CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation

Armin Rashidi; Corinna La Rosa; Julie Curtsinger; Qing Cao; Qiao Zhou; Chetan Raj Lingaraju; Daniel J. Weisdorf; Frank Cichocki; Jeffrey S. Miller; Don J. Diamond

doi:10.1016/j.jtct.2022.03.003

CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation

Armin Rashidi, Corinna La Rosa, Julie Curtsinger, Qing Cao, Qiao Zhou, Chetan Raj Lingaraju, Daniel J. Weisdorf, Frank Cichocki, Jeffrey S. Miller, Don J. Diamond

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4 Scopus citations

Abstract

Cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation (HCT) augments adaptive (CD56^dimNKG2C⁺CD57⁺) natural killer (NK) and CMV-specific T cells, with potential antitumor effects. Our recent work found an association between higher abundance of adaptive NK cells after auto-HCT and lower risk of relapse in patients with multiple myeloma. Triplex vaccine is a recombinant modified vaccinia Ankara expressing immunodominant CMV antigens, which significantly enhanced CMV-specific T-cell immune responses in allo-HCT recipients. We evaluated whether 2 doses of the vaccine after auto-HCT in patients with lymphoma or myeloma improves reconstitution of adaptive NK and CMV-specific T cells. The primary endpoint was the number of adaptive NK cells at day 100 (∼1 month after dose 2) relative to day 28 (before dose 1). We conducted a single-arm phase 2 clinical trial of 20 patients with lymphoma or myeloma undergoing auto-HCT. Two doses of the vaccine were given on days 28 and 56. Adaptive NK cells increased in CMV-seronegative patients (P = .02), a rise that was more substantial than in unvaccinated historical CMV-seronegative cohorts (P = .03 comparing the rise between the 2 cohorts). There was also an increase in both CD4⁺ and CD8⁺ CMV-specific T cells in CMV-seronegative patients (P = .01) and CMV-specific CD8⁺ effector T cells in CMV-seropositive patients (P = .03). Triplex vaccine improved reconstitution of adaptive NK and CMV-specific T cells after auto-HCT in patients with lymphoma and myeloma. Further study is needed to determine the clinical impact of this modulation of immune response.

Original language	English (US)
Pages (from-to)	343.e1-343.e4
Journal	Transplantation and Cellular Therapy
Volume	28
Issue number	6
DOIs	https://doi.org/10.1016/j.jtct.2022.03.003
State	Published - Jun 2022

Bibliographical note

Funding Information:
Financial disclosure: Supported by grants from the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences KL2TR002492 (A.R), NIH R35 4 2 CA197292 (J.S.M), NIH P01 CA111412 (J.S.M), NIH P01 CA65493 (J.S.M), National Cancer Institute (NCI) 5R01 CA077544 (D.J.D), NCI P30 CA033572 (D.J.D), and NCISAIC-Frederick 28XS061 (D.J.D). Statistical analysis was performed with Biostatistics Shared Resource of the University of Minnesota Masonic Cancer Center, supported by NIH/NCI grant P30CA07759 (J.S.M). D.J.D. is partially supported by the following grants; P50CA107399 (Forman), U19AI128913 (A.R.), R01CA181045 (D.J.D.). Also supported in part by NIH P30 CA77598 utilizing the Translational Therapy Laboratory Shared Resource of the Masonic Cancer Center, University of Minnesota.

Funding Information:
The authors thank Dr. Bernard Moss from the National Institute of Allergy and Infectious Disease, Laboratory of Viral Diseases, who provided materials. HCMV pp65 Peptide Pool was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH. CLR La Rosa received consulting fees and research funding from Helocyte Inc. DJD received fees for royalties, research funding, and fees for serving on the advisory board of Helocyte Inc.

Funding Information:
The authors thank Dr. Bernard Moss from the National Institute of Allergy and Infectious Disease, Laboratory of Viral Diseases, who provided materials. HCMV pp65 Peptide Pool was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH. CLR La Rosa received consulting fees and research funding from Helocyte Inc. DJD received fees for royalties, research funding, and fees for serving on the advisory board of Helocyte Inc. Financial disclosure: Supported by grants from the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences KL2TR002492 (A.R), NIH R35 4 2 CA197292 (J.S.M), NIH P01 CA111412 (J.S.M), NIH P01 CA65493 (J.S.M), National Cancer Institute (NCI) 5R01 CA077544 (D.J.D), NCI P30 CA033572 (D.J.D), and NCISAIC-Frederick 28XS061 (D.J.D). Statistical analysis was performed with Biostatistics Shared Resource of the University of Minnesota Masonic Cancer Center, supported by NIH/NCI grant P30CA07759 (J.S.M). D.J.D. is partially supported by the following grants; P50CA107399 (Forman), U19AI128913 (A.R.), R01CA181045 (D.J.D.). Also supported in part by NIH P30 CA77598 utilizing the Translational Therapy Laboratory Shared Resource of the Masonic Cancer Center, University of Minnesota. Conflict of interest statement: Dr. Diamond has conflicts to declare based on his association with Helocyte, the exclusive licensee of the Triplex vaccine. No funds from Helocyte were used in any aspect of the study and they were not shown the manuscript prior to submission. Authorship statement: J.S.M. D.J.W. A.R. and D.J.D. conceived and designed the clinical trial. A.R. conducted the clinical trial. A.R. and C.L.R. wrote the manuscript. Q.C. performed statistical analyses. C.L.R. J.C. and F.C. performed the immunological experiments. All authors reviewed the manuscript and provided critical feedback. Financial disclosure: See Acknowledgments on page 343.e4.

