Factors Affecting the Cancer Immunotherapeutic Efficacy of T Cell Bispecific Antibodies and Strategies for Improvement

References

• Abramson JS, Palomba L, Gordon LI, Lunning M, Arnason J, Forero-Torres A, Albertson TM, Exton VS, Sutherland C, Xie B, et al. 2016. Transcend NHL 001: immunotherapy with the CD19-directed CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-hodgkin lymphoma. Blood. 128(22): 4192-92.
   PubMed Web of Science ®Google Scholar
• Advani A, Moseley A, O’Dwyer K, Wood B, Park JH, Wieduwilt M, Jeyakumar D, Yaghmour G, Atallah EL, Gerds AT, et al. 2021. A phase 2 study of dasatinib, prednisone, and blinatumomab for older patients with Philadelphia-Chromosome (Ph) positive or Ph-like acute lymphoblastic leukemia (ALL) (with dasatinib sensitive fusions/mutations). Blood. 138. 3397.
   Web of Science ®Google Scholar
• Agarwal SK, Bhagwat S, Mehta K, Hindoyan A, Stein AS, Ravandi F, Subklewe M, Walter RB, Jongen-Lavrencic M, Ossenkoppele GJ, et al. 2020. Characterization of clinical pharmacokinetics and exposure-response relationships of AMG 330, a bispecific CD33 T-cell engager antibody construct, in patients with relapsed/refractory AML. J Clin Oncolog. 38(15_suppl): 7536-36. doi:10.1200/JCO.2020.38.15_suppl.7536.
   Web of Science ®Google Scholar
• Aichele P, Brduscha-Riem K, Zinkernagel RM, Hengartner H, Pircher H. 1995. T cell priming versus T cell tolerance induced by synthetic peptides. J Exp Med. 182(1):261–66.
   PubMed Web of Science ®Google Scholar
• Andreatta M, Corria-Osorio J, Müller S, Cubas R, Coukos G, Carmona SJ. 2021. Interpretation of T cell states from single-cell transcriptomics data using reference atlases. Nat Commun. 12(1):2965.
   PubMed Web of Science ®Google Scholar
• Arenas EJ, Martínez-Sabadell A, Rius Ruiz I, Román Alonso M, Escorihuela M, Luque A, Fajardo CA, Gros A, Klein C, Arribas J. 2021. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation. Nat Commun. 12(1):1237.
   PubMed Web of Science ®Google Scholar
• Arjomandnejad M, Kopec AL, Keeler AM. 2022. CAR-T regulatory (CAR-Treg) cells: engineering and Applications. Biomed. 10(2):287.
   Google Scholar
• Augsberger C, Hänel G, Xu W, Pulko V, Hanisch LJ, Augustin A, Challier J, Hunt K, Vick B, Rovatti PE, et al. 2021. Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody. Blood. 138(25):2655–69.
   PubMed Web of Science ®Google Scholar
• Bacac M, Fauti T, Sam J, Colombetti S, Weinzierl T, Ouaret D, Bodmer W, Lehmann S, Hofer T, Hosse RJ, et al. 2016. A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin Cancer Res. 22(13):3286–97.
   PubMed Web of Science ®Google Scholar
• Bartkowiak T, Jaiswal AR, Ager CR, Chin R, Chen CH, Budhani P, Ai M, Reilley MJ, Sebastian MM, Hong DS, et al. 2018. Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27–dependent pathway. Clin Cancer Res. 24(5):1138–51.
   PubMed Web of Science ®Google Scholar
• Belmontes B, Sawant DV, Zhong W, Tan H, Kaul A, Aeffner F, O’Brien SA, Chun M, Noubade R, Eng J, et al. 2021. Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell–cold solid tumors. Sci Transl Med. 13(608):eabd1524.
   PubMed Web of Science ®Google Scholar
• Blagih J, Buck MD, Vousden KH, Lennon-Duménil AM. 2020. P53, cancer and the immune response. J Cell Sci. 133(5). doi:10.1242/jcs.237453
   PubMed Web of Science ®Google Scholar
• Bohlen H, Hopff T, Manzke O, Engert A, Kube D, Wickramanayake PD, Diehl V, Tesch H. 1993. Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies. Blood. 82(6):1803–12.
   PubMed Web of Science ®Google Scholar
• Bohlen H, Manzke O, Titzer S, Lorenzen J, Kube D, Engert A, Abken H, Wolf J, Diehl V, Tesch H. 1997. Prevention of epstein-barr virus-induced human B-cell lymphoma in severe combined immunodeficient mice treated with CD3xCD19 bispecific antibodies, CD28 monospecific antibodies, and autologous T cells1. Cancer Res. 57(9):1704–09.
   PubMed Web of Science ®Google Scholar
• Bono JSD, Fong L, Beer TM, Gao X, Geynisman DM, Burris HA III, Strauss JF, Courtney KD, Quinn DI, VanderWeele DJ, et al. 2021. Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncolog. 39(15_suppl): 5013-13. doi:10.1200/JCO.2021.39.15_suppl.5013.
   Google Scholar
• Bourgeois-Daigneault MC, Roy DG, Falls T, Twumasi-Boateng K, St-Germain LE, Marguerie M, Garcia V, Selman M, Jennings VA, Pettigrew J, et al. 2016. Oncolytic vesicular stomatitis virus expressing interferon-σ has enhanced therapeutic activity. Mol Ther Oncolytics. 3:316001.
   Web of Science ®Google Scholar
• Brandl M, Grosse-Hovest L, Holler E, Kolb HJ, Jung G. 1999. Bispecific antibody fragments with CD20 X CD28 specificity allow effective autologous and allogeneic T-cell activation against malignant cells in peripheral blood and bone marrow cultures from patients with B-cell lineage leukemia and lymphoma. Exp Hematol. 27(8):1264–70.
   PubMed Web of Science ®Google Scholar
• Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, et al. 2013. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 5(177): 177ra38-77ra38. doi:10.1126/scitranslmed.3005930.
   PubMed Web of Science ®Google Scholar
• Bretscher PA. 1999. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A. 96(1):185–90.
   PubMed Web of Science ®Google Scholar
• Brischwein K, Parr L, Pflanz S, Volkland J, Lumsden J, Klinger M, Locher M, Hammond SA, Kiener P, Kufer P, et al. 2007. Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J Immunother (1991). 30(8):798–807.
   Web of Science ®Google Scholar
• Bronger H, Singer J, Windmüller C, Reuning U, Zech D, Delbridge C, Dorn J, Kiechle M, Schmalfeldt B, Schmitt M, et al. 2016. CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. Br J Cancer. 115(5):553–63.
   PubMed Web of Science ®Google Scholar
• Bröske AE, Korfi K, Belousov A, Wilson S, Ooi CH, Bolen CR, Canamero M, Alcaide EG, James I, Piccione EC, et al. 2022. Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-hodgkin lymphoma. Blood Adv. 6(3):1025–37.
   PubMed Web of Science ®Google Scholar
• Brouwer-Visser J, Fiaschi N, Deering RP, Dhanik A, Cygan KJ, Zhang W, Jeong S, Pourpe S, Boucher L, Hamon S, et al. 2020. Baseline biomarkers of T-cell function correlate with clinical responses to odronextamab (REGN1979), and loss of CD20 target antigen expression identified as a mechanism of treatment resistance. Blood. 136(Supplement 1):10–11.
