Prognostic Relevance of Multi-Antigenic Myeloma-Specific T-Cell Assay in Patients with Monoclonal Gammopathies
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Samples
2.2. Multi-Antigenic MM-Specific Antigen Stimulation
2.3. Enzyme-Linked Immunospot (ELISpot) Assay
2.4. Cytokine Secretion Assay (CSA)
2.5. 51Chromium-Release Assay
2.6. Statistical Analysis
3. Results
3.1. Screening and Quantitation of MM-Specific T-Cell Responses in MGUS/SMM Patients
3.2. Correlation of MM-Specific T-Cell Immunity (MaMs Test) with Clinical Course in MGUS/SMM Patients
3.3. Phenotypic and Functional Characterization of Myeloma–Specific T Cells
3.4. Cytotoxic Activity of Ex-Vivo Expanded Myeloma-Specific CTLs
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Van de Donk, N.W.C.J.; Pawlyn, C.; Yong, K.L. Multiple Myeloma. Lancet 2021, 397, 410–427. [Google Scholar] [CrossRef] [PubMed]
- Mouhieddine, T.H.; Weeks, L.D.; Ghobrial, I.M. Monoclonal Gammopathy of Undetermined Significance. Blood 2019, 133, 2484–2494. [Google Scholar] [CrossRef]
- Rajkumar, S.V.; Landgren, O.; Mateos, M.V. Smoldering Multiple Myeloma. Blood 2015, 125, 3069–3075. [Google Scholar] [CrossRef] [PubMed]
- Musto, P.; Engelhardt, M.; Caers, J.; Bolli, N.; Kaiser, M.; van de Donk, N.; Terpos, E.; Broijl, A.; de Larrea, C.F.; Gay, F.; et al. 2021 European Myeloma Network Review and Consensus Statement on Smoldering Multiple Myeloma: How to Distinguish (and Manage) Dr. Jekyll and Mr. Hyde. Haematologica 2021, 106, 2799–2812. [Google Scholar] [CrossRef] [PubMed]
- Van de Donk, N.W.J.C.; Mutis, T.; Poddighe, P.J.; Lokhorst, H.M.; Zweegman, S. Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Int. J. Lab. Hematol. 2016, 38, 110–122. [Google Scholar] [CrossRef]
- Dutta, A.K.; Alberge, J.-B.; Sklavenitis-Pistofidis, R.; Lightbody, E.D.; Getz, G.; Ghobrial, I.M. Single-Cell Profiling of Tumour Evolution in Multiple Myeloma—Opportunities for Precision Medicine. Nat. Rev. Clin. Oncol. 2022, 19, 223–236. [Google Scholar] [CrossRef]
- Hagen, P.; Zhang, J.; Barton, K. High-Risk Disease in Newly Diagnosed Multiple Myeloma: Beyond the R-ISS and IMWG Definitions. Blood Cancer J. 2022, 12, 83. [Google Scholar] [CrossRef]
- Lannes, R.; Samur, M.; Perrot, A.; Mazzotti, C.; Divoux, M.; Cazaubiel, T.; Leleu, X.; Schavgoulidze, A.; Chretien, M.-L.; Manier, S.; et al. In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present From Diagnosis in Tiny, Undetectable Subclonal Populations. J. Clin. Oncol. 2022. [Google Scholar] [CrossRef]
- Pawlyn, C.; Morgan, G.J. Evolutionary Biology of High-Risk Multiple Myeloma. Nat. Rev. 2017, 17, 543–556. [Google Scholar] [CrossRef]
- Ho, M.; Goh, C.Y.; Patel, A.; Staunton, S.; O’Connor, R.; Godeau, M.; Bianchi, G. Role of the Bone Marrow Milieu in Multiple Myeloma Progression and Therapeutic Resistance. Clin. Lymphoma Myeloma Leuk. 2020, 20, e752–e768. [Google Scholar] [CrossRef]
- Dufva, O.; Pölönen, P.; Brück, O.; Keränen, M.A.I.; Klievink, J.; Mehtonen, J.; Huuhtanen, J.; Kumar, A.; Malani, D.; Siitonen, S.; et al. Immunogenomic Landscape of Hematological Malignancies. Cancer Cell 2020, 38, 380–399.e13. [Google Scholar] [CrossRef] [PubMed]