Publisher Copyright:
© 2022 The American Society for Transplantation and Cellular Therapy

Keywords

Autologous transplantation
Immune reconstitution
Lymphoma
Myeloma
Triplex vaccine

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jtct.2022.03.003

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Rashidi, A., La Rosa, C., Curtsinger, J., Cao, Q., Zhou, Q., Lingaraju, C. R., Weisdorf, D. J., Cichocki, F., Miller, J. S., & Diamond, D. J. (2022). CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation. Transplantation and Cellular Therapy, 28(6), 343.e1-343.e4. https://doi.org/10.1016/j.jtct.2022.03.003

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title = "CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation",

abstract = "Cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation (HCT) augments adaptive (CD56dimNKG2C+CD57+) natural killer (NK) and CMV-specific T cells, with potential antitumor effects. Our recent work found an association between higher abundance of adaptive NK cells after auto-HCT and lower risk of relapse in patients with multiple myeloma. Triplex vaccine is a recombinant modified vaccinia Ankara expressing immunodominant CMV antigens, which significantly enhanced CMV-specific T-cell immune responses in allo-HCT recipients. We evaluated whether 2 doses of the vaccine after auto-HCT in patients with lymphoma or myeloma improves reconstitution of adaptive NK and CMV-specific T cells. The primary endpoint was the number of adaptive NK cells at day 100 (∼1 month after dose 2) relative to day 28 (before dose 1). We conducted a single-arm phase 2 clinical trial of 20 patients with lymphoma or myeloma undergoing auto-HCT. Two doses of the vaccine were given on days 28 and 56. Adaptive NK cells increased in CMV-seronegative patients (P = .02), a rise that was more substantial than in unvaccinated historical CMV-seronegative cohorts (P = .03 comparing the rise between the 2 cohorts). There was also an increase in both CD4+ and CD8+ CMV-specific T cells in CMV-seronegative patients (P = .01) and CMV-specific CD8+ effector T cells in CMV-seropositive patients (P = .03). Triplex vaccine improved reconstitution of adaptive NK and CMV-specific T cells after auto-HCT in patients with lymphoma and myeloma. Further study is needed to determine the clinical impact of this modulation of immune response.",

keywords = "Autologous transplantation, Immune reconstitution, Lymphoma, Myeloma, Triplex vaccine",

author = "Armin Rashidi and {La Rosa}, Corinna and Julie Curtsinger and Qing Cao and Qiao Zhou and Lingaraju, {Chetan Raj} and Weisdorf, {Daniel J.} and Frank Cichocki and Miller, {Jeffrey S.} and Diamond, {Don J.}",