   Google Scholar
• Brouwer-Visser J, Fiaschi N, Deering RP, Dhanik A, Cygan KJ, Zhang W, Jeong S, Pourpe S, Boucher L, Hamon S, et al. 2021. Clinical responses to odronextamab (regn1979): correlation with loss of cd20 expression as a potential mechanism of resistance and baseline biomarkers of tumor T cells. Hematol Oncol. 39(S2). doi:10.1002/hon.6_2880.
   Google Scholar
• Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, et al. 2021. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of B-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 325(9):833–42.
   PubMed Web of Science ®Google Scholar
• Budde LE, Assouline S, Sehn LH, Schuster SJ, Yoon SS, Yoon DH, Matasar MJ, Bosch F, Kim WS, Nastoupil LJ, et al. 2022. Single-agent Mosunetuzumab shows durable complete responses in patients with relapsed or refractory B-cell lymphomas: phase I dose-escalation study. J Clin Oncol. 40(5):481–91.
   PubMed Web of Science ®Google Scholar
• Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ. 2018. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol. 9:847.
   Web of Science ®Google Scholar
• Cauwels A, Van Lint S, Garcin G, Bultinck J, Paul F, Gerlo S, Van der Heyden J, Bordat Y, Catteeuw D, De Cauwer L, et al. 2018. A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment. Oncoimmunol. 7(3):e1398876.
   PubMed Web of Science ®Google Scholar
• Chen W, Yang F, Wang C, Narula J, Pascua E, Ni I, Ding S, Deng X, Chu MH, Pham A, et al. 2021. One size does not fit all: navigating the multi-dimensional space to optimize T-cell engaging protein therapeutics. mAbs. 13(1):1871171.
   PubMed Web of Science ®Google Scholar
• Chiu C, Hiemstra IH, Johnson P, Soong D, Oliveri RS, Clausen MR, Mous R, Lopez J, Chamuleau MED, Rule S, et al. 2020a. Evaluation of pharmacodynamic biomarkers of epcoritamab (GEN3013; CD3× CD20): results from a phase I/II dose-escalation study in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. EHA Annu Meeting 2020. Abstract: EP1330.
   Google Scholar
• Chiu D, Tavaré R, Haber L, Aina OH, Vazzana K, Ram P, Danton M, Finney J, Jalal S, Krueger P, et al. 2020b. A PSMA-targeting CD3 bispecific antibody Induces antitumor responses that are enhanced by 4-1BB costimulation. Cancer Immunol Res. 8(5):596–608.
   PubMed Web of Science ®Google Scholar
• Choi BD, Gedeon PC, Sanchez-Perez L, Bigner DD, Sampson JH. 2013. Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody. Oncoimmunol. 2(12): e26757-e57. doi:10.4161/onci.26757.
   Web of Science ®Google Scholar
• Cho SF, Lin L, Xing L, Li Y, Wen K, Yu T, Hsieh PA, Munshi N, Wahl J, Matthes K, et al. 2020. The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models. Blood Adv. 4(17):4195–207.
   PubMed Web of Science ®Google Scholar
• Choudhuri K, Parker M, Milicic A, Cole DK, Shaw MK, Sewell AK, Stewart-Jones G, Dong T, Gould KG, van der Merwe PA. 2009. Peptide-major histocompatibility complex dimensions control proximal kinase-phosphatase balance during T cell activation. J Biol Chem. 284(38):26096–105.
   PubMed Web of Science ®Google Scholar
• Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, Albrecht R, Herter S, Schlenker R, Hüsser T, et al. 2019. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med. 11(496):eaav5989.
   PubMed Web of Science ®Google Scholar
• Cochlovius B, Kipriyanov SM, Stassar MJ, Christ O, Schuhmacher J, Strauss G, Moldenhauer G, Little M. 2000a. Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells. J Immunol. 165(2):888–95.
   PubMed Web of Science ®Google Scholar
• Cochlovius B, Kipriyanov SM, Stassar MJ, Schuhmacher J, Benner A, Moldenhauer G, Little M. 2000b. Cure of Burkitt’s lymphoma in severe combined immunodeficiency mice by T cells, tetravalent CD3 x CD19 tandem diabody, and CD28 costimulation. Cancer Res. 60(16):4336–41.
   PubMed Web of Science ®Google Scholar
• Croci Diego D, Cerliani Juan J, Dalotto-Moreno T, Méndez-Huergo SP, Mascanfroni Ivan I, Dergan-Dylon S, Toscano Marta M, Caramelo Julio J, García-Vallejo JJ, Ouyang J, et al. 2014. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell. 156(4):744–58.
   PubMed Web of Science ®Google Scholar
• Croci DO, Salatino M, Rubinstein N, Cerliani JP, Cavallin LE, Leung HJ, Ouyang J, Ilarregui JM, Toscano MA, Domaica CI, et al. 2012. Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi’s sarcoma. J Exp Med. 209(11):1985–2000.
   PubMed Web of Science ®Google Scholar
• Croft M, Bradley LM, Swain SL. 1994. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol. 152(6):2675–85.
   PubMed Web of Science ®Google Scholar
• Csóka M, Strauss G, Debatin KM, Moldenhauer G. 1996. Activation of T cell cytotoxicity against autologous common acute lymphoblastic leukemia (cALL) blasts by CD3xCD19 bispecific antibody. Leukemia. 10(11):1765–72.
   PubMed Web of Science ®Google Scholar
• Curiel T, Thibodeaux S, Wall S, Pandeswara SL, Daniel B, Drerup J, Murthy K, Kryczek I, Zou W, Barnett B. 2014. Denileukin diftitox depletes regulatory T cells without clinical benefit in advanced stage epithelial ovarian carcinoma (VAC3P.945). J Immunol. 192(1 Supplement): 73.7-73.7.
   Google Scholar
• Curnis F, Gasparri A, Sacchi A, Cattaneo A, Magni F, Corti A. 2005. Targeted delivery of IFNγ to tumor vessels uncouples antitumor from counterregulatory mechanisms. Cancer Res. 65(7):2906–13.
   PubMed Web of Science ®Google Scholar
• Daniel PT, Kroidl A, Kopp J, Sturm I, Moldenhauer G, Dorken B, Pezzutto A. 1998. Immunotherapy of B-cell lymphoma with CD3x19 bispecific antibodies: costimulation via CD28 prevents “veto” apoptosis of antibody-targeted cytotoxic T cells. Blood. 92(12):4750–57.
   PubMed Web of Science ®Google Scholar
• Dao T, Mun SS, Scott AC, Jarvis CA, Korontsvit T, Yang Z, Liu L, Klatt MG, Guerreiro M, Selvakumar A, et al. 2019. Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody. Oncoimmunol. 8(7):1570778.
   PubMed Web of Science ®Google Scholar
• Davar D, Sweis RF, Blumenschein G Jr., Gutierrez R, Melero I, Chen HA, Thistlethwaite F, Moore KN, Segal NH, Garralda E, et al. 2021. 91P phase I dose escalation of IMC-C103C, a CD3×MAGE-A4 T-cell receptor (TCR) bispecific protein. Annals Oncol. 32: 32S1411-SS13. doi:10.1016/j.annonc.2021.10.109.
   Web of Science ®Google Scholar
• Dawson NAJ, Rosado-Sánchez I, Novakovsky GE, Fung VCW, Huang Q, McIver E, Sun G, Gillies J, Speck M, Orban PC, et al. 2020. Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells. Sci Transl Med. 12(557):eaaz3866.
