A novel cancer vaccine for melanoma based on an approved vaccine against measles, mumps, and rubella

Abstract

Common vaccines for infectious diseases have been repurposed as cancer immunotherapies. The intratumoral administration of these repurposed vaccines can induce immune cell infiltration into the treated tumor. Here, we have used an approved trivalent live attenuated measles, mumps, and rubella (MMR) vaccine in our previously developed PeptiENV cancer vaccine platform. The intratumoral administration of this novel MMR-containing PeptiENV cancer vaccine significantly increased both intratumoral as well as systemic tumor-specific T cell responses. In addition, PeptiENV therapy, in combination with immune checkpoint inhibitor therapy, improved tumor growth control and survival as well as increased the number of mice responsive to immune checkpoint inhibitor therapy. Importantly, mice pre-vaccinated with the MMR vaccine responded equally well, if not better, to the PeptiENV therapy, indicating that pre-existing immunity against the MMR vaccine viruses does not compromise the use of this novel cancer vaccine platform. Common vaccines for infectious diseases have been repurposed as cancer immunotherapies. The intratumoral administration of these repurposed vaccines can induce immune cell infiltration into the treated tumor. Here, we have used an approved trivalent live attenuated measles, mumps, and rubella (MMR) vaccine in our previously developed PeptiENV cancer vaccine platform. The intratumoral administration of this novel MMR-containing PeptiENV cancer vaccine significantly increased both intratumoral as well as systemic tumor-specific T cell responses. In addition, PeptiENV therapy, in combination with immune checkpoint inhibitor therapy, improved tumor growth control and survival as well as increased the number of mice responsive to immune checkpoint inhibitor therapy. Importantly, mice pre-vaccinated with the MMR vaccine responded equally well, if not better, to the PeptiENV therapy, indicating that pre-existing immunity against the MMR vaccine viruses does not compromise the use of this novel cancer vaccine platform. IntroductionThe measles, mumps, and rubella (MMR) vaccine is a trivalent vaccine that contains live attenuated strains of MMR viruses. MMR vaccines are indicated for the routine immunization of children for the prevention of measles, mumps, and rubella. Recently, common vaccines for infectious diseases, such as a seasonal influenza vaccine, rotavirus vaccines, and a vaccine against yellow fever, have been repurposed as intratumoral immunotherapies for the modulation of the tumor microenvironment (TME).1Aznar M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google Scholar, 2Newman J.H. Chesson C.B. Herzog N.L. Bommareddy P.K. Aspromonte S.M. Pepe R. Estupinian R. Aboelatta M.M. Buddhadev S. Tarabichi S. et al.Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.Proc. Natl. Acad. Sci. U S A. 2020; 117: 1119-1128https://doi.org/10.1073/pnas.1904022116Google Scholar, 3Shekarian T. Sivado E. Jallas A.C. Depil S. Kielbassa J. Janoueix-Lerosey I. Hutter G. Goutagny N. Bergeron C. Viari A. et al.Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade.Sci. Transl. Med. 2019; 11: eaat5025https://doi.org/10.1126/scitranslmed.aat5025Google Scholar By intratumoral administration of these viral vaccines, they were able to elicit immunostimulatory effects, such as enhancement of infiltration of cytotoxic T cells (CTLs), natural killer cells and CD4+ Th1 T helper cells, reduction of T regulatory cells and in some cases, exert oncolytic properties.1Aznar M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google Scholar, 2Newman J.H. Chesson C.B. Herzog N.L. Bommareddy P.K. Aspromonte S.M. Pepe R. Estupinian R. Aboelatta M.M. Buddhadev S. Tarabichi S. et al.Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.Proc. Natl. Acad. Sci. U S A. 2020; 117: 1119-1128https://doi.org/10.1073/pnas.1904022116Google Scholar, 3Shekarian T. Sivado E. Jallas A.C. Depil S. Kielbassa J. Janoueix-Lerosey I. Hutter G. Goutagny N. Bergeron C. Viari A. et al.Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade.Sci. Transl. Med. 2019; 11: eaat5025https://doi.org/10.1126/scitranslmed.aat5025Google Scholar, 4Melero I. Gato M. Shekarian T. Aznar A. Valsesia-Wittmann S. Caux C. Etxeberrria I. Teijeira A. Marabelle A. Repurposing infectious disease vaccines for intratumoral immunotherapy.J. Immunother. Cancer. 