-spE1A-αPD-1 treatment to a significant in the and T cells, which indicated that T cell was In the of T cells was in the AdC68-spE1A-αPD-1 treatment that in the combination therapy from the tumor indicated that the memory response was by AdC68-spE1A-αPD-1 we the of memory T cells and memory T cells of and in the AdC68-spE1A-αPD-1 in the and T cells and compared with of AdC68-spE1A-ΔE3 However, was significant the AdC68-spE1A-αPD-1 and combination therapy for the enhanced the of immune on the treatment. for and of the T cells from the T cells was by of the immune inhibitor PD-1 in the and T cells was and of memory T cells and memory T cells in T cells also result is in the and the of 1 is in the the the from was the was by as T cell response was an in the with the tumor cells, was enhanced in the AdC68-spE1A-αPD-1 compared with that in the treatment response was in In the tumor of in this in which a to that in that injection of AdC68-spE1A-αPD-1 could systemic antitumor which to therapeutic of PD-1 and PD-L1 have in the of ICI monotherapy clinical outcomes only in certain cancer combination strategies with treatment with virotherapy, have been and have been in that to ICI R. P. combination of oncolytic virus and PD-L1 to therapeutic 2017; 8: I. A. S. D. virus in combination with immune checkpoint curative A. S. R. et of tumors to by 2015; first clinical of the combination of OV with ICI to the antitumor efficacy was in a phase study, by et I. Minor D. Hamid O. A. A. J. et in combination with ipilimumab in 2016; Scholar that intratumoral injection of with the systemic administration of anti-CTLA4 antibody antitumor efficacy compared with that of ipilimumab in the of combination therapy is for et R. P. combination of oncolytic virus and PD-L1 to therapeutic 2017; 8: Scholar demonstrated that was to a administration of the OV and ICI the ICI was the OV the ICI was the immune checkpoint high to efficiently of the OV to express ICI the is a we a novel AdC68-spE1A-αPD-1, which was based on the chimpanzee adenoviral vector to efficiently express αPD-1 tumor that AdC68-spE1A-αPD-1 demonstrated and which the of for combination first of an oncolytic adenovirus a human full-length was by et O. I. A. K. S. A. S. A. et cancer immunotherapy with oncolytic adenovirus for a human monoclonal antibody for Scholar study that the in the and the antitumor in this for clinical applications. was tumor for the the of the and could by pre-existing antibodies against D. H. A. S. et immune in to Immunol. Scholar a chimpanzee adenovirus that in was and its was to by a J. vector based on a chimpanzee Scholar to cancer from the of the was also as a of the which could with the to adenovirus of adenovirus and of its by Scholar Thus, in tumor cells of the of a was the tumor cells could and we that αPD-1 was efficiently expressed and in tumor cells infected with AdC68-spE1A-αPD-1, which demonstrated infected with the expressed αPD-1 was bound to and efficiently the as the commercial antibody of has also been in et P. V. D. et in an oncolytic virus of an a and a against programmed cell death (PD-1) intratumoral and an 2016; Scholar of a monoclonal antibody against in oncolytic virus and demonstrated that the full-length and the antibody and to that of the et I. J. K. H. V. K. et an oncolytic virus 1 with a antibody against PD-1 for 2019; Scholar an oncolytic to express a antibody and that a therapeutic in types of mouse model. et S. W. K. therapeutic efficacy of a novel oncolytic virus an antibody against programmed cell death 2019; Scholar constructed an oncolytic an antibody and that activated immune cells, and in the and the systemic immune virus with antibodies against PD-L1 only tumor and R. S. D. I. V. D.M. W. et and PD-L1 checkpoint oncolytic virus Scholar of this study that the oncolytic chimpanzee adenovirus could with the expressed αPD-1. In an hPD-1 knockin mouse tumor AdC68-spE1A-αPD-1 tumor and tumor in of the is that the efficacy of AdC68-spE1A-αPD-1 in cells was that in human tumor cells in the therapeutic effects of AdC68-spE1A-αPD-1 in the tumor that the efficacy of AdC68-spE1A-αPD-1 was by the systemic antitumor response of the with low the of AdC68-spE1A-αPD-1 was in tumor cells we the treatment as a strategy to the as indicated in was in oncolytic which an in and immunity to and tumor A. O. P. P. cell death and in cancer Rev. J. J. J. et and the response and in J. Scholar the tumor inhibition was to the PD-1 in T in and tumor cells infected with AdC68-spE1A-αPD-1 of αPD-1 infected with in also that PD-1 in T cells was efficiently in the AdC68-spE1A-αPD-1 in the in vivo, that