   PubMed Web of Science ®Google Scholar
• Deegen P, Thomas O, Nolan-Stevaux O, Li S, Wahl J, Bogner P, Aeffner F, Friedrich M, Liao MZ, Matthes K, et al. 2021. The PSMA-targeting half-life extended BiTE therapy AMG 160 has potent antitumor activity in preclinical models of metastatic castration-resistant prostate cancer. Clin Cancer Res. 27(10):2928–37.
   PubMed Web of Science ®Google Scholar
• Dees S, Ganesan R, Singh S, Grewal IS. 2021. Regulatory T cell targeting in cancer: emerging strategies in immunotherapy. Eur J Immunol. 51(2):280–91.
   PubMed Web of Science ®Google Scholar
• Deeths MJ, Kedl RM, Mescher MF. 1999. CD8+ T cells become nonresponsive (anergic) following activation in the presence of costimulation. J Immunol. 163(1):102–10.
   PubMed Web of Science ®Google Scholar
• Deisting W, Raum T, Kufer P, Baeuerle PA, Münz M, Chatenoud L. 2015. Impact of diverse immune evasion mechanisms of cancer cells on T cells engaged by EpCAM/CD3-bispecific antibody construct AMG 110. PLoS One. 10(10):e0141669.
   PubMed Web of Science ®Google Scholar
• Delord J-P, Awada A, Raymond E, Lokiec F, Herait P, Rezai K, Lachaux N, Rabinovich GA, Gomez-Roca C, Aftimos P, et al. 2013. Abstract A72: a first-in-man phase I study of the galectin-1 (gal-1) inhibitor OTX008 given subcutaneously as a single agent to patients with advanced solid tumors. Mol Cancer Ther. 12(11_Supplement): A72-A72.
   Web of Science ®Google Scholar
• Demanet C, Brissinck J, De Jonge J, Thielemans K. 1996. Bispecific antibody-mediated immunotherapy of the BCL1 lymphoma: increased efficacy with multiple injections and CD28-induced costimulation. Blood. 87(10):4390–98.
   PubMed Web of Science ®Google Scholar
• Donnadieu E, Dupré L, Pinho LG, Cotta-de-Almeida V. 2020. Surmounting the obstacles that impede effective CAR T cell trafficking to solid tumors. J Leukoc Biol. 108(4):1067–79.
   PubMed Web of Science ®Google Scholar
• Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, Rasche L, Hartmann E, Dandekar T, Einsele H, et al. 2017. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL. Leukemia. 31(10):2181–90.
   PubMed Web of Science ®Google Scholar
• Eyvazi S, Farajnia S, Dastmalchi S, Kanipour F, Zarredar H, Bandehpour M. 2018. Antibody based EpCAM targeted therapy of cancer, review and update. Curr Cancer Drug Targets. 18(9):857–68.
   PubMed Web of Science ®Google Scholar
• Falchi L, Offner F, Belada D, Brody J, Linton KM, Karimi Y, Cordoba R, Snauwaert S, Abbas A, Wang L, et al. 2022. First-line treatment (Tx) with subcutaneous (SC) epcoritamab (epco) + R-CHOP in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL): phase 1/2 data update. J Clin Oncol. 40(16_suppl): 7523-23.
   Google Scholar
• Faroudi M, Utzny C, Salio M, Cerundolo V, Guiraud M, Müller S, Valitutti S. 2003. Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: manifestation of a dual activation threshold. Proc Natl Acad Sci U S A. 100(24):14145–50.
   PubMed Web of Science ®Google Scholar
• Fearon DT. 2017. Immune-suppressing cellular elements of the tumor microenvironment. Annu Rev Cancer Biol. 1(1):241–55.
   Google Scholar
• Fleming S, Venn N, Reynolds J, Nguyen U, Kwan J, Moore J, Yeung DT, Leahy MF, Greenwood M, Verner E, et al. 2019. Preliminary minimal residual disease analysis of the Australasian leukaemia & lymphoma group (ALLG) ALL8 study of front-line blinatumomab with chemotherapy in adults with Ph negative B-cell acute lymphoblastic leukaemia. Blood. 134(Supplement_1): 1300-00. doi:10.1182/blood-2019-132048.
   Google Scholar
• Frankel SR, Baeuerle PA. 2013. Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol. 17(3):385–92.
   PubMed Web of Science ®Google Scholar
• Fuse S, Zhang W, Usherwood EJ. 2008. Control of memory CD8+ T cell differentiation by CD80/CD86-CD28 costimulation and restoration by IL-2 during the recall response. J Immunol. 180(2):1148–57.
   PubMed Web of Science ®Google Scholar
• Gardner R, Finney O, Smithers H, Leger KJ, Annesley CE, Summers C, Brown C, Mgebroff S, Lindgren C, Spratt K, et al. 2016. CD19CAR T cell products of defined CD4:cD8 composition and transgene expression show prolonged persistence and durable MRD-negative remission in pediatric and young adult B-cell ALL. Blood. 128(22): 219-19. doi:10.1182/blood.V128.22.219.219.
   PubMed Web of Science ®Google Scholar
• Ghobadi A, Rettig MP, Cashen AF, Gehrs L, Christ S, Mehta-Shah N, Westervelt P, Kahl BS, Bartlett NL, DiPersio JF. 2020. Blinatumomab consolidation post autologous hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma. Blood. 136(Supp 1):3-4.
   Google Scholar
• Ghosh N, Townsend W, Dickinson M, Topp M, Tani M, Santoro A, Crump M, Morschhauser F, Le Gouill S, Mehta A, et al. 2021. Glofitamab plus R-CHOP induces high response rates with minimal cytokine release syndrome (CRS) in patients (pts) with relapsed/refractory (R/R) non-hodgkin lymphoma (NHL) and previously untreated (1L) diffuse large B-cell lymphoma (DLBCL): preliminary results from a dose-escalation and safety run-in phase Ib study. Blood. 138(Supplement 1): 2479-79.
   Google Scholar
• Goebeler ME, Bargou RC. 2020. T cell-engaging therapies — BiTes and beyond. Nat Rev Clin Oncol. 17(7):418–34.
   PubMed Web of Science ®Google Scholar
• Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, Noppeney R, Hess G, Kallert S, Mackensen A, et al. 2016. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 34(10):1104–11.
   PubMed Web of Science ®Google Scholar
• Goekbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Havelange V, Buss EC, Faul C, Bruggemann M, Ganser A, et al. 2014. BLAST: a confirmatory, single-arm, phase 2 study of blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct, in patients with minimal residual disease B-precursor acute lymphoblastic leukemia (ALL). Blood. 124(21): 379-79. doi:10.1182/blood.V124.21.379.379.
   Web of Science ®Google Scholar
• Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Brüggemann M, Horst HA, et al. 2018. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 131(14):1522–31.
   PubMed Web of Science ®Google Scholar
• Gökbuget N, Zugmaier G, Klinger M, Kufer P, Stelljes M, Viardot A, Horst HA, Neumann S, Brüggemann M, Ottmann OG, et al. 2017. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica. 102(4):e132–35.
   PubMed Web of Science ®Google Scholar
• Goldstein JS, Chen T, Brunswick M, Mostowsky H, Kozlowski S. 1998. Purified MHC class I and peptide complexes activate naive CD8+ T cells independently of the CD28/B7 and LFA-1/ICAM-1 costimulatory interactions. J Immunol. 160(7):3180–87.