2020; 8: e000443https://doi.org/10.1136/jitc-2019-000443Google Scholar, 5Zhang Z. Zhou L. Xie N. Nice E.C. Zhang T. Cui Y. Huang C. Overcoming cancer therapeutic bottleneck by drug repurposing.Signal. Transduct. Target. Ther. 2020; 5: 113https://doi.org/10.1038/s41392-020-00213-8Google Scholar Immune checkpoint inhibitors (ICIs), a novel class of therapeutic antibodies that target immune checkpoint molecules such as programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T lymphocyte-associated antigen 4, can activate pre-existing anti-tumor immune responses.6Ott P.A. Hodi F.S. Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients.Clin. Cancer Res. 2013; 19: 5300-5309https://doi.org/10.1158/1078-0432.Ccr-13-0143Google Scholar ICIs have demonstrated induction of durable tumor regression in some cancer patients, with response rates of 10%–25% in the majority of cancers.7Schoenfeld A.J. Hellmann M.D. Acquired resistance to immune checkpoint inhibitors.Cancer Cell. 2020; 37: 443-455https://doi.org/10.1016/j.ccell.2020.03.017Google Scholar The shared feature of the patients responsive to ICI therapy seems to be that they have an existing anti-tumor immunity and immune cell infiltration in the tumor tissue before ICI therapy.8Ku G.Y. Yuan J. Page D.B. Schroeder S.E.A. Panageas K.S. Carvajal R.D. Chapman P.B. Schwartz G.K. Allison J.P. Wolchok J.D. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival.Cancer. 2010; 116: 1767-1775https://doi.org/10.1002/cncr.24951Google Scholar,9Yuan J. Adamow M. Ginsberg B.A. Rasalan T.S. Ritter E. Gallardo H.F. Xu Y. Pogoriler E. Terzulli S.L. Kuk D. et al.Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.Proc. Natl. Acad. Sci. U S A. 2011; 108: 16723-16728https://doi.org/10.1073/pnas.1110814108Google Scholar This pre-exiting anti-tumor immunity can then be enhanced and rendered functional by the ICI therapy. However, the remaining 75%–90% of the patients are not responding owing to various immune-suppressive properties of the TME, such as the lack of immune cell infiltration into the TME.10Jenkins R.W. Barbie D.A. Flaherty K.T. Mechanisms of resistance to immune checkpoint inhibitors.Br. J. Cancer. 2018; 118: 9-16https://doi.org/10.1038/bjc.2017.434Google Scholar As a consequence, novel therapies that can modulate the TME and enhance the infiltration of tumor-specific CD8+ T cells into the TME to increase the number of patients benefiting from the ICI therapy are much needed. PeptiENV cancer vaccine platform consists of clinically relevant (oncolytic) enveloped viruses combined with tumor antigen peptides containing envelope-attaching or -anchoring moieties. By physically attaching tumor antigen peptides onto the envelope of enveloped viruses, PeptiENV platform can broaden the virus-induced immune response the The of therapeutic viruses combined with tumor antigen immune response can enhance anti-tumor immunity and enhance the infiltration of tumor-specific T cells into the E. C. C. M. L. A. S. et cancer vaccine platform for clinically relevant oncolytic enveloped Ther. 2018; we the use of an and MMR vaccine in the PeptiENV platform to broaden the MMR immune responses to tumor The intratumoral administration of PeptiENV significantly increased the number of tumor-specific T cells as well as systemic tumor-specific T In addition, with PeptiENV tumor growth in of This platform then in combination with ICI therapy. PeptiENV in tumor growth as a PeptiENV with an ICI tumor growth control and increased the number of mice responding to ICI therapy. As a number of have been with an MMR vaccine, we the of PeptiENV in mice pre-vaccinated with immunity against the MMR vaccine not the of the PeptiENV the PeptiENV therapy in pre-vaccinated mice and to tumor in of the treated The of the PeptiENV platform is that the of approved vaccines, such as the MMR vaccine, or oncolytic enveloped viruses to be into cancer vaccine viruses can be with therapeutic peptides by a as an attenuated strains of the MMR vaccine are enveloped viruses containing a from the cell J.H. Scholar we that therapeutic peptides be onto the of these enveloped viruses by our developed cancer vaccine platform E. C. C. M. L. A. S. et cancer vaccine platform for clinically relevant oncolytic enveloped Ther. 2018; Scholar 1 for a of the the we used a from the This by for therapeutic peptides onto the of the MMR viruses. The a viral and the to the as the