the was by of αPD-1 expressed by AdC68-spE1A-αPD-1, which was to the of T cells that the was the systemic and in the AdC68-spE1A-αPD-1 for therapeutic outcomes and of from the tumor compared with AdC68-spE1A-ΔE3 and AdC68-spE1A-αPD-1 systemic antitumor and the therapeutic with combination AdC68-spE1A-αPD-1 is for and extensive clinical cancer treatment could the high pre-existing immunity against in as have tumors immune D. strategies that by tumor Rev. Immunol. Scholar AdC68-spE1A-αPD-1 was to with with as and as a However, the of study is that the and of αPD-1 in and the immune in the have been the antitumor efficacy in tumor we that the and oncolytic of AdC68-spE1A-αPD-1 in human tumor In the we to the therapeutic of AdC68-spE1A-αPD-1 in tumor and the mechanisms and we constructed a novel AdC68-spE1A-αPD-1, which OV and ICI in and enhanced antitumor This novel the for cancer treatment and and kidney cells, human cell human cell human cell human cell and cell from human cell human cell and cell from the of for cell was from cells in with and and in cell with of adenoviral in the and D. and of adenoviral 2016; Scholar To the parental OV we the with the by and the of to AdC68-spE1A-αPD-1, we the the and of the monoclonal antibody from the and with the and of human To and of and we a J. S. K. antibody therapeutic the Scholar the antibody by and the with and to to AdC68-spE1A-αPD-1, we the the of the oncolytic AdC68-spE1A-ΔE3 by was the approach as adenovirus constructed with and cells the in cells and the adenovirus was in and to cells in a to the was a to the the and H. of J. 27: Scholar of to was based on the and in a and cells infected with an of and the cells and with to the for the of by and the for the of of and αPD-1 to the 1 of from was to a to the and αPD-1 a used as and and αPD-1 and was used as the and the used and and for and of was as was to cells in and infected with the oncolytic and cells and and with the cells in 1 of and to of the was to the cells by in a the of was the and of as the of and which indicated the of the virus the and in a and cells infected with for and the a blocking with for the was with anti-human the signaling we infected the and cells with and the cells with and with inhibitors the of was a to that the was and the was with the antibody against and the was with the antibodies and tumor cells infected with AdC68-spE1A-αPD-1 and in the a was the and with for the and the commercial hPD-1 antibody in and to the for anti-human was and for 1 was and the was with was a According to the by the commercial hPD-1 the of the expressed αPD-1 of the expressed αPD-1 to PD-1 was also by the as the by hPD-1 and the and anti-human was hPD-1 and antibodies used as oncolytic cells and a of tumor cells and in a and and AdC68-spE1A-αPD-1 from to 1 in with and infected cells in used as cell was the the was a in with the and of the of the of hPD-1 knockin in which the was by the human from with tumor cells in the the tumor and to intratumoral treatment with of AdC68-spE1A-αPD-1, combination therapy with intratumoral injection of AdC68-spE1A-ΔE3 administration of commercial αPD-1 an of and in tumor was with a and was the the the tumor the treatment for and and the tumors 5 the treatment for and the tumor with AdC68-spE1A-αPD-1 the combination which to with a of tumor cells in the that the of tumor cells used as tumors with 1 of in in and was the as by the and a of the cells was cells from the from the treatment and the with a cell cells with an antibody for for was the the cells with antibodies against and on for a and the the antibodies used and the of T cells we to the activated with and with antibodies against with and with for from treatment and to the and with tumor cells for in a cell with the cells and the with the with antibody in for and was and for 1 immune by with the and with the the was by of as of the and IntroductionIn recent years, with the approval of immune checkpoint inhibitors (ICIs) by the US Food and Drug Administration (FDA), cancer immunotherapy has made great progress in clinical applications.1Xu W. Atkins M.B. McDermott D.F. Checkpoint inhibitor immunotherapy in kidney cancer.Nat. Rev. Urol. 2020; 17: 137-150https://doi.org/10.1038/s41585-020-0282-3Google Scholar Ipilimumab, the first FDA-approved monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA4), represents a milestone for ICI therapy.2Bagchi S. Yuan R. Engleman E.G. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance.Annu. Rev. Pathol. 