   PubMed Web of Science ®Google Scholar
• Gore L, Locatelli F, Zugmaier G, Handgretinger R, O’Brien MM, Bader P, Bhojwani D, Schlegel PG, Tuglus CA, von Stackelberg A. 2018. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J. 8(9): 80-80. doi: 10.1038/s41408-018-0117-0.
   Google Scholar
• Gottschalk R, Miller R, Woodruff B, Lucas A, Haglin E, Pavlik P, Nelson MH, Ramos HJ. 2022. Abstract 3434: aPVO442 is a distinct PSMA x CD3 targeted bispecific candidate designed to optimize T cell fitness and distribution to solid tumors. Cancer Res. 82(12_Supplement): 3434-34. doi: 10.1158/1538-7445.AM2022-3434.
   Web of Science ®Google Scholar
• Goyal R, Nasrah N, Johnson D, Ho W. 2021. 548 phase 2 study of FLX475 in combination with ipilimumab in advanced melanoma. J ImmunoTher Cancer. 9(Suppl 2): A578-A78.
   Google Scholar
• Grupp SA, Maude SL, Shaw PA, Aplenc R, Barrett DM, Callahan C, Lacey SF, Levine BL, Melenhorst JJ, Motley L, et al. 2015. Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Blood. 126(23): 681-81. doi:10.1182/blood.V126.23.681.681.
   PubMed Web of Science ®Google Scholar
• Gu Y, Zhao Y, Zhang Z, Hao J, Zheng Y, Liu Q, Liu Y, Shi L. 2021. An antibody-like polymeric nanoparticle removes intratumoral Galectin-1 to enhance antitumor T-cell responses in cancer immunotherapy. ACS Appl Mater Interfaces. 13(19):22159–68.
   PubMed Web of Science ®Google Scholar
• Haense N, Atmaca A, Pauligk C, Steinmetz K, Marmé F, Haag GM, Rieger M, Ottmann OG, Ruf P, Lindhofer H, et al. 2016. A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors. BMC Cancer. 16(1):420.
   PubMedGoogle Scholar
• He Q, Jiang X, Zhou X, Weng J. 2019. Targeting cancers through TCR-peptide/mhc interactions. J Hematol Oncol. 12(1):139.
   PubMed Web of Science ®Google Scholar
• Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al. 2014. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nat. 515(7528):563–67.
   Google Scholar
• Hernandez G, Huw LY, Belousov A, Wilson D, Koeppen H, McCord R, Peng K, Bartlett NL, Budde LE, Assouline S, et al. 2019. Pharmacodynamic effects and immune correlates of response to the CD20/CD3 bispecific antibody mosunetuzumab in relapsed or refractory non-hodgkin lymphoma. Blood. 134(Supp 1):1585.
   Web of Science ®Google Scholar
• Hoffmann P, Hofmeister R, Brischwein K, Brandl C, Crommer S, Bargou R, Itin C, Prang N, Baeuerle PA. 2005. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int J Cancer. 115(1):98–104.
   PubMed Web of Science ®Google Scholar
• Hombach AA, Kofler D, Rappl G, Abken H. 2009. Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity. Gene Ther. 16(9):1088–96.
   PubMed Web of Science ®Google Scholar
• Hombach A, Sent D, Schneider C, Heuser C, Koch D, Pohl C, Seliger B, Abken H. 2001. T-cell activation by recombinant receptors: cD28 costimulation is required for Interleukin 2 secretion and receptor-mediated T-cell proliferation but does not affect receptor-mediated target cell Lysis1. Cancer Res. 61(5):1976–82.
   PubMed Web of Science ®Google Scholar
• Hong S, Zhang Z, Liu H, Tian M, Zhu X, Zhang Z, Wang W, Zhou X, Zhang F, Ge Q, et al. 2018. B cells are the dominant antigen-presenting cells that activate naive CD4+ T cells upon immunization with a virus-derived nanoparticle antigen. Immun. 49(4):695–708.e4.
   Google Scholar
• Höpken UE, Rehm A. 2019. Targeting the tumor microenvironment of leukemia and lymphoma. Trends Cancer. 5(6):351–64.
   PubMed Web of Science ®Google Scholar
• Humeau J, Le Naour J, Galluzzi L, Kroemer G, Pol JG. 2021. Trial watch: intratumoral immunotherapy. OncoImmunol. 10(1):1984677.
   PubMed Web of Science ®Google Scholar
• Hummel HD, Kufer P, Grüllich C, Deschler-Baier B, Chatterjee M, Goebeler ME, Miller K, De Santis M, Loidl WC, Buck A, et al. 2020. Phase I study of pasotuxizumab (AMG 212/BAY 2010112), a PSMA-targeting BiTE (Bispecific T-cell Engager) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 38(6_suppl): 124-24. doi:10.1200/JCO.2020.38.6_suppl.124.
   Google Scholar
• Huo Y, Sheng Z, Lu DR, Ellwanger DC, Li CM, Homann O, Wang S, Yin H, Ren R. 2021. Blinatumomab-induced T cell activation at single cell transcriptome resolution. BMC Genomics. 22(1):145.
   PubMed Web of Science ®Google Scholar
• Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, Lewis DJ, Sureda Balari A, Cunningham D, Oliveri RS, et al. 2021. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-hodgkin lymphoma: an open-label, phase 1/2 study. The Lancet. 398(10306):1157–69.
   PubMed Web of Science ®Google Scholar
• Jabbour E, Düll J, Yilmaz M, Khoury JD, Ravandi F, Jain N, Einsele H, Garcia-Manero G, Konopleva M, Short NJ, et al. 2018. Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: no change in the level of CD19 expression. Am J Hematol. 93(3):371–74.
   PubMed Web of Science ®Google Scholar
• Jacobs K, Viero C, Godwin J, Baughman J, Sun J, Ying K, Muth J, Hong S, Vey N, Sweet KL, et al. 2017. Management of cytokine release syndrome in AML patients treated with flotetuzumab, a CD123 x CD3 bispecific dart® molecule for T-cell redirected therapy. Blood. 132(Suppl 1): 3856-56. doi:10.1182/blood-2018-99-112615.
   Google Scholar
• Jacobs K, Viero C, Godwin J, Baughman J, Sun J, Ying K, Muth J, Hong S, Vey N, Sweet KL, et al. 2018. Management of cytokine release syndrome in AML patients treated with flotetuzumab, a CD123 x CD3 bispecific dart® molecule for T-cell redirected therapy. Blood. 132(Suppl 1): 2738-38. doi:10.1182/blood-2018-99-112615.
   Google Scholar
• Jenkins MK, Khoruts A, Ingulli E, Mueller DL, McSorley SJ, Reinhardt RL, Itano A, Pape KA. 2001. In vivo activation of antigen-specific CD4 T cells. Annu Rev Immunol. 19(1):23–45.
   PubMedGoogle Scholar
• Junttila TT, Li J, Johnston J, Hristopoulos M, Clark R, Ellerman D, Wang BE, Li Y, Mathieu M, Li G, et al. 2014. Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Cancer Res. 74(19):5561–71.
   PubMed Web of Science ®Google Scholar
• Katz DA, Morris JD, Chu MP, David KA, Thieblemont C, Morley NJ, Khan SS, Viardot A, Martín García-Sancho A, Rodríguez-García G, et al. 2022a. Open-label, phase 2 study of blinatumomab after frontline R-chemotherapy in adults with newly diagnosed, high-risk DLBCL. Leukemia Lymphoma. 1–11. doi:10.1080/10428194.2022.2064981.
