Anti-CD19/BCMA Bispecific CAR-T Cell Therapy for R/R MM

Summary

The goal of this clinical trial is to study the feasibility and efficacy of anti-CD19/BCMA bispecific chimeric antigen receptors (CARs) T cell therapy for relapsed and refractory multiple myeloma.

Timeline

Start

2018-10-30

Primary completion

2020-07

Completion

2021-12

Publications

• Background Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018 Jan;68(1):7-30. doi: 10.3322/caac.21442. Epub 2018 Jan 4.
• Background Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. doi: 10.1056/NEJMoa022340.
• Background Hari PN, McCarthy PL. Multiple myeloma: future directions in autologous transplantation and novel agents. Biol Blood Marrow Transplant. 2013 Jan;19(1 Suppl):S20-5. doi: 10.1016/j.bbmt.2012.11.002. No abstract available.
• Background Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omede P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20. doi: 10.1056/NEJMoa065464.
• Background Hideshima T, Podar K, Chauhan D, Ishitsuka K, Mitsiades C, Tai YT, Hamasaki M, Raje N, Hideshima H, Schreiner G, Nguyen AN, Navas T, Munshi NC, Richardson PG, Higgins LS, Anderson KC. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene. 2004 Nov 18;23(54):8766-76. doi: 10.1038/sj.onc.1208118.
• Background Shringarpure R, Catley L, Bhole D, Burger R, Podar K, Tai YT, Kessler B, Galardy P, Ploegh H, Tassone P, Hideshima T, Mitsiades C, Munshi NC, Chauhan D, Anderson KC. Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib. Br J Haematol. 2006 Jul;134(2):145-56. doi: 10.1111/j.1365-2141.2006.06132.x.
• Background Godfrey J, Benson DM Jr. The role of natural killer cells in immunity against multiple myeloma. Leuk Lymphoma. 2012 Sep;53(9):1666-76. doi: 10.3109/10428194.2012.676175. Epub 2012 Apr 19.
• Background Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011 Oct 25;11(11):750-61. doi: 10.1038/nri3088.
• Background Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B, Fogli M, Ferri E, Della Cuna GR, Tura S, Baccarani M, Lemoli RM. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood. 2002 Jul 1;100(1):230-7. doi: 10.1182/blood.v100.1.230.
• Background Favaloro J, Brown R, Aklilu E, Yang S, Suen H, Hart D, Fromm P, Gibson J, Khoo L, Ho PJ, Joshua D. Myeloma skews regulatory T and pro-inflammatory T helper 17 cell balance in favor of a suppressive state. Leuk Lymphoma. 2014 May;55(5):1090-8. doi: 10.3109/10428194.2013.825905. Epub 2013 Aug 28.
• Background Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8. doi: 10.1126/science.aaa4967.
• Background Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, Dengel K, Kerr ND, Bagg A, Levine BL, June CH, Stadtmauer EA. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med. 2015 Sep 10;373(11):1040-7. doi: 10.1056/NEJMoa1504542.
• Background Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, Gentner B, Gullotta F, Ponzoni M, Bernardi M, Marcatti M, Saudemont A, Bordignon C, Savoldo B, Ciceri F, Naldini L, Dotti G, Bonini C, Bondanza A. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 2013 Nov 14;122(20):3461-72. doi: 10.1182/blood-2013-04-493361. Epub 2013 Sep 9.
• Background Shaffer DR, Savoldo B, Yi Z, Chow KK, Kakarla S, Spencer DM, Dotti G, Wu MF, Liu H, Kenney S, Gottschalk S. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood. 2011 Apr 21;117(16):4304-14. doi: 10.1182/blood-2010-04-278218. Epub 2011 Feb 8.
• Background Drent E, Groen RW, Noort WA, Themeli M, Lammerts van Bueren JJ, Parren PW, Kuball J, Sebestyen Z, Yuan H, de Bruijn J, van de Donk NW, Martens AC, Lokhorst HM, Mutis T. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Haematologica. 2016 May;101(5):616-25. doi: 10.3324/haematol.2015.137620. Epub 2016 Feb 8.