control the viral of the PeptiENV of the the and vaccine and the and with with control or by to and in of the cells of and were by is the of the of with cells can PeptiENV we PeptiENV platform can therapeutic peptides into cells and if they can the class from these cell with with control or and the of of the of the by The of by of the cells to with control and indicating that does not the or of the peptides by the However, were in the to induce as by the increased of of and by the in the by the In with the not or with control and with both indicating that can as a for the with PeptiENV a immune response against the therapeutic onto the viral of the MMR the of physically the therapeutic peptides onto the of the MMR viruses, we mice with with or with control the the vaccine or were used as mice were for the induction of systemic T cell responses by the As with or not induce T cell responses. with with the T cell the majority of the responses were count In PeptiENV significantly enhanced T cell the of physically the antigen and the count T cell responses by physically tumor antigen and the mice were with with control or as a and after the mice were and were for the of CD8+ for the tumor by a is the of the of with a systemic and intratumoral infiltration of tumor-specific T cells in a of the of the PeptiENV platform with the anti-tumor we used a melanoma as a of into the class of antigen and Scholar mice were treated with PeptiENV peptides or with a increase in tumor growth control as with the tumor of for the in and not have a tumor with mice as to the therapy in In a tumor growth with mice responding to the therapy. we the by the not in the number of or in the number of cytotoxic CD8+ T cells into the tumors the However, mice a significantly enhanced infiltration of tumor-specific CD8+ T cells into the TME as with the tumors of or mice In addition, we an increase of tumor-specific CD8+ T cells in of as with the In with the and a induction of a systemic T cell response in the mice with intratumoral and systemic tumor-specific T cell responses in a of peptides or as a and after tumor tumor growth for are The number of mice in The of is the of the of tumors and of treated with with the number of to therapy, tumor and systemic anti-tumor immune responses in a of we the PeptiENV platform in a of melanoma a antigen from 2 in combination with ICI therapy. The melanoma is a of a melanoma that is to be responsive to cancer immunotherapies the A. M. L. of melanoma cells in and Scholar after tumor mice were treated with in combination with or in combination with or were and were and therapy Here, with the tumor a tumor of for the in In with the the and tumor growth control with response rates of and in combination with tumor growth control with a response tumor growth control with a response of in combination with the tumor growth with a response By this the response for therapy increased from to increased the survival of the as with the with or in combination with increased the survival of the and by the mice in the of the in combination with mice were systemic anti-tumor immunity by the mice were with a the of the tumor cells into the mice used as tumor growth and after the developed tumors with an of In mice in the in combination with and in combination with significantly with of and In addition, of mice in in combination with and in not tumor growth as with in the in combination with indicating an induction of a systemic anti-tumor immunity by these modalities in combination with tumor growth control and and a systemic anti-tumor response in a of or in combination with and or in combination with or and after tumor and a tumor growth for are The of is the of the The number of mice in survival for tumor for mice after tumor mice were used as with of mice with MMR vaccine before intratumoral with does not we the of pre-existing MMR vaccine immunity the anti-tumor of of mice were with a to a to with of mice and used as after the vaccine mice and control mice were with after tumor mice were treated with or the tumor of for the in In with that not tumor growth the tumor growth control with a response of response as in the to not tumor growth control tumor growth or tumor In with the tumor growth control response with of mice the tumor response the immunity and tumor-specific from of the treated mice mice with the vaccine, indicating immunization by doses of the As responses were in the