   Web of Science ®Google Scholar
• Katz DA, Morris JD, Chu MP, David KA, Thieblemont C, Morley NJ, Khan SS, Viardot A, Martín García-Sancho A, Rodríguez-García G, et al. 2022b. Open-label, phase 2 study of blinatumomab after frontline R-chemotherapy in adults with newly diagnosed, high-risk DLBCL. Leuk Lymphoma. 1–11. doi:10.1080/10428194.2022.2064981.
   Web of Science ®Google Scholar
• Kebenko M, Goebeler ME, Wolf M, Hasenburg A, Seggewiss-Bernhardt R, Ritter B, Rautenberg B, Atanackovic D, Kratzer A, Rottman JB, et al. 2018. A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors. OncoImmunol. 7(8):e1450710.
   PubMed Web of Science ®Google Scholar
• Kipriyanov SM, Cochlovius B, Schäfer HJ, Moldenhauer G, Bähre A, Le Gall F, Knackmuss S, Little M. 2002. Synergistic antitumor effect of bispecific CD19 × CD3 and CD19 × CD16 diabodies in a preclinical model of non-hodgkin’s lymphoma. J Immunol. 169(1):137–44.
   PubMed Web of Science ®Google Scholar
• Klyosov A, Zomer E, Platt D. 2012. DAVANAT (GM-CT-01) and Colon Cancer: Preclinical and Clinical (Phase I and II) Studies. Glycobiology and Drug Design (American Chemical Society). 89–130.
   Google Scholar
• Köhnke T, Krupka C, Tischer J, Knösel T, Subklewe M. 2015. Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab. J Hematol Oncol. 8(1). doi:10.1186/s13045-015-0213-6
   PubMedGoogle Scholar
• Koristka S, Cartellieri M, Arndt C, Feldmann A, Seliger B, Ehninger G, Bachmann MP. 2015. Tregs activated by bispecific antibodies. OncoImmunol. 4(3):e994441.
   PubMed Web of Science ®Google Scholar
• Koristka S, Cartellieri M, Arndt C, Feldmann A, Töpfer K, Michalk I, Temme A, Ehninger G, Bachmann M. 2014. Cytotoxic response of human regulatory T cells upon T-cell receptor-mediated activation: a matter of purity. Blood Cancer J. 4(4):e199.
   PubMedGoogle Scholar
• Koristka S, Cartellieri M, Theil A, Feldmann A, Arndt C, Stamova S, Michalk I, Töpfer K, Temme A, Kretschmer K, et al. 2012. Retargeting of human regulatory T cells by single-chain bispecific antibodies. J Immunol. 188(3):1551–58.
   PubMed Web of Science ®Google Scholar
• Krupka C, Kufer P, Kischel R, Zugmaier G, Lichtenegger FS, Köhnke T, Vick B, Jeremias I, Metzeler KH, Altmann T, et al. 2016. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia. 30(2):484–91.
   PubMed Web of Science ®Google Scholar
• Ku G, Bendell JC, Tolcher AW, Hurvitz SA, Krishnamurthy A, El-Khoueiry AB, Patnaik A, Shroff RT, Noonan A, Hahn NM, et al. 2020. 525O a phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies. Ann Oncol. 31:31S462–SS63.
   Web of Science ®Google Scholar
• Lakhani N, Johnson M, Groisberg R, Han H, Casey K, Li S, Skokos D, Seebach F, Lowy I, Fury M, et al. 2021. 535 a phase I/II study of REGN7075 (EGFRxCD28 costimulatory bispecific antibody) in combination with cemiplimab (anti–pd-1) in patients with advanced solid tumors. J ImmunoTher Cancer. 9(Suppl 2): A565-A65. doi:10.1136/jitc-2021-SITC2021.535.
   Google Scholar
• Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM, Bouffard AA, Scarfó I, Leick MB, Grauwet K, Berger TR, et al. 2022. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nat. 604(7906):563–70.
   Google Scholar
• Laszlo GS, Gudgeon CJ, Harrington KH, Walter RB. 2015. T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330. Blood Cancer J. 5(8):e340.
   PubMed Web of Science ®Google Scholar
• Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, et al. 2015. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. The Lancet. 385(9967):517–28.
   PubMed Web of Science ®Google Scholar
• Lee SJ, Rossi RJ, Lee SK, Croft M, Kwon BS, Mittler RS, Vella AT. 2007. CD134 costimulation couples the CD137 pathway to induce production of supereffector CD8 T cells that become IL-7 dependent. J Immunol. 179(4):2203–14.
   PubMed Web of Science ®Google Scholar
• Lee DW, Stetler-Stevenson M, Yuan CM, Shah NN, Delbrook C, Yates B, Zhang H, Zhang L, Kochenderfer JN, Rosenberg SA, et al. 2016. Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation. Blood. 128(22): 218-18. doi:10.1182/blood.V128.22.218.218.
   Google Scholar
• Lesokhin AM, Arnulf B, Niesvizky R, Mohty M, Bahlis NJ, Tomasson MH, Rodríguez-Otero P, Quach H, Raje NS, Iida S, et al. 2022. Initial safety results for MagnetisMM-3: a phase 2 trial of elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM). J Clin Oncol. 40(16_suppl): 8006-06.
   Web of Science ®Google Scholar
• Limagne E, Nuttin L, Thibaudin M, Jacquin E, Aucagne R, Bon M, Revy S, Barnestein R, Ballot E, Truntzer C, et al. 2022. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells. Cancer Cell. 40(2):136–52.e12.
   PubMed Web of Science ®Google Scholar
• Linke R, Klein A, Seimetz D. 2010. Catumaxomab: clinical development and future directions. MAbs. 2(2):129–36.
   PubMed Web of Science ®Google Scholar
• Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C. 2007. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood. 110(9):3192–201.
   PubMed Web of Science ®Google Scholar
• Li J, Ybarra R, Mak J, Herault A, De Almeida P, Arrazate A, Ziai J, Totpal K, Junttila MR, Walsh KB, et al. 2018. IFNγ-induced chemokines are required for CXCR3-mediated T-cell recruitment and antitumor efficacy of anti-HER2/CD3 bispecific antibody. Clin Cancer Res. 24(24):6447–58.
   PubMed Web of Science ®Google Scholar
• Locatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, Bourquin JP, Handgretinger R, Brethon B, Rossig C, et al. 2020. Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, an expanded access study. Blood Cancer J. 10(7):77.
   PubMed Web of Science ®Google Scholar
• Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, Ghobadi A, Budde LE, Bot A, Rossi JM, et al. 2017. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 25(1):285–95.
   PubMed Web of Science ®Google Scholar
• Löffler A, Gruen M, Wuchter C, Schriever F, Kufer P, Dreier T, Hanakam F, Baeuerle PA, Bommert K, Karawajew L, et al. 2003. Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Leukemia. 17(5):900–09.
   PubMed Web of Science ®Google Scholar
• London CA, Lodge MP, Abbas AK. 2000. Functional responses and costimulator dependence of memory CD4+ T cells. J Immunol. 164(1):265–72.
   PubMed Web of Science ®Google Scholar
• Lopez J, Shinde R, Burgess MA, Sato T, Thistlethwaite F, Van Tine B, Rodon JA, Dukes J, Easton R, Marshall S. 2019. 1309tip - trial in progress: first-in-human study of a novel anti-NY-ESO-1–anti-CD3, TCR-based bispecific (IMCnyeso) as monotherapy in NY-ESO-1/LAGE-1A-positive advanced solid tumours (IMCnyeso-101). Ann Oncol. 30:30v532.
