To expand the breadth and extent of current multiple myeloma (MM)-specific immunotherapy, we have identified various antigens on CD138+ tumor cells from newly diagnosed MM patients (n = 616) and confirmed B-cell maturation antigen (BCMA) as a key myeloma-associated antigen. The aim of this study is to target the BCMA, which promotes MM cell growth and survival, by generating BCMA-specific memory CD8+ CTL that mediate effective and long-lasting immunity against MM. Here we report the identification of novel engineered peptides specific to BCMA, BCMA72-80 (YLMFLLRKI), and BCMA54-62 (YILWTCLGL), which display improved affinity/stability to HLA-A2 compared to their native peptides and induce highly functional BCMA-specific CTL with increased activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecule expression. Importantly, the heteroclitic BCMA72-80 specific CTL demonstrated poly-functional Th1-specific immune activities [IFN-γ/IL-2/TNF-α production, proliferation, cytotoxicity] against MM, which were correlated with expansion of Tetramer+ and memory CD8+ CTL. Additionally, heteroclitic BCMA72-80 specific CTL treated with anti-OX40 (immune agonist) or anti-LAG-3 (checkpoint inhibitor) display increased immune function, mainly by central memory CTL. These results provide the framework for clinical application of heteroclitic BCMA72-80 peptide, alone and in combination with anti-LAG3 and/or anti-OX40 therapy, in vaccination and/or adoptive immunotherapeutic strategies to generate long-lasting anti-tumor immunity in patients with MM or other BCMA expressing tumors.
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Köhler M, Greil C, Hudecek M, Lonial S, Raje N, Wäsch R, et al. Current developments in immunotherapy in the treatment of multiple myeloma. Cancer. 2018;124:2075–85.
Musto P, Anderson KC, Attal M, Richardson PG, Badros A, Hou J, et al. Second primary malignancies in multiple myeloma: an overview and IMWG consensus. Ann Oncol. 2018;29:1074.
Falank C, Fairfield H, Reagan MR. Signaling interplay between bone marrow adipose tissue and multiple myeloma cells. Front Endocrinol. 2016;7:67.
Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Xu YY, Kalos M, et al. Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. Clin Cancer Res. 2014;20:1355–65.
Shinde P, Fernandes S, Melinkeri S, Kale V, Limaye L. Compromised functionality of monocyte-derived dendritic cells in multiple myeloma patients may limit their use in cancer immunotherapy. Sci Rep. 2018;8:5705.
Karp Leaf R, Cho HJ, Avigan D. Immunotherapy for multiple myeloma, past, present, and future: monoclonal antibodies, vaccines, and cellular therapies. Curr Hematol Malig Rep. 2015;10:395–404.
Allegra A, Penna G, Innao V, Greve B, Maisano V, Russo S, et al. Vaccination of multiple myeloma: current strategies and future prospects. Crit Rev Oncol Hematol. 2015;96:339–54.
Leaf RK, Stroopinsky D, Pyzer AR, Kruisbeek AM, van Wetering S, Washington A, et al. DCOne as an allogeneic cell-based vaccine for multiple myeloma. J Immunother. 2017;40:315–22.
Hos BJ, Tondini E, van Kasteren SI, Ossendorp F. Approaches to improve chemically defined synthetic peptide vaccines. Front Immunol. 2018;9:884.
Obara W, Kanehira M, Katagiri T, Kato R, Kato Y, Takata R. Present status and future perspective of peptide-based vaccine therapy for urological cancer. Cancer Sci. 2018;109:550–9.
Bae J, Hideshima T, Zhang GL, Zhou J, Keskin DB, Munshi NC, et al. Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia. 2018;32:752–64.
Sundar R, Rha SY, Yamaue H, Katsuda M, Kono K, Kim HS, et al. A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer. BMC Cancer. 2018;18:332–42.
Fujiwara Y, Okada K, Omori T, Sugimura K, Miyata H, Ohue M, et al. Multiple therapeutic peptide vaccines for patients with advanced gastric cancer. Int J Oncol. 2017;50:1655–62.
Waki K, Kawano K, Tsuda N, Ushijima K, Itoh K, Yamada A. Plasma levels of high-mobility group box 1 during peptide vaccination in patients with recurrent ovarian cancer. J Immunol Res. 2017;2017:1423683.