- Bedognetti, D. A Multi-Layer Molecular Fresco of the Immune Diversity across Hematologic Malignancies. Cancer Cell 2020, 38, 313–316. [Google Scholar] [CrossRef]
- Weng, J.; Neelapu, S.S.; Woo, A.F.; Kwak, L.W. Identification of Human Idiotype-Specific T Cells in Lymphoma and Myeloma. In Cancer Immunology and Immunotherapy; Dranoff, G., Ed.; Current Topics in Microbiology and Immunology; Springer: Berlin/Heidelberg, Germany, 2011; pp. 193–210. ISBN 978-3-642-14136-2. [Google Scholar]
- Bogen, B.; Ruffini, P.A.; Corthay, A.; Fredriksen, A.B.; Frøyland, M.; Lundin, K.; Røsjø, E.; Thompson, K.; Massaia, M. Idiotype-Specific Immunotherapy in Multiple Myeloma: Suggestions for Future Directions of Research. Haematologica 2006, 91, 941–948. [Google Scholar] [PubMed]
- Wen, Y.-J.; Barlogie, B.; Yi, Q. Idiotype-Specific Cytotoxic T Lymphocytes in Multiple Myeloma: Evidence for Their Capacity to Lyse Autologous Primary Tumor Cells. Blood 2001, 97, 1750–1755. [Google Scholar] [CrossRef] [PubMed]
- Lagreca, I.; Riva, G.; Nasillo, V.; Barozzi, P.; Castelli, I.; Basso, S.; Bettelli, F.; Giusti, D.; Cuoghi, A.; Bresciani, P.; et al. The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches. Int. J. Mol. Sci. 2022, 23, 5242. [Google Scholar] [CrossRef] [PubMed]
- Dhodapkar, M.V.; Krasovsky, J.; Osman, K.; Geller, M.D. Vigorous Premalignancy-Specific Effector T Cell Response in Bone Marrow of Patients with Monoclonal Gammopathy. J. Exp. Med. 2003, 198, 1753–1757. [Google Scholar] [CrossRef]
- Goodyear, O.C.; Pratt, G.; McLarnon, A.; Cook, M.; Piper, K.; Moss, P. Differential Pattern of CD4+ and CD8+ T-Cell Immunity to MAGE-A1/A2/A3 in Patients with MGUS and Multiple Myeloma. Blood 2008, 112, 3362–3372. [Google Scholar] [CrossRef]
- Dhodapkar, M.V.; Sexton, R.; Das, R. Prospective Analysis of Antigen-Specific Immunity, Stem-Cell Antigens, and Immune Checkpoints in Monoclonal Gammopathy. Blood 2015, 126, 2475–2478. [Google Scholar] [CrossRef]
- Tyler, E.M.; Jungbluth, A.A.; O’Reilly, R.J.; Koehne, G. WT1-Specific T-Cell Responses in High-Risk Multiple Myeloma Patients Undergoing Allogeneic T Cell-Depleted Hematopoietic Stem Cell Transplantation and Donor Lymphocyte Infusions. Blood 2013, 121, 308–317. [Google Scholar] [CrossRef]
- Bellucci, R.; Alyea, E.P.; Chiaretti, S.; Wu, C.J.; Zorn, E.; Weller, E.; Wu, B.; Canning, C.; Schlossman, R.; Munshi, N.C.; et al. Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor. Blood 2005, 105, 3945–3950. [Google Scholar] [CrossRef]
- Minnie, S.A.; Hill, G.R. Immunotherapy of Multiple Myeloma. J. Clin. Investig. 2020, 130, 1565–1575. [Google Scholar] [CrossRef] [PubMed]
- Dong, S.; Ghobrial, I.M. Autologous Graft versus Myeloma: It’s Not a Myth. J. Clin. Investig. 2019, 129, 48–50. [Google Scholar] [CrossRef] [PubMed]
- Vuckovic, S.; Minnie, S.A.; Smith, D.; Gartlan, K.H.; Watkins, T.S.; Markey, K.A.; Mukhopadhyay, P.; Guillerey, C.; Kuns, R.D.; Locke, K.R.; et al. Bone Marrow Transplantation Generates T Cell-Dependent Control of Myeloma in Mice. J. Clin. Investig. 2019, 129, 106–121. [Google Scholar] [CrossRef]