   Web of Science ®Google Scholar
• Luke JJ, Zha Y, Matijevich K, Gajewski TF. 2016. Single dose denileukin diftitox does not enhance vaccine-induced T cell responses or effectively deplete tregs in advanced melanoma: immune monitoring and clinical results of a randomized phase II trial. J Immunother Cancer. 435(4). doi:10.1186/s40425-016-0140-2
   Google Scholar
• Lum LG, Al-Kadhimi Z, Deol A, Kondadasula V, Schalk D, Tomashewski E, Steele P, Fields K, Giroux M, Liu Q, et al. 2021. Phase II clinical trial using anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) consolidation therapy for HER2 negative (0–2+) metastatic breast cancer. J ImmunoTher Cancer. 9(6):e002194.
   PubMed Web of Science ®Google Scholar
• Lum LG, Thakur A, Choi M, Deol A, Kondadasula V, Schalk D, Fields K, Dufrense M, Philip P, Dyson G, et al. 2020. Clinical and immune responses to anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) in pancreatic cancer patients. Oncoimmunol. 9(1):1773201.
   PubMed Web of Science ®Google Scholar
• Mahalingam D, Wang JS, Hamilton EP, Sarantopoulos J, Nemunaitis J, Weems G, Carter L, Hu X, Schreeder M, Wilkins HJ. 2019. Phase 1 open-label, multicenter study of first-in-class RORγ agonist LYC-55716 (cintirorgon): safety, tolerability, and preliminary evidence of antitumor activity. Clin Cancer Res. 25(12):3508–16.
   PubMed Web of Science ®Google Scholar
• Majzner RG, Frank MJ, Mount C, Tousley A, Kurtz DM, Sworder B, Murphy KA, Manousopoulou A, Kohler K, Rotiroti MC, et al. 2020. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Blood. 136(Supplement 1):53–54.
   Google Scholar
• Ma J, Mo Y, Tang M, Shen J, Qi Y, Zhao W, Huang Y, Xu Y, Qian C. 2021. Bispecific antibodies: from research to clinical application. Front Immunol. 12.
   Web of Science ®Google Scholar
• Mandikian D, Takahashi N, Lo AA, Li J, Eastham-Anderson J, Slaga D, Ho J, Hristopoulos M, Clark R, Totpal K, et al. 2018. Relative target affinities of T-cell–dependent bispecific antibodies determine biodistribution in a solid tumor mouse model. Mol Cancer Ther. 17(4):776–85.
   PubMed Web of Science ®Google Scholar
• Marcinek A, Brauchle B, Hänel G, Lacher SM, Zieger N, Kischel R, von Bergwelt M, Spiekermann K, Theurich S, James JR, et al. 2021. CD33 BiTE ® construct mediated immunological synapse formation and downstream signaling in T cells is dependent on expression of costimulatory molecules on target cells. Blood. 138:1382237.
   Web of Science ®Google Scholar
• Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C, et al. 2017. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia Chromosome–Positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol. 35(16):1795–802.
   PubMed Web of Science ®Google Scholar
• Mathur D, Root AR, Bugaj-Gaweda B, Bisulco S, Tan X, Fang W, Kearney JC, Lucas J, Guffroy M, Golas J, et al. 2020. A novel GUCY2C-CD3 T-cell engaging bispecific construct (PF-07062119) for the treatment of gastrointestinal cancers. Clin Cancer Res. 26(9):2188–202.
   PubMed Web of Science ®Google Scholar
• Meermeier EW, Welsh SJ, Sharik ME, Du MT, Garbitt VM, Riggs DL, Shi C-X, Stein CK, Bergsagel M, Chau B, et al. 2021. Tumor burden limits bispecific antibody efficacy through T-cell exhaustion averted by concurrent cytotoxic therapy. Blood Cancer Discovery. 2(4):354–69.
   PubMedGoogle Scholar
• Mejstríková E, Hrusak O, Borowitz MJ, Whitlock JA, Brethon B, Trippett TM, Zugmaier G, Gore L, von Stackelberg A, Locatelli F. 2017. CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J. 7(12):659.
   PubMed Web of Science ®Google Scholar
• Mescher MF, Popescu FE, Gerner M, Hammerbeck CD, Curtsinger JM. 2007. Activation-induced non-responsiveness (anergy) limits CD8 T cell responses to tumors. Semin Cancer Biol. 17(4):299–308.
   PubMed Web of Science ®Google Scholar
• Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, Steven NM, Evans TRJ, Anthoney A, Shoushtari AN, Hamid O, et al. 2020. Tebentafusp, a TCR/Anti-CD3 bispecific fusion protein targeting gp100, potently activated antitumor immune responses in patients with metastatic melanoma. Clin Cancer Res. 26(22):5869–78.
   PubMed Web of Science ®Google Scholar
• Mikhailova E, Gluhanyuk E, Illarionova O, Zerkalenkova E, Kashpor S, Miakova N, Diakonova Y, Olshanskaya Y, Shelikhova L, Novichkova G, et al. 2021. Immunophenotypic changes of leukemic blasts in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia, who have been treated with blinatumomab. Haematologica. 106(7):2009–12.
   PubMed Web of Science ®Google Scholar
• Miller CL, Sagiv-Barfi I, Neuhöfer P, Czerwinski DK, Artandi SE, Bertozzi CR, Levy R, Cochran JR. 2022. Systemic delivery of a targeted synthetic immunostimulant transforms the immune landscape for effective tumor regression. Cell Chem Biol. 29(3):451–62.e8.
   PubMed Web of Science ®Google Scholar
• Minnema MC, Krishnan AY, Berdeja JG, Rocafiguera AO, Donk N, Rodríguez-Otero P, Morillo D, Mateos M-V, Costa LJ, Caers J, et al. 2022. Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): updated results from MonumenTAL-1. J Clin Oncol. 40(16_suppl): 8015-15. doi:10.1200/JCO.2022.40.16_suppl.8015.
   PubMed Web of Science ®Google Scholar
• Mittrücker HW, Kursar M, Köhler A, Hurwitz R, Kaufmann SH. 2001. Role of CD28 for the generation and expansion of antigen-specific CD8(+) T lymphocytes during infection with listeria monocytogenes. J Immunol. 167(10):5620–27.
   PubMed Web of Science ®Google Scholar
• Moek KL, Fiedler WM, von Einem JC, Verheul HM, Seufferlein T, de Groot DJ, Heinemann V, Kebenko M, Menke-van der Houven van Oordt CW, Ettrich TJ, et al. 2018. Phase I study of AMG 211/MEDI-565 administered as continuous intravenous infusion (cIV) for relapsed/refractory gastrointestinal (GI) adenocarcinoma. Ann Oncol. 29(Supp 8):viii29139–40.
   Web of Science ®Google Scholar
• Mølhøj M, Crommer S, Brischwein K, Rau D, Sriskandarajah M, Hoffmann P, Kufer P, Hofmeister R, Baeuerle PA. 2007. CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis. Mol Immunol. 44(8):1935–43.
   PubMed Web of Science ®Google Scholar
• Moore GL, Zeng V, Diaz J, Bonzon C, Avery KN, Love R, Dragovich M, Rashid R, Hackett M, Leung IW, et al. 2021. Abstract 1880: pDL1-targeted CD28 costimulatory bispecific antibodies enhance T cell activation in solid tumors. Cancer Res. 81(13_Supplement): 1880-80. doi:10.1158/1538-7445.AM2021-1880.