Sakamoto S, Yamada T, Terazaki Y, Yoshiyama K, Sugawara S, Takamori S, et al. Feasibility study of personalized peptide vaccination for advanced small cell lung cancer. Clin Lung Cancer. 2017;18:e385–e394.
Lee L, Bounds D, Paterson J, Herledan G, Sully K, Seestaller-Wehr LM, et al. Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma. Br J Haematol. 2016;174:911–22.
Coquery CM, Erickson LD. Regulatory roles of the tumor necrosis factor receptor BCMA. Crit Rev Immunol. 2012;32:287–305.
Sanchez E, Smith EJ, Yashar MA, Patil S, Li M, Porter AL, et al. The role of B-Cell Maturation Antigen in the biology and management of, and as a potential therapeutic target in, multiple myeloma. Target Oncol. 2018;13:39–47.
Moreaux J, Legouffe E, Jourdan E, Quittet P, Re’me T, Lugagne C, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103:3148–57.
O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199:91–98.
Varga C, Laubach JP, Anderson KC, Richardson PG. Investigational agents in immunotherapy: a new horizon for the treatment of multiple myeloma. Br J Haematol. 2018;181:433–46.
Terpos E, International Myeloma Society. Multiple myeloma: clinical updates from the American Society of Hematology Annual Meeting, 2017. Clin Lymphoma Myeloma Leuk. 2018;18:321–34.
Sanchez E, Tanenbaum EJ, Patil S, Li M, Soof CM, Vidisheva A, et al. The clinical significance of B-cell maturation antigen as a therapeutic target and biomarker. Expert Rev Mol Diagn. 2018;18:319–29.
Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, et al. B-cell matu- ration antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19:2048–60.
Bellucci R, Alyea EP, Chiaretti S, Wu CJ, Zorn E, Weller E, 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;105:3945–50.
Ng LG, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML, et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol. 2004;173:807–17.
Seckinger A, Delgado JA, Moser S, Moreno L, Neuber B, Grab A, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell. 2017;31:396–410.
Hipp S, Tai YT, Blanset D, Deegen P, Wahl J, Thomas O, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia. 2017;31:1743–51.
Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, et al. T cells expressing an anti- B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128:1688–1700.
Cohen AD, Garfall AL, Stadtmauer EA, Lacey SF, Lancaster E, Vogl DT, et al. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM): initial safety and efficacy from a phase I study. Am Soc Hematol. 2016;128:1147.
Kevin MF, Garrett TE, Evans JW, Horton HM, Latimer HJ, Seidel SL, et al. Effective targeting of multiple B-cell maturation antigen–expressing hematological malignances by anti-B-cell maturation antigen chimeric antigen receptor T cells. Hum Gene Ther. 2018;29:585–601.
Dou H, Yan Z, Zhang M, Xu X. APRIL, BCMA and TACI proteins are abnormally expressed in non-small cell lung cancer. Oncol Lett. 2016;12:3351–5.
Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M, et al. Sensitive and viable identification of antigen-specific CD8 + T cells by a flow cytometric assay for degranulation. J Immunol Methods. 2003;281:65–78.
Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294:15–22.
Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17:1511–22.
Tricot G, Jagannath S, Vesole DH, Bracy D, Desikan KR, Siegel D, et al. Hematopoietic stem cell transplants for multiple myeloma. Leuk Lymphoma. 1996;22:25–36.
Rossmann E, Österborg A, Löfvenberg E, Choudhury A, Forssmann U, von Heydebreck A, et al. Mucin 1-specific active cancer immunotherapy with tecemotide (L-BLP25) in patients with multiple myeloma: an exploratory study. Hum Vaccin Immunother. 2014;10:3394–408.
Bae J, Munshi NC, Anderson KC. Immunotherapy strategies in multiple myeloma. Hematol Oncol Clin North Am. 2014;28:927–43.
Berry J, Vreeland T, Trappey A, Hale D, Peace K, Tyler J, et al. Cancer vaccines in colon and rectal cancer over the last decade: lessons learned and future directions. Expert Rev Clin Immunol. 2017;13:235–45.
