DNA vaccines against GPRC5D synergize with PD-1 blockade to treat multiple myeloma.
Journal
NPJ vaccines
ISSN: 2059-0105
Titre abrégé: NPJ Vaccines
Pays: England
ID NLM: 101699863
Informations de publication
Date de publication:
01 Oct 2024
01 Oct 2024
Historique:
received:
29
05
2024
accepted:
19
09
2024
medline:
2
10
2024
pubmed:
2
10
2024
entrez:
1
10
2024
Statut:
epublish
Résumé
Multiple myeloma (MM), a hematological malignancy of the bone marrow, remains largely incurable. The orphan G protein-coupled receptor, GPRC5D, which is uniquely expressed in plasma cells and highly expressed in MM, is a compelling candidate for immunotherapy. In this study, we investigated the efficacy of a combination of DNA vaccine encoding mouse GPRC5D and PD-1 blockade in preventing and treating MM using the 5TGM1 murine model of MM. The mouse vaccine alone was effective in preventing myeloma growth but required PD-1 antibodies to inhibit established MM tumors. We next evaluated the prophylactic and therapeutic efficacy of a nanoplasmid vector encoding human GPRC5D in several murine syngeneic tumor models. Similar results for tumor inhibition were observed, as human GPRC5D-specific T cells and antibodies were induced by DNA vaccines. Taken together, these findings underscore the potential of GPRC5D-targeted DNA vaccines as versatile platforms for the treatment and prevention of MM.
Identifiants
pubmed: 39353958
doi: 10.1038/s41541-024-00979-w
pii: 10.1038/s41541-024-00979-w
doi:
Types de publication
Journal Article
Langues
eng
Pagination
180Informations de copyright
© 2024. The Author(s).
Références
Kumar, S. K. et al. Multiple myeloma. Nat. Rev. Dis. Prim. 3, 17046 (2017).
pubmed: 28726797
doi: 10.1038/nrdp.2017.46
Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 73, 17–48 (2023).
pubmed: 36633525
doi: 10.3322/caac.21763
Kyle, R. A. et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 378, 241–249 (2018).
pubmed: 29342381
pmcid: 5852672
doi: 10.1056/NEJMoa1709974
Kyle, R. A. et al. Prevalence of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 354, 1362–1369 (2006).
pubmed: 16571879
doi: 10.1056/NEJMoa054494
Kyle, R. A. et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N. Engl. J. Med. 356, 2582–2590 (2007).
pubmed: 17582068
doi: 10.1056/NEJMoa070389
Kyle, R. A. et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 346, 564–569 (2002).
pubmed: 11856795
doi: 10.1056/NEJMoa01133202
Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014).
pubmed: 24553386
pmcid: 4684949
doi: 10.1126/scitranslmed.3008226
Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).
pubmed: 28249141
pmcid: 5881572
doi: 10.1056/NEJMoa1609783
Wang, X. et al. Expanding anti-CD38 immunotherapy for lymphoid malignancies. J. Exp. Clin. Cancer Res. 41, 210 (2022).
pubmed: 35765110
pmcid: 9237984
doi: 10.1186/s13046-022-02421-2
Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).
pubmed: 29385376
pmcid: 6637939
doi: 10.1056/NEJMoa1709919
Ali, S. A. et al. T cells expressing an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128, 1688–1700 (2016).
pubmed: 27412889
pmcid: 5043125
doi: 10.1182/blood-2016-04-711903
Brudno, J. N. et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36, 2267–2280 (2018).
pubmed: 29812997
pmcid: 6067798
doi: 10.1200/JCO.2018.77.8084
Laurent, S. A. et al. γ-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat. Commun. 6, 7333 (2015).
pubmed: 26065893
doi: 10.1038/ncomms8333
Brudno, J. N. et al. T cells genetically modified to express an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36, 2267–2280 (2018).
pubmed: 29812997
pmcid: 6067798
doi: 10.1200/JCO.2018.77.8084
Cohen, A. D. et al. Safety and efficacy of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood 130, 505 (2017).
Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).
pubmed: 29155426
doi: 10.1038/nm.4441
Gardner, R. et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127, 2406–2410 (2016).
pubmed: 26907630
pmcid: 4874221
doi: 10.1182/blood-2015-08-665547
Gilman, A. G. G proteins: transducers of receptor-generated signals. Annu. Rev. Biochem. 56, 615–649 (1987).
pubmed: 3113327
doi: 10.1146/annurev.bi.56.070187.003151
Sriram, K. & Insel, P. A. G protein-coupled receptors as targets for approved drugs: how many targets and how many drugs? Mol. Pharm. 93, 251–258 (2018).
doi: 10.1124/mol.117.111062
Mullard, A. Setting GPCRs free. Nat. Rev. Drug Discov. 22, 347–348 (2023).
pubmed: 37069282
doi: 10.1038/d41573-023-00064-2
Smith, E. L. et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci. Transl. Med. 11, eaau7746 (2019).
pubmed: 30918115
pmcid: 7508042
doi: 10.1126/scitranslmed.aau7746
Pillarisetti, K. et al. A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Blood 135, 1232–1243 (2020).
pubmed: 32040549
pmcid: 7146017
doi: 10.1182/blood.2019003342
Verkleij, C. P. M. et al. Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma. Blood Adv. 5, 2196–2215 (2021).
pubmed: 33890981
pmcid: 8095149
doi: 10.1182/bloodadvances.2020003805
Braunstein, M., Weltz, J. & Davies, F. A new decade: novel immunotherapies on the horizon for relapsed/refractory multiple myeloma. Expert Rev. Hematol. 14, 377–389 (2021).
pubmed: 33769179
doi: 10.1080/17474086.2021.1909469
Moreau, P. & Touzeau, C. T-cell redirecting bispecific antibodies in multiple myeloma: a revolution? Blood 139, 3681–3687 (2022).