   Web of Science ®Google Scholar
• Moreau JM, Velegraki M, Bolyard C, Rosenblum MD, Li Z. 2022. Transforming growth factor–β1 in regulatory T cell biology. Sci Immunol. 7(69):eabi4613.
   PubMed Web of Science ®Google Scholar
• Muik A, Garralda E, Altintas I, Gieseke F, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso PM, Alonso G, et al. 2022. Preclinical characterization and phase I trial results of a bispecific antibody targeting PD-L1 and 4-1BB (GEN1046) in patients with advanced refractory solid tumors. Cancer Discov. 12(5):1248–65.
   PubMed Web of Science ®Google Scholar
• Mulligan AM, Raitman I, Feeley L, Pinnaduwage D, Nguyen LT, O’Malley FP, Ohashi PS, Andrulis IL. 2013. Tumoral lymphocytic infiltration and expression of the chemokine CXCL10 in breast cancers from the ontario familial breast cancer registry. Clin Cancer Res. 19(2):336–46.
   PubMed Web of Science ®Google Scholar
• Nägele V, Zugmaier G, Goebeler ME, Viardot A, Bargou R, Kufer P, Klinger M. 2021. Relationship of T- and B-cell kinetics to clinical response in patients with relapsed/refractory non-hodgkin lymphoma treated with blinatumomab. Exp Hematol. 100:32–36.
   PubMed Web of Science ®Google Scholar
• Nagorsen D, Bargou R, Rüttinger D, Kufer P, Baeuerle PA, Zugmaier G. 2009. Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab. Leukemia Lymphoma. 50(6):886–91.
   PubMed Web of Science ®Google Scholar
• Nakamura R, Lear S, Wilson D, Koeppen H, Vaze A, Trudel S, Spencer A, Harrison SJ, Cohen AD, Fine BM, et al. 2020. Early pharmacodynamic changes in T-cell activation, proliferation, and cytokine production confirm the mode of action of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in patients with relapsed/refractory multiple myeloma. Blood. 136(Supplement 1):14–15.
   Google Scholar
• Nathan P, Hassel JC, Rutkowski P, Baurain JF, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R, Kirkwood JM, et al. 2021. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 385(13):1196–206.
   PubMed Web of Science ®Google Scholar
• Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, et al. 2017. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 377(26):2531–2544.
   PubMed Web of Science ®Google Scholar
• Ni X, Jorgensen JL, Goswami M, Challagundla P, Decker WK, Kim YH, Duvic MA. 2015. Reduction of regulatory T cells by mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and sézary syndrome. Clin Cancer Res. 21(2):274–85.
   PubMed Web of Science ®Google Scholar
• Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja M-K, Yu XZ, Dong C. 2006. T-cell tolerance or function is determined by combinatorial costimulatory signals. Embo J. 25(11):2623–33.
   PubMed Web of Science ®Google Scholar
• Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA. 2006. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol. 43(6):763–71.
   PubMed Web of Science ®Google Scholar
• Osada T, Patel SP, Hammond SA, Osada K, Morse MA, Lyerly HK. 2015. CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1. Cancer Immunol, Immunother. 64(6):677–88.
   PubMed Web of Science ®Google Scholar
• Ouyang J, Juszczynski P, Rodig SJ, Green MR, O’Donnell E, Currie T, Armant M, Takeyama K, Monti S, Rabinovich GA, et al. 2011. Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders. Blood. 117(16):4315–22.
   PubMed Web of Science ®Google Scholar
• Owonikoko TK, Champiat S, Johnson ML, Govindan R, Izumi H, Lai WVV, Borghaei H, Boyer MJ, Boosman RJ, Hummel HD, et al. 2021. Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immuno-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC). J Clin Oncol. 39(15_suppl): 8510-10. doi:10.1200/JCO.2021.39.15_suppl.8510.
   PubMed Web of Science ®Google Scholar
• Park JA, Wang L, Cheung NK. 2021. Modulating tumor infiltrating myeloid cells to enhance bispecific antibody-driven T cell infiltration and anti-tumor response. J Hematol Oncol. 14(1):142.
   PubMed Web of Science ®Google Scholar
• Patel K, Michot JM, Chanan-Khan A, Ghesquieres H, Bouabdallah K, Byrd JC, Cartron G, Portell CA, Solh M, Tilly H, et al. 2021. Safety and anti-tumor activity of plamotamab (XmAb13676), an anti-CD20 x Anti-CD3 bispecific antibody, in subjects with relapsed/refractory non-hodgkin’s lymphoma. Blood. 138(Supp 1):2494.
   Google Scholar
• Pérez Sáez JM, Hockl PF, Cagnoni AJ, Méndez Huergo SP, García PA, Gatto SG, Cerliani JP, Croci DO, Rabinovich GA. 2021. Characterization of a neutralizing anti-human galectin-1 monoclonal antibody with angioregulatory and immunomodulatory activities. Angiogenesis. 24(1):1–5.
   PubMed Web of Science ®Google Scholar
• Phillips TJ, Olszewski AJ, Munoz J, Kim TM, Yoon DH, Greil R, Westin J, Jaeger U, Canales M, Chen C, et al. 2020. Mosunetuzumab, a novel CD20/CD3 bispecific antibody, in combination with CHOP confers high response rates in patients with diffuse large B-cell lymphoma. Blood. 136(Supplement 1):13637–38.
   Google Scholar
• Qui HZ, Hagymasi AT, Bandyopadhyay S, St Rose MC, Ramanarasimhaiah R, Ménoret A, Mittler RS, Gordon SM, Reiner SL, Vella AT, et al. 2011. CD134 plus CD137 dual costimulation induces Eomesodermin in CD4 T cells to program cytotoxic Th1 differentiation. J Immunol. 187(7):3555–64.
   PubMed Web of Science ®Google Scholar
• Raab-Westphal S, Marshall JF, Goodman SL. 2017. Integrins as therapeutic targets: successes and cancers. Cancers (Basel). 9(9):110.
   PubMed Web of Science ®Google Scholar
• Rabinovich GA, Conejo-García JR. 2016. Shaping the immune landscape in cancer by galectin-driven regulatory pathways. J Mol Biol. 428(16):3266–81.
   PubMed Web of Science ®Google Scholar
• Ravandi F, Bashey A, Stock W, Foran JM, Mawad R, Egan D, Blum W, Yang A, Pastore A, Johnson C, et al. 2020a. Complete responses in relapsed/refractory acute myeloid leukemia (AML) patients on a weekly dosing schedule of vibecotamab (XmAb14045), a CD123 x CD3 T cell-engaging bispecific antibody; initial results of a phase 1 study. Blood. 136(Supp 1):4-5.
   PubMedGoogle Scholar
• Ravandi F, Walter RB, Subklewe M, Buecklein V, Jongen-Lavrencic M, Paschka P, Ossenkoppele GJ, Kantarjian HM, Hindoyan A, Agarwal SK, et al. 2020b. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML). J Clin Oncol. 38(15_suppl): 7508-08. doi:10.1200/JCO.2020.38.15_suppl.7508.
   Web of Science ®Google Scholar
• Reschke R, Yu J, Flood BA, Higgs EF, Hatogai K, Gajewski TF. 2021. Immune cell and tumor cell-derived CXCL10 is indicative of immunotherapy response in metastatic melanoma. J ImmunoTher Cancer. 9(9):e003521.