2021; 16: 223-249https://doi.org/10.1146/annurev-pathol-042020-042741Google Scholar Notably, novel therapeutic antibodies targeting programmed cell death-1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) exhibit fewer side effects compared with that of the anti-CTLA4 antibody and have been developed as a powerful strategy in the clinical treatment of multiple types of cancer.3Sharma P. Allison J.P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.Cell. 2015; 161: 205-214https://doi.org/10.1016/j.cell.2015.03.030Google Scholar, 4Riley R.S. June C.H. Langer R. Mitchell M.J. Delivery technologies for cancer immunotherapy.Nat. Rev. Drug Discov. 2019; 18: 175-196https://doi.org/10.1038/s41573-018-0006-zGoogle Scholar, 5Alsaab H.O. Sau S. Alzhrani R. Tatiparti K. Bhise K. Kashaw S.K. Iyer A.K. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome.Front. Pharmacol. 2017; 8: 561https://doi.org/10.3389/fphar.2017.00561Google ScholarPD-1, also known as CD279, is mainly expressed on activated T cells and acts as a co-inhibitory molecule to regulate the extent of T cell activation.5Alsaab H.O. Sau S. Alzhrani R. Tatiparti K. Bhise K. Kashaw S.K. Iyer A.K. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome.Front. Pharmacol. 2017; 8: 561https://doi.org/10.3389/fphar.2017.00561Google Scholar,6Munn D.H. Bronte V. Immune suppressive mechanisms in the tumor microenvironment.Curr. Opin. Immunol. 2016; 39: 1-6https://doi.org/10.1016/j.coi.2015.10.009Google Scholar To obviate the recognition and elimination by cytotoxic T cells, the majority of tumor cells overexpress PD-L1 to yield downstream inhibitory signals and result in T cell dysfunction by interacting with PD-1.7Mahoney K.M. Rennert P.D. Freeman G.J. Combination cancer immunotherapy and new immunomodulatory targets.Nat. Rev. Drug Discov. 2015; 14: 561-584https://doi.org/10.1038/nrd4591Google Scholar Thus, blocking the PD-1 and PD-L1 interaction with the responsible antibodies could rescue the T cell-mediated antitumor immune response.8Topalian S.L. Drake C.G. Pardoll D.M. Immune checkpoint blockade: a common denominator approach to cancer therapy.Cancer Cell. 2015; 27: 450-461https://doi.org/10.1016/j.ccell.2015.03.001Google Scholar In general, ICI monotherapy fails to solve the “cold tumors” problem, which is often characterized by insufficient T cell infiltration, low PD-L1 expression, and defective antigen processing and presentation.9Galon J. Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies.Nat. Rev. Drug Discov. 2019; 18: 197-218https://doi.org/10.1038/s41573-018-0007-yGoogle Scholar According to previous studies, only approximately 10%–40% of patients with certain tumors could generate an inspiring response to ICI.10Weber J. Thompson J.A. Hamid O. Minor D. Amin A. Ron I. Ridolfi R. Assi H. Maraveyas A. Berman D. et al.A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab with in patients with J. K. McDermott D. et and ipilimumab ipilimumab in J. 2015; Scholar the years, the ICI monotherapy has been toward combination in which effects therapeutic the PD-1 and PD-L1 and in combination with oncolytic virotherapy, in and clinical P. Allison J.P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.Cell. 2015; 161: 205-214https://doi.org/10.1016/j.cell.2015.03.030Google and PD-1 blockade: in the 2015; J. A. with in the of immune checkpoint Rev. 2020; 17: combination oncolytic virus (OV) represents a new of therapeutic its in tumor cells targeting J. oncolytic with cancer immunotherapy: a new of cancer Immunol. 2020; Scholar This PD-L1 in tumor cells and antigen which to extensive T cell in the tumor S. oncolytic to antitumor progress and 2020; R. P. combination of oncolytic virus and PD-L1 to therapeutic 2017; 8: Scholar the suppressive tumor from T cells and cells by OV on the tumor 2015; H. J. et by intratumoral oncolytic virus the efficacy of 2019; of have been developed as virus and and have been developed as of the used of its and in and clinical D.M. to oncolytic for of Combination of oncolytic adenovirus with antitumor in mouse 2019; 8: Scholar oncolytic from that Combination of oncolytic adenovirus with antitumor in mouse 2019; 8: S. R. A. A. D. and of injection with an adenovirus of the a phase 8: Scholar the of has a high for which to of by D. K. H. R. J.A. et serotype 5 Scholar In the majority of have antibodies against of which the antitumor effects in clinical of novel based on is an for this the therapeutic efficacy of the combination of OV and the clinical the of the and the on antibodies that in the To a we an innovative oncolytic chimpanzee adenovirus with αPD-1 and its efficacy in cancer cell and a human PD-1 (hPD-1) knockin mouse tumor model.

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