Radl, J., De Glopper, E. D., Schuit, H. R. & Zurcher, C. Idiopathic paraproteinemia. II. Transplantation of the paraprotein-producing clone from old to young C57BL/KaLwRij mice. J. Immunol. 122, 609–613 (1979).
pubmed: 368243
doi: 10.4049/jimmunol.122.2.609
Garrett, I. R., Dallas, S., Radl, J. & Mundy, G. R. A murine model of human myeloma bone disease. Bone 20, 515–520 (1997).
pubmed: 9177864
doi: 10.1016/S8756-3282(97)00056-2
Williams, J. A. & Paez, P. A. Improving cell and gene therapy safety and performance using next-generation nanoplasmid vectors. Mol. Ther. Nucleic Acids 32, 494–503 (2023).
pubmed: 37346980
pmcid: 10280095
doi: 10.1016/j.omtn.2023.04.003
Cowan, A. J. et al. Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016. JAMA Oncol. 4, 1221–1227 (2018).
pubmed: 29800065
pmcid: 6143021
doi: 10.1001/jamaoncol.2018.2128
Atamaniuk, J. et al. Overexpression of G protein‐coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. Eur. J. Clin. Invest. 42, 953–960 (2012).
pubmed: 22591013
doi: 10.1111/j.1365-2362.2012.02679.x
Cohen, Y., Gutwein, O., Garach-Jehoshua, O., Bar-Haim, A. & Kornberg, A. GPRC5D is a promising marker for monitoring the tumor load and to target multiple myeloma cells. Hematology 18, 348–351 (2013).
pubmed: 23510526
doi: 10.1179/1607845413Y.0000000079
Kodama, T. et al. Anti-GPRC5D/CD3 bispecific T-cell–redirecting antibody for the treatment of multiple myeloma. Mol. Cancer Ther. 18, 1555–1564 (2019).
pubmed: 31270154
doi: 10.1158/1535-7163.MCT-18-1216
Mailankody, S. et al. GPRC5D-targeted CAR T cells for myeloma. N. Engl. J. Med. 387, 1196–1206 (2022).
pubmed: 36170501
pmcid: 10309537
doi: 10.1056/NEJMoa2209900
Huang, W. et al. Abstract 6020: Preclinical activity of LM-305 targeting G-protein-coupled receptor class 5 member D (GPRC5D) antibody drug conjugate for the treatment of multiple myeloma. Cancer Res. 82, 6020–6020 (2022).
doi: 10.1158/1538-7445.AM2022-6020
Moreau, P. et al. Teclistamab in relapsed or refractory multiple myeloma. N. Engl. J. Med. 387, 495–505 (2022).
pubmed: 35661166
pmcid: 10587778
doi: 10.1056/NEJMoa2203478
Chari, A. et al. Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N. Engl. J. Med. 387, 2232–2244 (2022).
pubmed: 36507686
doi: 10.1056/NEJMoa2204591
Luke, J. M. et al. Coexpressed RIG-I agonist enhances humoral immune response to influenza virus DNA vaccine. J. Virol. 85, 1370–1383 (2011).
pubmed: 21106745
doi: 10.1128/JVI.01250-10
Sato, Y. et al. Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352–354 (1996).
pubmed: 8662521
doi: 10.1126/science.273.5273.352
Klinman, D. M., Yamshchikov, G. & Ishigatsubo, Y. Contribution of CpG motifs to the immunogenicity of DNA vaccines. J. Immunol. 158, 3635–3639 (1997).
pubmed: 9103425
doi: 10.4049/jimmunol.158.8.3635
Sardesai, N. Y. & Weiner, D. B. Electroporation delivery of DNA vaccines: prospects for success. Curr. Opin. Immunol. 23, 421–429 (2011).
pubmed: 21530212
pmcid: 3109217
doi: 10.1016/j.coi.2011.03.008
Liu, J., Kjeken, R., Mathiesen, I. & Barouch, D. H. Recruitment of antigen-presenting cells to the site of inoculation and augmentation of human immunodeficiency virus type 1 DNA vaccine immunogenicity by in vivo electroporation. J. Virol. 82, 5643–5649 (2008).
pubmed: 18353952
pmcid: 2395223
doi: 10.1128/JVI.02564-07
Ahlén, G. et al. In vivo electroporation enhances the immunogenicity of hepatitis C virus nonstructural 3/4A DNA by increased local DNA uptake, protein expression, inflammation, and infiltration of CD3+ T cells. J. Immunol. 179, 4741–4753 (2007).
pubmed: 17878373
doi: 10.4049/jimmunol.179.7.4741
Neeli, P. et al. Comparison of DNA vaccines with AS03 as an adjuvant and an mRNA vaccine against SARS-CoV-2. iScience 26, 107120 (2023).
pubmed: 37361876
pmcid: 10271916
doi: 10.1016/j.isci.2023.107120