• Background Drent E, Themeli M, Poels R, de Jong-Korlaar R, Yuan H, de Bruijn J, Martens ACM, Zweegman S, van de Donk NWCJ, Groen RWJ, Lokhorst HM, Mutis T. A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization. Mol Ther. 2017 Aug 2;25(8):1946-1958. doi: 10.1016/j.ymthe.2017.04.024. Epub 2017 May 13.
• Background O'Connell FP, Pinkus JL, Pinkus GS. CD138 (syndecan-1), a plasma cell marker immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms. Am J Clin Pathol. 2004 Feb;121(2):254-63. doi: 10.1309/617D-WB5G-NFWX-HW4L.
• Background Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I, McNiece I, Lin L, Ambinder RF, Peacock C, Watkins DN, Huff CA, Jones RJ. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008 Jan 1;68(1):190-7. doi: 10.1158/0008-5472.CAN-07-3096.
• Background Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O, Liu E, Carrum G, Kamble RT, Gee AP, Mei Z, Wu MF, Liu H, Grilley B, Rooney CM, Brenner MK, Heslop HE, Dotti G. Clinical responses with T lymphocytes targeting malignancy-associated kappa light chains. J Clin Invest. 2016 Jul 1;126(7):2588-96. doi: 10.1172/JCI86000. Epub 2016 Jun 6.
• Background Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y, Rice AG, van Abbema A, Wong M, Liu G, Zhan F, Dillon M, Chen S, Rhodes S, Fuh F, Tsurushita N, Kumar S, Vexler V, Shaughnessy JD Jr, Barlogie B, van Rhee F, Hussein M, Afar DE, Williams MB. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008 May 1;14(9):2775-84. doi: 10.1158/1078-0432.CCR-07-4246.
• Background Chu J, He S, Deng Y, Zhang J, Peng Y, Hughes T, Yi L, Kwon CH, Wang QE, Devine SM, He X, Bai XF, Hofmeister CC, Yu J. Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells. Clin Cancer Res. 2014 Aug 1;20(15):3989-4000. doi: 10.1158/1078-0432.CCR-13-2510. Epub 2014 Mar 27.
• Background Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, Brudno JN, Stetler-Stevenson M, Feldman SA, Hansen BG, Fellowes VS, Hakim FT, Gress RE, Kochenderfer JN. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016 Sep 29;128(13):1688-700. doi: 10.1182/blood-2016-04-711903. Epub 2016 Jul 13.
• Background Rotolo A, Caputo V, Karadimitris A. The prospects and promise of chimeric antigen receptor immunotherapy in multiple myeloma. Br J Haematol. 2016 May;173(3):350-64. doi: 10.1111/bjh.13976. Epub 2016 Mar 8.
• Background Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress RE, Hakim FT, Kochenderfer JN. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013 Apr 15;19(8):2048-60. doi: 10.1158/1078-0432.CCR-12-2422. Epub 2013 Jan 23.
• Background Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, Gross JA, Greipp PR, Jelinek DF. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004 Jan 15;103(2):689-94. doi: 10.1182/blood-2003-06-2043. Epub 2003 Sep 25.
• Background Ryan MC, Hering M, Peckham D, McDonagh CF, Brown L, Kim KM, Meyer DL, Zabinski RF, Grewal IS, Carter PJ. Antibody targeting of B-cell maturation antigen on malignant plasma cells. Mol Cancer Ther. 2007 Nov;6(11):3009-18. doi: 10.1158/1535-7163.MCT-07-0464.
• Background Xu S, Lam KP. B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. Mol Cell Biol. 2001 Jun;21(12):4067-74. doi: 10.1128/MCB.21.12.4067-4074.2001.
• Background Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, Smith BD, Civin CI, Jones RJ. Characterization of clonogenic multiple myeloma cells. Blood. 2004 Mar 15;103(6):2332-6. doi: 10.1182/blood-2003-09-3064. Epub 2003 Nov 20.
• Background Zah E, Lin MY, Silva-Benedict A, Jensen MC, Chen YY. T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells. Cancer Immunol Res. 2016 Jun;4(6):498-508. doi: 10.1158/2326-6066.CIR-15-0231. Epub 2016 Apr 8.
• Background Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schonfeld K, Koch J, Dotti G, Heslop HE, Gottschalk S, Wels WS, Baker ML, Ahmed N. TanCAR: A Novel Bispecific Chimeric Antigen Receptor for Cancer Immunotherapy. Mol Ther Nucleic Acids. 2013 Jul 9;2(7):e105. doi: 10.1038/mtna.2013.32.

Drugs

Indications