- Christensen, O.; Lupu, A.; Schmidt, S.; Condomines, M.; Belle, S.; Maier, A.; Hose, D.; Neuber, B.; Moos, M.; Kleist, C.; et al. Melan-A/MART1 Analog Peptide Triggers Anti-Myeloma T-Cells through Crossreactivity with HM1.24. J. Immunother. 2009, 32, 613–621. [Google Scholar] [CrossRef] [PubMed]
- Racanelli, V.; Leone, P.; Frassanito, M.A.; Brunetti, C.; Perosa, F.; Ferrone, S.; Dammacco, F. Alterations in the Antigen Processing-Presenting Machinery of Transformed Plasma Cells Are Associated with Reduced Recognition by CD8+ T Cells and Characterize the Progression of MGUS to Multiple Myeloma. Blood 2010, 115, 1185–1193. [Google Scholar] [CrossRef] [PubMed]
- van Rhee, F.; Szmania, S.M.; Zhan, F.; Gupta, S.K.; Pomtree, M.; Lin, P.; Batchu, R.B.; Moreno, A.; Spagnoli, G.; Shaughnessy, J.; et al. NY-ESO-1 Is Highly Expressed in Poor-Prognosis Multiple Myeloma and Induces Spontaneous Humoral and Cellular Immune Responses. Blood 2005, 105, 3939–3944. [Google Scholar] [CrossRef]
- Ocadlikova, D.; Kryukov, F.; Mollova, K.; Kovarova, L.; Buresdova, I.; Matejkova, E.; Penka, M.; Buchler, T.; Hajek, R.; Michalek, J. Generation of Myeloma-Specific T Cells Using Dendritic Cells Loaded with MUC1- and HTERT- Drived Nonapeptides or Myeloma Cell Apoptotic Bodies. Neoplasma 2010, 57, 455–464. [Google Scholar] [CrossRef]
- Spisek, R.; Kukreja, A.; Chen, L.-C.; Matthews, P.; Mazumder, A.; Vesole, D.; Jagannath, S.; Zebroski, H.A.; Simpson, A.J.G.; Ritter, G.; et al. Frequent and Specific Immunity to the Embryonal Stem Cell-Associated Antigen SOX2 in Patients with Monoclonal Gammopathy. J. Exp. Med. 2007, 204, 831–840. [Google Scholar] [CrossRef]
- Qian, J.; Xie, J.; Hong, S.; Yang, J.; Zhang, L.; Han, X.; Wang, M.; Zhan, F.; Shaughnessy, J.D.; Epstein, J.; et al. Dickkopf-1 (DKK1) Is a Widely Expressed and Potent Tumor-Associated Antigen in Multiple Myeloma. Blood 2007, 110, 1587–1594. [Google Scholar] [CrossRef]
- Solimando, A.G.; Brandl, A.; Mattenheimer, K.; Graf, C.; Ritz, M.; Ruckdeschel, A.; Stühmer, T.; Mokhtari, Z.; Rudelius, M.; Dotterweich, J.; et al. JAM-A as a Prognostic Factor and New Therapeutic Target in Multiple Myeloma. Leukemia 2018, 32, 736–743. [Google Scholar] [CrossRef] [Green Version]
- Bae, J.; Prabhala, R.; Voskertchian, A.; Brown, A.; Maguire, C.; Richardson, P.; Dranoff, G.; Anderson, K.C.; Munshi, N.C. A Multiepitope of XBP1, CD138 and CS1 Peptides Induces Myeloma-Specific Cytotoxic T Lymphocytes in T Cells of Smoldering Myeloma Patients. Leukemia 2015, 29, 218–229. [Google Scholar] [CrossRef] [PubMed]
- Bae, J.; Samur, M.; Richardson, P.; Munshi, N.C.; Anderson, K.C. Selective Targeting of Multiple Myeloma by B Cell Maturation Antigen (BCMA)-Specific Central Memory CD8+ Cytotoxic T Lymphocytes: Immunotherapeutic Application in Vaccination and Adoptive Immunotherapy. Leukemia 2019, 33, 2208–2226. [Google Scholar] [CrossRef] [PubMed]
- Riva, G.; Luppi, M.; Barozzi, P.; Quadrelli, C.; Basso, S.; Vallerini, D.; Zanetti, E.; Morselli, M.; Forghieri, F.; Maccaferri, M.; et al. Emergence of BCR-ABL–Specific Cytotoxic T Cells in the Bone Marrow of Patients with Ph+ Acute Lymphoblastic Leukemia during Long-Term Imatinib Mesylate Treatment. Blood 2010, 115, 1512–1518. [Google Scholar] [CrossRef] [PubMed]