immunity against measles, mumps, and rubella does not intratumoral pre-vaccinated with or mice were with and treated and after tumor with or as the tumor growth for are The of is the of the The number of mice response is The number of mice in this we have the immunostimulatory of a and used and vaccine against measles, mumps, and the MMR vaccine of contains of attenuated strains of MMR viruses. As these vaccine viruses are we to the of vaccine in our developed cancer vaccine platform for enveloped viruses E. C. C. M. L. A. S. et cancer vaccine platform for clinically relevant oncolytic enveloped Ther. 2018; Scholar By we that the from can as an to the of tumor our the of the to the therapeutic peptides does not the of tumor from these E. C. C. M. L. A. S. et cancer vaccine platform for clinically relevant oncolytic enveloped Ther. 2018; Scholar By an from as a we were able to the of antigen and by the PeptiENV platform. able to tumor into and induce were with with control the in are in a cell does not into the in of peptides and the in in the tumor antigen physically to the viruses we significantly improved T cell responses as with the the and not have a with The in T cell responses the with and the physically is to the of as the and in the is as viral doses or be to physically the antigen to the to increase the of to the for induction of T cell the of the and immunostimulatory of we to the of the PeptiENV platform tumor growth and T cell induction in a melanoma of as a we a tumor growth control with we a increase in systemic and intratumoral T cells as well as an increased number of T cells in to the PeptiENV platform in combination with as these therapies can benefit from the increased immune cell infiltration into the J. Adamow M. Ginsberg B.A. Rasalan T.S. Ritter E. Gallardo H.F. Xu Y. Pogoriler E. Terzulli S.L. Kuk D. et al.Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.Proc. Natl. Acad. Sci. U S A. 2011; 108: 16723-16728https://doi.org/10.1073/pnas.1110814108Google Scholar the of the PeptiENV platform in combination with ICI tumor growth and tumor-specific T cell we used a of melanoma with a relevant tumor from antigen both and a tumor growth the combination therapy an enhanced tumor growth However, as a a tumor growth combined with therapy, the were strains of and have been for oncolytic cancer I. A. E. oncolytic strains as cancer Zhang L. N. N.L. of and viruses oncolytic against 2018; Scholar However, the number of viral have been the of infectious viral is used in this of contains and of and mumps, we to use the that been used in for against measles, mumps, and rubella. the we not by the combined with the PeptiENV as an for the tumor antigen peptides and able to induce the of tumor T cell common live attenuated vaccines for various infectious diseases have been repurposed as intratumoral immunotherapy for the modulation of the M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google T. Sivado E. Jallas A.C. Depil S. Kielbassa J. Janoueix-Lerosey I. Hutter G. Goutagny N. Bergeron C. Viari A. et al.Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade.Sci. Transl. Med. 2019; 11: eaat5025https://doi.org/10.1126/scitranslmed.aat5025Google Scholar As an Aznar et M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google Scholar repurposed a live attenuated yellow vaccine as an cancer However, the used much the for against the yellow fever of of infectious As the yellow is an enveloped is to by the yellow fever vaccine in the PeptiENV enhance the number of intratumoral tumor-specific CD8+ T cells and increase the anti-tumor of the yellow vaccine for a in the of vaccine used to the of and have previously that pre-existing immunity against the vaccine or viral used in intratumoral cancer is not the therapeutic M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google S. C. M. S. M. S. E. et vaccines increase the response to in and 2018; Scholar However, as of of have been against we the of PeptiENV in mice with not a in the therapeutic of PeptiENV in mice pre-vaccinated with in the therapeutic to be are in with the yellow fever vaccine M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google have that with the MMR vaccine induce some immunity against disease A. S. for 19: can MMR vaccines and Immunother. 