note = "Funding Information: Financial disclosure: Supported by grants from the National Institutes of Health (NIH){\textquoteright}s National Center for Advancing Translational Sciences KL2TR002492 (A.R), NIH R35 4 2 CA197292 (J.S.M), NIH P01 CA111412 (J.S.M), NIH P01 CA65493 (J.S.M), National Cancer Institute (NCI) 5R01 CA077544 (D.J.D), NCI P30 CA033572 (D.J.D), and NCISAIC-Frederick 28XS061 (D.J.D). Statistical analysis was performed with Biostatistics Shared Resource of the University of Minnesota Masonic Cancer Center, supported by NIH/NCI grant P30CA07759 (J.S.M). D.J.D. is partially supported by the following grants; P50CA107399 (Forman), U19AI128913 (A.R.), R01CA181045 (D.J.D.). Also supported in part by NIH P30 CA77598 utilizing the Translational Therapy Laboratory Shared Resource of the Masonic Cancer Center, University of Minnesota. Funding Information: The authors thank Dr. Bernard Moss from the National Institute of Allergy and Infectious Disease, Laboratory of Viral Diseases, who provided materials. HCMV pp65 Peptide Pool was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH. CLR La Rosa received consulting fees and research funding from Helocyte Inc. DJD received fees for royalties, research funding, and fees for serving on the advisory board of Helocyte Inc. Funding Information: The authors thank Dr. Bernard Moss from the National Institute of Allergy and Infectious Disease, Laboratory of Viral Diseases, who provided materials. HCMV pp65 Peptide Pool was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH. CLR La Rosa received consulting fees and research funding from Helocyte Inc. DJD received fees for royalties, research funding, and fees for serving on the advisory board of Helocyte Inc. Financial disclosure: Supported by grants from the National Institutes of Health (NIH){\textquoteright}s National Center for Advancing Translational Sciences KL2TR002492 (A.R), NIH R35 4 2 CA197292 (J.S.M), NIH P01 CA111412 (J.S.M), NIH P01 CA65493 (J.S.M), National Cancer Institute (NCI) 5R01 CA077544 (D.J.D), NCI P30 CA033572 (D.J.D), and NCISAIC-Frederick 28XS061 (D.J.D). Statistical analysis was performed with Biostatistics Shared Resource of the University of Minnesota Masonic Cancer Center, supported by NIH/NCI grant P30CA07759 (J.S.M). D.J.D. is partially supported by the following grants; P50CA107399 (Forman), U19AI128913 (A.R.), R01CA181045 (D.J.D.). Also supported in part by NIH P30 CA77598 utilizing the Translational Therapy Laboratory Shared Resource of the Masonic Cancer Center, University of Minnesota. Conflict of interest statement: Dr. Diamond has conflicts to declare based on his association with Helocyte, the exclusive licensee of the Triplex vaccine. No funds from Helocyte were used in any aspect of the study and they were not shown the manuscript prior to submission. Authorship statement: J.S.M. D.J.W. A.R. and D.J.D. conceived and designed the clinical trial. A.R. conducted the clinical trial. A.R. and C.L.R. wrote the manuscript. Q.C. performed statistical analyses. C.L.R. J.C. and F.C. performed the immunological experiments. All authors reviewed the manuscript and provided critical feedback. Financial disclosure: See Acknowledgments on page 343.e4. Publisher Copyright: {\textcopyright} 2022 The American Society for Transplantation and Cellular Therapy",

year = "2022",

month = jun,

doi = "10.1016/j.jtct.2022.03.003",

language = "English (US)",

volume = "28",

pages = "343.e1--343.e4",

journal = "Transplantation and Cellular Therapy",

issn = "2666-6367",

publisher = "Elsevier B.V.",

number = "6",

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TY - JOUR

T1 - CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation

AU - Rashidi, Armin

AU - La Rosa, Corinna

AU - Curtsinger, Julie

AU - Cao, Qing

AU - Zhou, Qiao

AU - Lingaraju, Chetan Raj

AU - Weisdorf, Daniel J.

AU - Cichocki, Frank

AU - Miller, Jeffrey S.

AU - Diamond, Don J.

N1 - Funding Information: Financial disclosure: Supported by grants from the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences KL2TR002492 (A.R), NIH R35 4 2 CA197292 (J.S.M), NIH P01 CA111412 (J.S.M), NIH P01 CA65493 (J.S.M), National Cancer Institute (NCI) 5R01 CA077544 (D.J.D), NCI P30 CA033572 (D.J.D), and NCISAIC-Frederick 28XS061 (D.J.D). Statistical analysis was performed with Biostatistics Shared Resource of the University of Minnesota Masonic Cancer Center, supported by NIH/NCI grant P30CA07759 (J.S.M). D.J.D. is partially supported by the following grants; P50CA107399 (Forman), U19AI128913 (A.R.), R01CA181045 (D.J.D.). Also supported in part by NIH P30 CA77598 utilizing the Translational Therapy Laboratory Shared Resource of the Masonic Cancer Center, University of Minnesota. Funding Information: The authors thank Dr. Bernard Moss from the National Institute of Allergy and Infectious Disease, Laboratory of Viral Diseases, who provided materials. HCMV pp65 Peptide Pool was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH. CLR La Rosa received consulting fees and research funding from Helocyte Inc. DJD received fees for royalties, research funding, and fees for serving on the advisory board of Helocyte Inc. Funding Information: The authors thank Dr. Bernard Moss from the National Institute of Allergy and Infectious Disease, Laboratory of Viral Diseases, who provided materials. HCMV pp65 Peptide Pool was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH. CLR La Rosa received consulting fees and research funding from Helocyte Inc. DJD received fees for royalties, research funding, and fees for serving on the advisory board of Helocyte Inc. Financial disclosure: Supported by grants from the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences KL2TR002492 (A.R), NIH R35 4 2 CA197292 (J.S.M), NIH P01 CA111412 (J.S.M), NIH P01 CA65493 (J.S.M), National Cancer Institute (NCI) 5R01 CA077544 (D.J.D), NCI P30 CA033572 (D.J.D), and NCISAIC-Frederick 28XS061 (D.J.D). Statistical analysis was performed with Biostatistics Shared Resource of the University of Minnesota Masonic Cancer Center, supported by NIH/NCI grant P30CA07759 (J.S.M). D.J.D. is partially supported by the following grants; P50CA107399 (Forman), U19AI128913 (A.R.), R01CA181045 (D.J.D.). Also supported in part by NIH P30 CA77598 utilizing the Translational Therapy Laboratory Shared Resource of the Masonic Cancer Center, University of Minnesota. Conflict of interest statement: Dr. Diamond has conflicts to declare based on his association with Helocyte, the exclusive licensee of the Triplex vaccine. No funds from Helocyte were used in any aspect of the study and they were not shown the manuscript prior to submission. Authorship statement: J.S.M. D.J.W. A.R. and D.J.D. conceived and designed the clinical trial. A.R. conducted the clinical trial. A.R. and C.L.R. wrote the manuscript. Q.C. performed statistical analyses. C.L.R. J.C. and F.C. performed the immunological experiments. All authors reviewed the manuscript and provided critical feedback. Financial disclosure: See Acknowledgments on page 343.e4. Publisher Copyright: © 2022 The American Society for Transplantation and Cellular Therapy