- Forghieri, F.; Riva, G.; Lagreca, I.; Barozzi, P.; Vallerini, D.; Morselli, M.; Paolini, A.; Bresciani, P.; Colaci, E.; Maccaferri, M.; et al. Characterization and Dynamics of Specific T Cells against Nucleophosmin-1 (NPM1)-Mutated Peptides in Patients with NPM1-Mutated Acute Myeloid Leukemia. Oncotarget 2019, 10, 869–882. [Google Scholar] [CrossRef] [PubMed]
- Janetzki, S.; Price, L.; Schroeder, H.; Britten, C.M.; Welters, M.J.P.; Hoos, A. Guidelines for the Automated Evaluation of Elispot Assays. Nat. Protoc. 2015, 10, 1098–1115. [Google Scholar] [CrossRef]
- Ruiz-Heredia, Y.; Ortiz-Ruiz, A.; Samur, M.K.; Garrido, V.; Rufian, L.; Sanchez, R.; Aguilar-Garrido, P.; Barrio, S.; Martín, M.A.; Bolli, N.; et al. Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma. Cancers 2021, 13, 3189. [Google Scholar] [CrossRef]
- Dhodapkar, M.V. The Immune System in Multiple Myeloma and Precursor States: Lessons and Implications for Immunotherapy and Interception. Am. J. Hematol. 2022. early view. [Google Scholar] [CrossRef]
- Riva, G.; Nasillo, V.; Ottomano, A.M.; Bergonzini, G.; Paolini, A.; Forghieri, F.; Lusenti, B.; Barozzi, P.; Lagreca, I.; Fiorcari, S.; et al. Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges. Cancers 2021, 13, 4582. [Google Scholar] [CrossRef]
- Manier, S.; Ingegnere, T.; Escure, G.; Prodhomme, C.; Nudel, M.; Mitra, S.; Facon, T. Current State and Next-Generation CAR-T Cells in Multiple Myeloma. Blood Rev. 2022, 54, 100929. [Google Scholar] [CrossRef]
- Lakshman, A.; Kumar, S.K. Chimeric Antigen Receptor T-Cells, Bispecific Antibodies, and Antibody-Drug Conjugates for Multiple Myeloma: An Update. Am. J. Hematol. 2022, 97, 99–118. [Google Scholar] [CrossRef]
- Landgren, O.; Kyle, R.A.; Rajkumar, S.V. From Myeloma Precursor Disease to Multiple Myeloma: New Diagnostic Concepts and Opportunities for Early Intervention. Clin. Cancer Res. 2011, 17, 1243–1252. [Google Scholar] [CrossRef]
- Ho, M.; Patel, A.; Go, C.Y.; Moscvin, M.; Zhang, L.; Bianchi, G. Changing Paradigms in Diagnosis and Treatment of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Leukemia 2020, 34, 3111–3125. [Google Scholar] [CrossRef] [PubMed]
- Mateos, M.V.; Hernandez, M.T.; Giraldo, P.; de la Rubia, J.; de Arriba, F.; López Corral, L.; Rosiñol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma. N. Engl. J. Med. 2013, 369, 438–447. [Google Scholar] [CrossRef] [PubMed]
- Mateos, M.V.; Hernandez, M.T.; Giraldo, P.; de la Rubia, J.; de Arriba, F.; Corral, L.L.; Rosiñol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Lenalidomide plus Dexamethasone versus Observation in Patients with High-Risk Smouldering Multiple Myeloma (QuiRedex): Long-Term Follow-up of a Randomised, Controlled, Phase 3 Trial. Lancet Oncol. 2016, 17, 1127–1136. [Google Scholar] [CrossRef] [PubMed]
- Mateos, M.V.; Hernandez, M.T.; Salvador, C.; de la Rubia, J.; de Arriba, F.; López Corral, L.; Rosiñol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Over Ten Years Of F/U For Phase 3 Trial In Smoldering Myeloma At High Risk Of Progression To Myeloma: Sustained Ttp And Os Benefit With Rd Versus No Treatment. In Proceedings of the 25th EHA Congress, European Hematology Association, Virtual, The Hague, The Netherlands, 11–21 June 2020. [Google Scholar]