2020; Scholar, S. R. M. I. M. In of and in MMR and of a Scholar, E. A. MMR vaccine and to or to Scholar, M. T. et T cell immunity in by MMR and vaccine Scholar and the of the against is clinically However, the of the MMR vaccine to against be significantly improved by the use of the PeptiENV platform with antigen we demonstrated that an vaccine against MMR can be used as a in the PeptiENV cancer vaccine platform. with PeptiENV tumor-specific T cell combined with ICI therapy, the number of mice responding to ICI therapy As cancer therapies are for the modulation of the TME for enhanced anti-tumor and for of ICI is a to existing vaccines for infectious diseases to be used in these and The PeptiENV vaccine platform be into clinical in combination with ICI and cell a melanoma cell by The cells were in with and of cell by and in with and The from and in with 1 and vaccine containing the live attenuated measles, from the and rubella strains of viruses from the of contains of cell infectious of the measles, of the mumps, and of the rubella strains to the vaccine peptides used in this and an class from an class from peptides were from of in for injection with peptides or or control were a used as a the and of used the and to with a of used for used for the the for the of MMR viruses onto the the peptides and viral of the peptides or control the as a were into a and into an The response for the then by the response in the from the response in the cells were in and with with control the or or were cells were by and with to antibody and antibody and by of the of and the of number and approved growth the tumors were and tumor were the to mice were treated and with of of with control of or as a were and were the melanoma to mice were in the with melanoma cells, and were treated and after tumor with of of peptides or as a were and and were the melanoma combined with therapy, to mice were in the with cells with a of and were treated and after tumor with of of or with after tumor growth and survival mice in the control or after tumor the of induction of systemic anti-tumor T cell mice were with cells in the and for tumor and the pre-existing immunity to mice were with doses of with after the of mice were in the with cells with a of and were treated and after tumor with of or mice were used as with tumor and number of T cells were by to the 2 used to the of and to for of the of from T cells were by to the 1 were and with 2 or of the cell and the of used in the and used to the number of T a or a and used for or were are as the of the IntroductionThe measles, mumps, and rubella (MMR) vaccine is a trivalent vaccine that contains live attenuated strains of MMR viruses. MMR vaccines are indicated for the routine immunization of children for the prevention of measles, mumps, and rubella. Recently, common vaccines for infectious diseases, such as a seasonal influenza vaccine, rotavirus vaccines, and a vaccine against yellow fever, have been repurposed as intratumoral immunotherapies for the modulation of the tumor microenvironment (TME).1Aznar M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google Scholar, 2Newman J.H. Chesson C.B. Herzog N.L. Bommareddy P.K. Aspromonte S.M. Pepe R. Estupinian R. Aboelatta M.M. Buddhadev S. Tarabichi S. et al.Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.Proc. Natl. Acad. Sci. U S A. 2020; 117: 1119-1128https://doi.org/10.1073/pnas.1904022116Google Scholar, 3Shekarian T. Sivado E. Jallas A.C. Depil S. Kielbassa J. Janoueix-Lerosey I. Hutter G. Goutagny N. Bergeron C. Viari A. et al.Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade.Sci. Transl. Med. 2019; 11: eaat5025https://doi.org/10.1126/scitranslmed.aat5025Google Scholar By intratumoral administration of these viral vaccines, they were able to elicit immunostimulatory effects, such as enhancement of infiltration of cytotoxic T cells (CTLs), natural killer cells and CD4+ Th1 T helper cells, reduction of T regulatory cells and in some cases, exert oncolytic properties.1Aznar M.A. Molina C. Teijeira A. Rodriguez I. Azpilikueta A. Garasa S. Sanchez-Paulete A.R. Cordeiro L. Etxeberria I. Alvarez M. et al.Repurposing the yellow fever vaccine for intratumoral immunotherapy.EMBO Mol. Med. 2020; 12: e10375https://doi.org/10.15252/emmm.201910375Google Scholar, 2Newman J.H. Chesson C.B. Herzog N.L. Bommareddy P.K. Aspromonte S.M. Pepe R. Estupinian R. Aboelatta M.M. Buddhadev S. Tarabichi S. et al.Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.Proc. Natl. Acad. Sci. U S A. 2020; 117: 1119-1128https://doi.org/10.1073/pnas.1904022116Google Scholar, 3Shekarian T. Sivado E. Jallas A.C. Depil S. Kielbassa J. Janoueix-Lerosey I. Hutter G. Goutagny N. Bergeron C. Viari A. et al.Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade.Sci. Transl. Med. 2019; 11: eaat5025https://doi.org/10.1126/scitranslmed.aat5025Google Scholar, 4Melero I. Gato M. Shekarian T. Aznar A. Valsesia-Wittmann S. Caux C. Etxeberrria I. Teijeira A. Marabelle A. Repurposing infectious disease vaccines for intratumoral immunotherapy.J. Immunother. Cancer. 2020; 8: e000443https://doi.org/10.1136/jitc-2019-000443Google Scholar, 5Zhang Z. Zhou L. Xie N. Nice E.C. Zhang T. Cui Y. Huang C. Overcoming cancer therapeutic bottleneck by drug repurposing.Signal. Transduct. Target. Ther. 2020; 5: 113https://doi.org/10.1038/s41392-020-00213-8Google Scholar Immune checkpoint inhibitors (ICIs), a novel class of therapeutic antibodies that target immune checkpoint molecules such as programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T lymphocyte-associated antigen 4, can activate pre-existing anti-tumor immune responses.6Ott P.A. Hodi F.S. Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients.Clin. Cancer Res. 2013; 19: 5300-5309https://doi.org/10.1158/1078-0432.Ccr-13-0143Google Scholar ICIs have demonstrated induction of durable tumor regression in some cancer patients, with response rates of 10%–25% in the majority of cancers.7Schoenfeld A.J. Hellmann M.D. Acquired resistance to immune checkpoint inhibitors.Cancer Cell. 2020; 37: 443-455https://doi.org/10.1016/j.ccell.2020.03.017Google Scholar The shared feature of the patients responsive to ICI therapy seems to be that they have an existing anti-tumor immunity and immune cell infiltration in the tumor tissue before ICI therapy.8Ku G.Y. Yuan J. Page D.B. Schroeder S.E.A. Panageas K.S. Carvajal R.D. Chapman P.B. Schwartz G.K. Allison J.P. Wolchok J.D. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival.Cancer. 2010; 116: 1767-1775https://doi.org/10.1002/cncr.24951Google Scholar,9Yuan J. Adamow M. Ginsberg B.A. Rasalan T.S. Ritter E. Gallardo H.F. Xu Y. Pogoriler E. Terzulli S.L. Kuk D. et al.Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.Proc. Natl. Acad. Sci. U S A. 2011; 108: 16723-16728https://doi.org/10.1073/pnas.1110814108Google Scholar This pre-exiting anti-tumor immunity can then be enhanced and rendered functional by the ICI therapy. However, the remaining 75%–90% of the patients are not responding owing to various immune-suppressive properties of the TME, such as the lack of immune cell infiltration into the TME.10Jenkins R.W. Barbie D.A. Flaherty K.T. Mechanisms of resistance to immune checkpoint inhibitors.Br. J. Cancer. 2018; 118: 9-16https://doi.org/10.1038/bjc.2017.434Google Scholar As a consequence, novel therapies that can modulate the TME and enhance the infiltration of tumor-specific CD8+ T cells into the TME to increase the number of patients benefiting from the ICI therapy are much needed. PeptiENV cancer vaccine platform consists of clinically relevant (oncolytic) enveloped viruses combined with tumor antigen peptides containing envelope-attaching or -anchoring moieties. By physically attaching tumor antigen peptides onto the envelope of enveloped viruses, PeptiENV platform can broaden the virus-induced immune response the The of therapeutic viruses combined with tumor antigen immune response can enhance anti-tumor immunity and enhance the infiltration of tumor-specific T cells into the E. C. C. M. L. A. S. et cancer vaccine platform for clinically relevant oncolytic enveloped Ther. 2018; we the use of an and MMR vaccine in the PeptiENV platform to broaden the MMR immune responses to tumor The intratumoral administration of PeptiENV significantly increased the number of tumor-specific T cells as well as systemic tumor-specific T In addition, with PeptiENV tumor growth in of This platform then in combination with ICI therapy. PeptiENV in tumor growth as a PeptiENV with an ICI tumor growth control and increased the number of mice responding to ICI therapy. As a number of have been with an MMR vaccine, we the of PeptiENV in mice pre-vaccinated with immunity against the MMR vaccine not the of the PeptiENV the PeptiENV therapy in pre-vaccinated mice and to tumor in of the treated The of the PeptiENV platform is that the of approved vaccines, such as the MMR vaccine, or oncolytic enveloped viruses to be into cancer

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