Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies

June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73.

Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.

Foster AE, Mahendravada A, Shinners NP, Chang W-C, Crisostomo J, Lu A, et al. Regulated expansion and survival of chimeric antigen receptor-modified T cells using small molecule-dependent inducible MyD88/CD40. Mol Ther. 2017;25:2176–88.

Mata M, Gerken C, Nguyen P, Krenciute G, Spencer DM, Gottschalk S. Inducible activation of MyD88 and CD40 in CAR T cells results in controllable and potent antitumor activity in preclinical solid tumor models. Cancer Discov. 2017;7:1306–19.

Narayanan P, Lapteva N, Seethammagari M, Levitt JM, Slawin KM, Spencer DM. A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy. J Clin Invest. 2011;121:1524–34.

Straathof KC, Pulè MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005;105:4247–54.

Zhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT, et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood. 2015;125:4103–13.

Philip B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, Flutter B, et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood. 2014;124:1277–87.

Du X, Ho M, Pastan I. New immunotoxins targeting CD123, a stem cell antigen on acute myeloid leukemia cells. J Immunother. 2007;30:607–13.

Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE, et al. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood. 2013;122:3138–48.

Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17:1453–64.

Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116:4099–102.

Chng J, Wang T, Nian R, Lau A, Hoi KM, Ho SCL, et al. Cleavage efficient 2A peptides for high level monoclonal antibody expression in CHO cells. MAbs. 2015;7:403–12.

Diaconu I, Ballard B, Zhang M, Chen Y, West J, Dotti G, et al. Inducible Caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells. Mol Ther. 2017;25:580–92.

Hofacre A, Yagiz K, Mendoza D, Lopez Espinoza F, Munday AW, Burrascano C, et al. Efficient therapeutic protein expression using retroviral replicating vector with 2A peptide in cancer models. Hum Gene Ther. 2018;29:437–51.

Hanks BA, Jiang J, Singh RAK, Song W, Barry M, Huls MH, et al. Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo. Nat Med. 2005;11:130–7.

Motshwene PG, Moncrieffe MC, Grossmann JG, Kao C, Ayaluru M, Sandercock AM, et al. An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4. J Biol Chem. 2009;284:25404–11.

Lin S-C, Lo Y-C, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature. 2010;465:885–90.

Wang L, Qiao Q, Ferrao R, Shen C, Hatcher JM, Buhrlage SJ, et al. Crystal structure of human IRAK1. Proc Natl Acad Sci USA. 2017;114:13507–12.

De Nardo D, Balka KR, Cardona Gloria Y, Rao VR, Latz E, Masters SL. Interleukin 1 receptor-associated kinase 4 (IRAK4) plays a dual role in Myddosome formation and Toll-like receptor signalling. J Biol Chem. 2018; https://doi.org/10.1074/jbc.RA118.003314

Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21:581–90.

Frigault MJ, Lee J, Basil MC, Carpenito C, Motohashi S, Scholler J, et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res. 2015;3:356–67.

Gomes-Silva D, Mukherjee M, Srinivasan M, Krenciute G, Dakhova O, Zheng Y, et al. Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep. 2017;21:17–26.

Sun J, Dotti G, Huye LE, Foster AE, Savoldo B, Gramatges MM, et al. T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms. Mol Ther. 2010;18:2006–17.

Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62.

Lee JC, Hayman E, Pegram HJ, Santos E, Heller G, Sadelain M, et al. In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy. Cancer Res. 2011;71:2871–81.

Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739–48.

Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain MCAR. T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24:731–38.