- Lonial, S.; Jacobus, S.; Fonseca, R.; Weiss, M.; Kumar, S.; Orlowski, R.Z.; Kaufman, J.L.; Yacoub, A.M.; Buadi, F.K.; O’Brien, T.; et al. Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. J. Clin. Oncol. 2020, 38, 1126–1137. [Google Scholar] [CrossRef]
- Paiva, B.; Mateos, M.V.; Sanchez-Abarca, L.I.; Puig, N.; Vidriales, M.B.; López Corral, L.; Corchete, R.A.; Hernandez, M.T.; Bargay, J.; de Arriba, F.; et al. Immune Status of High-Risk Smoldering Multiple Myeloma Patients and Its Therapeutic Modulation under LenDex: A Longitudinal Analysis. Blood 2016, 127, 1151–1162. [Google Scholar] [CrossRef]
- Comoli, P.; Basso, S.; Riva, G.; Barozzi, P.; Guido, I.; Gurrado, A.; Quartuccio, G.; Rubert, L.; Lagreca, I.; Vallerini, D.; et al. BCR-ABL–Specific T-Cell Therapy in Ph1 ALL Patients on Tyrosine-Kinase Inhibitors. Blood 2017, 129, 582–586. [Google Scholar] [CrossRef]
- Zitvogel, L.; Rusakiewicz, S.; Routy, B.; Ayyoub, M.; Kroemer, G. Immunological Off-Target Effects of Imatinib. Nat. Rev. Clin. Oncol. 2016, 13, 431–446. [Google Scholar] [CrossRef]
- Nasillo, V.; Riva, G.; Paolini, A.; Forghieri, F.; Roncati, L.; Lusenti, B.; Maccaferri, M.; Messerotti, A.; Pioli, V.; Gilioli, A.; et al. Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies. Int. J. Mol. Sci. 2021, 22, 1906. [Google Scholar] [CrossRef]
- Forghieri, F.; Riva, G.; Lagreca, I.; Barozzi, P.; Bettelli, F.; Paolini, A.; Nasillo, V.; Lusenti, B.; Pioli, V.; Giusti, D.; et al. Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia. Int. J. Mol. Sci. 2021, 22, 9159. [Google Scholar] [CrossRef]
Parameter | Value |
---|---|
Number of patients (Sex) | 33 (15 F, 18 M) |
Age at enrollment (years), median (range) | 65 (26–85) |
MGUS patients, total number | 22 |
Low Risk | 4 |
Intermediate-Low Risk | 10 |
Intermediate-High Risk | 8 |
SMM patients, total number | 11 |
Low Risk | 4 |
Intermediate Risk | 7 |
Follow-up (months), median (range) | 28 (6–44) |
Number of time-points/patient, mean (range) | 4, 6 (2–8) |
Tested samples, total number | 152 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Lagreca, I.; Nasillo, V.; Barozzi, P.; Castelli, I.; Basso, S.; Castellano, S.; Paolini, A.; Maccaferri, M.; Colaci, E.; Vallerini, D.; et al. Prognostic Relevance of Multi-Antigenic Myeloma-Specific T-Cell Assay in Patients with Monoclonal Gammopathies. Cancers 2023, 15, 972. https://doi.org/10.3390/cancers15030972
Lagreca I, Nasillo V, Barozzi P, Castelli I, Basso S, Castellano S, Paolini A, Maccaferri M, Colaci E, Vallerini D, et al. Prognostic Relevance of Multi-Antigenic Myeloma-Specific T-Cell Assay in Patients with Monoclonal Gammopathies. Cancers. 2023; 15(3):972. https://doi.org/10.3390/cancers15030972
Chicago/Turabian StyleLagreca, Ivana, Vincenzo Nasillo, Patrizia Barozzi, Ilaria Castelli, Sabrina Basso, Sara Castellano, Ambra Paolini, Monica Maccaferri, Elisabetta Colaci, Daniela Vallerini, and et al. 2023. "Prognostic Relevance of Multi-Antigenic Myeloma-Specific T-Cell Assay in Patients with Monoclonal Gammopathies" Cancers 15, no. 3: 972. https://doi.org/10.3390/cancers15030972