Cao JX, Zhang XY, Liu JL, Li JL, Liu YS, Wang M, et al. Validity of combination active specific immunotherapy for colorectal cancer: a meta-analysis of 2993 patients. Cytotherapy. 2015;17:1746–62.
Randazzo M, Terness P, Opelz G, Kleist C. Active-specific immunotherapy of human cancers with the heat shock protein Gp96-revisited. Int J Cancer. 2012;130:2219–31.
Bae J, Carrasco R, Lee AH, Prabhala R, Tai YT, Anderson KC, et al. Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma. Leukemia. 2011;25:1610–9.
Bae J, Tai YT, Anderson KC, Munshi NC. Novel epitope evoking CD138 antigen-specific cytotoxic T lymphocytes targeting multiple myeloma and other plasma cell disorders. Br J Haematol. 2011;155:349–61.
Bae J, Song W, Smith R, Daley J, Tai YT, Anderson KC, et al. A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma. Br J Haematol. 2012;157:687–701.
Bae J, Smith R, Daley J, Mimura N, Tai YT, Anderson KC, et al. Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma and other plasma cell disorders. Clin Cancer Res. 2012;18:4850–60.
Bae J, Prabhala R, Voskertchian A, Brown A, Maguire C, Richardson P, et al. A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia. 2015;29:218–29.
Bae J, Keskin DB, Cowens K, Lee AH, Dranoff G, Munshi NC, et al. Lenalidomide polarizes Th1-specific anti-tumor immune response and expands XBP1 antigen-specific central memory CD3+CD8+ T cells against various solid tumors. J Leuk. 2015;3:178.
Bae J, Hideshima T, Tai YT, Song Y, Richardson P, Raje N, et al. Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors. Leukemia. 2018;32:1932–47. https://doi.org/10.1038/s41375-018-0062-8
Nooka AJ, Wang M, Yee AJ, Thomas SK, O’Donnell EK, Shah JJ, et al. Final results of a Phase 1/2a, dose escalation study of Pvx-410 multi-peptide cancer vaccine in patients with smoldering multiple myeloma (SMM). Am Soc Hematol. 2016;128:2124.
Nooka AJ, Wang M, Yee AJ, Kaufman J, Bae J, Peterkin D, et al. Safety and immunogenicity of PVX-410 vaccine ± lenalidomide in smoldering multiple myeloma. JAMA Oncol. 2018;4:e183267. In Press
Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32:252–62.
Vanpouille-Box C, Lhuillier C, Bezu L, Aranda F, Yamazaki T, Kepp O, et al. Trial watch: immune checkpoint blockers for cancer therapy. Oncoimmunology. 2017;6:e1373237.
Costa R, Costa RB, Talamantes SM, Helenoswki I, Carneiro BA, Chae YK, et al. Analyses of selected safety endpoints in phase 1 and late-phase clinical trials of anti-PD-1 and PD-L1 inhibitors: prediction of immune-related toxicities. Oncotarget. 2017;8:67782–9.
Zhou G, Noordam L, Sprengers D, Doukas M, Boor PPC, van Beek AA, et al. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. Oncoimmunology. 2018;7:e1448332.
Andrews LP, Marciscano AE, Drake CG, Vignali DA. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017;276:80–96.
Waight JD, Chand D, Dietrich S, Gombos R, Horn T, Gonzalez AM, et al. Selective FcγR Co-engagement on APCs modulates the activity of therapeutic antibodies targeting T cell antigens. Cancer Cell. 2018;33:1033–47.
Pham Minh N, Murata S, Kitamura N, Ueki T, Kojima M, Miyake T, et al. In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro. Int J Cancer. 2018;142:2335–43.
Dushyanthen S, Teo ZL, Caramia F, Savas P, Mintoff CP, Virassamy B, et al. Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer. Nat Commun. 2017;8:606.
The authors acknowledge the Miriam and Sheldon G Adelson Medical Research Foundation. This work was also supported in part by grants from the National Institutes of Health Grants Special Program in Oncology Research Excellence (SPORE) P50 100707, RO1 CA 207237, and RO1 CA 050947. Dr. Kenneth C. Anderson is an American Cancer Society Clinical Research Professor.
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Bae, J., Samur, M., Richardson, P. et al. 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 33, 2208–2226 (2019). https://doi.org/10.1038/s41375-019-0414-z
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