PY - 2022/6

Y1 - 2022/6

N2 - Cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation (HCT) augments adaptive (CD56dimNKG2C+CD57+) natural killer (NK) and CMV-specific T cells, with potential antitumor effects. Our recent work found an association between higher abundance of adaptive NK cells after auto-HCT and lower risk of relapse in patients with multiple myeloma. Triplex vaccine is a recombinant modified vaccinia Ankara expressing immunodominant CMV antigens, which significantly enhanced CMV-specific T-cell immune responses in allo-HCT recipients. We evaluated whether 2 doses of the vaccine after auto-HCT in patients with lymphoma or myeloma improves reconstitution of adaptive NK and CMV-specific T cells. The primary endpoint was the number of adaptive NK cells at day 100 (∼1 month after dose 2) relative to day 28 (before dose 1). We conducted a single-arm phase 2 clinical trial of 20 patients with lymphoma or myeloma undergoing auto-HCT. Two doses of the vaccine were given on days 28 and 56. Adaptive NK cells increased in CMV-seronegative patients (P = .02), a rise that was more substantial than in unvaccinated historical CMV-seronegative cohorts (P = .03 comparing the rise between the 2 cohorts). There was also an increase in both CD4+ and CD8+ CMV-specific T cells in CMV-seronegative patients (P = .01) and CMV-specific CD8+ effector T cells in CMV-seropositive patients (P = .03). Triplex vaccine improved reconstitution of adaptive NK and CMV-specific T cells after auto-HCT in patients with lymphoma and myeloma. Further study is needed to determine the clinical impact of this modulation of immune response.

AB - Cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation (HCT) augments adaptive (CD56dimNKG2C+CD57+) natural killer (NK) and CMV-specific T cells, with potential antitumor effects. Our recent work found an association between higher abundance of adaptive NK cells after auto-HCT and lower risk of relapse in patients with multiple myeloma. Triplex vaccine is a recombinant modified vaccinia Ankara expressing immunodominant CMV antigens, which significantly enhanced CMV-specific T-cell immune responses in allo-HCT recipients. We evaluated whether 2 doses of the vaccine after auto-HCT in patients with lymphoma or myeloma improves reconstitution of adaptive NK and CMV-specific T cells. The primary endpoint was the number of adaptive NK cells at day 100 (∼1 month after dose 2) relative to day 28 (before dose 1). We conducted a single-arm phase 2 clinical trial of 20 patients with lymphoma or myeloma undergoing auto-HCT. Two doses of the vaccine were given on days 28 and 56. Adaptive NK cells increased in CMV-seronegative patients (P = .02), a rise that was more substantial than in unvaccinated historical CMV-seronegative cohorts (P = .03 comparing the rise between the 2 cohorts). There was also an increase in both CD4+ and CD8+ CMV-specific T cells in CMV-seronegative patients (P = .01) and CMV-specific CD8+ effector T cells in CMV-seropositive patients (P = .03). Triplex vaccine improved reconstitution of adaptive NK and CMV-specific T cells after auto-HCT in patients with lymphoma and myeloma. Further study is needed to determine the clinical impact of this modulation of immune response.

KW - Autologous transplantation

KW - Immune reconstitution

KW - Lymphoma

KW - Myeloma

KW - Triplex vaccine

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AN - SCOPUS:85128606007

SN - 2666-6367

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SP - 343.e1-343.e4

JO - Transplantation and Cellular Therapy

JF - Transplantation and Cellular Therapy

IS - 6

ER -

CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation

Abstract

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