   PubMed Web of Science ®Google Scholar
• Revenko A, Carnevalli LS, Sinclair C, Johnson B, Peter A, Taylor M, Hettrick L, Chapman M, Klein S, Solanki A, et al. 2022. Direct targeting of FOXP3 in tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer. J Immunother Cancer. 10(4):e003892.
   PubMed Web of Science ®Google Scholar
• Rogala B, Freyer CW, Ontiveros EP, Griffiths EA, Wang ES, Wetzler M. 2015. Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies. Expert Opin Biol Ther. 15(6):895–908.
   PubMed Web of Science ®Google Scholar
• Sam J, Colombetti S, Fauti T, Roller A, Biehl M, Fahrni L, Nicolini V, Perro M, Nayak T, Bommer E, et al. 2020. Combination of T-cell bispecific antibodies with PD-L1 checkpoint inhibition elicits superior anti-tumor activity. Front Oncol. 10. doi:10.3389/fonc.2020.575737
   PubMed Web of Science ®Google Scholar
• Samur MK, Fulciniti M, Aktas-Samur A, Bazarbachi AH, Tai YT, Campbell TB, Petrocca F, Hege K, Kaiser S, Anderson K, et al. 2020. Biallelic loss of BCMA triggers resistance to anti-BCMA CAR T Cell therapy in multiple myeloma. Blood. 136(Supp 1):14.
   Web of Science ®Google Scholar
• Satoh K, Kobayashi Y, Fujimaki K, Hayashi S, Ishida S, Sugiyama D, Sato T, Lim K, Miyamoto M, Kozuma S, et al. 2021. Novel anti-GARP antibody DS-1055a augments anti-tumor immunity by depleting highly suppressive GARP+ regulatory T cells. Int Immunol. 33(8):435–46.
   PubMed Web of Science ®Google Scholar
• Schau I, Michen S, Hagstotz A, Janke A, Schackert G, Appelhans D, Temme A. 2019. Targeted delivery of TLR3 agonist to tumor cells with single chain antibody fragment-conjugated nanoparticles induces type I-interferon response and apoptosis. Sci Rep. 9(1):3299.
   PubMed Web of Science ®Google Scholar
• Schuster SJ, Svoboda J, Dwivedy Nasta S, Porter DL, Chong EA, Landsburg DJ, Mato AR, Lacey SF, Melenhorst JJ, Chew A, et al. 2015. Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood. 126(23): 183-83. doi:10.1182/blood.V126.23.183.183.
   Web of Science ®Google Scholar
• Shahinian A, Pfeffer K, Lee KP, Kündig TM, Kishihara K, Wakeham A, Kawai K, Ohashi PS, Thompson CB, Mak TW. 1993. Differential T cell costimulatory requirements in CD28-deficient mice. Sci. 261(5121):609–12.
   PubMed Web of Science ®Google Scholar
• Shen Y, Eng JS, Fajardo F, Liang L, Li C, Collins P, Tedesco D, Nolan-Stevaux O. 2022. Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway. J ImmunoTher Cancer. 10(3):e004348.
   PubMed Web of Science ®Google Scholar
• Shen J, Lu L, Li LF, Wu WKK, Li ZJ, Cho CH. 2015. Targeted delivery of TNF-alpha and IFN-gamma by tumor targeting peptide inhibited orthotopic colorectal cancer growth. The FASEB J. 29(S1):945.2.
   Google Scholar
• Short NJ, Kantarjian H, Konopleva M, Desikan SPP, Jain N, Ravandi F, Huang X, Wierda WG, Borthakur G, Sasaki K, et al. 2021. Updated results of a phase II study of ponatinib and blinatumomab for patients with Philadelphia Chromosome-positive acute lymphoblastic leukemia. Blood. 138(Supplement 1): 2298-98.
   Google Scholar
• Short NJ, Kantarjian HM, Ravandi F, Huang X, Ferrajoli A, Kadia TM, Thompson PA, Alvarado Y, Jain N, Yilmaz M, et al. 2020. Hyper-CVAD and sequential blinatumomab in adults with newly diagnosed Philadelphia Chromosome-negative B-cell acute lymphoblastic leukemia: results from a phase II study. Blood. 136(Supp 1):9-11.
   Google Scholar
• Skokos D, Waite JC, Haber L, Crawford A, Hermann A, Ullman E, Slim R, Godin S, Ajithdoss D, Ye X, et al. 2020. A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies. Sci Transl Med. 12(525):eaaw7888.
   PubMed Web of Science ®Google Scholar
• Smits NC, Sentman CL. 2016. Bispecific T-cell engagers (BiTes) as treatment of B-cell lymphoma. J Clin Oncol. 34(10):1131–33.
   PubMed Web of Science ®Google Scholar
• Staufer O, Leithner A, Zhou S, Crames M, Comeau S, Young D, Low S, Jenkins E, Davis SJ, Nixon A, et al. 2022. Segmental flexibility of bispecific T-cell engagers regulates the dynamics of immune synapse formation. bioRxiv. 2022.06.15.496334.
   Google Scholar
• Stein AS, Kantarjian H, Gökbuget N, Bargou R, Litzow MR, Rambaldi A, Ribera JM, Zhang A, Zimmerman Z, Zugmaier G, et al. 2019. Blinatumomab for acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 25(8):1498–504.
   PubMed Web of Science ®Google Scholar
• Subudhi SK, Siddiqui BA, Maly JJ, Nandagopal L, Lam ET, Whang YE, Minocha M, Gupta V, Penny X, Cooner F, et al. 2021. Safety and efficacy of AMG 160, a half-life extended BiTE immune therapy targeting prostate-specific membrane antigen (PSMA), and other therapies for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 39(15_suppl): TPS5088-TPS88.
   Google Scholar
• Sundblad V, Morosi LG, Geffner JR, Rabinovich GA. 2017. Galectin-1: a jack-of-all-trades in the resolution of acute and chronic inflammation. J Immunol. 199(11):3721–30.
   PubMed Web of Science ®Google Scholar
• Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. 2006. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 355(10):1018–28.
   PubMed Web of Science ®Google Scholar
• Suresh M, Whitmire JK, Harrington LE, Larsen CP, Pearson TC, Altman JD, Ahmed R. 2001a. Role of CD28-B7 interactions in generation and maintenance of CD8 T cell memory. J Immunol. 167(10):5565–73.
   PubMed Web of Science ®Google Scholar
• Suresh M, Whitmire JK, Harrington LE, Larsen CP, Pearson TC, Altman JD, Ahmed R. 2001b. Role of CD28-B7 interactions in generation and maintenance of CD8 T cell memory. J Immunol. 167(10):5565–73.
   PubMed Web of Science ®Google Scholar
• Suyama T, Furuya M, Nishiyama M, Kasuya Y, Kimura S, Ichikawa T, Ueda T, Nikaido T, Ito H, Ishikura H. 2005. Up-regulation of the interferon γ (IFN-γ)-inducible chemokines IFN-inducible T-cell α chemoattractant and monokine induced by IFN-γ and of their receptor CXC receptor 3 in human renal cell carcinoma. Cancer. 103(2):258–67.
   PubMed Web of Science ®Google Scholar
• Tabernero J, Melero I, Ros W, Argiles G, Marabelle A, Rodriguez-Ruiz ME, Albanell J, Calvo E, Moreno V, Cleary JM, et al. 2017. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 35(15_suppl): 3002-02. doi:10.1200/JCO.2017.35.15_suppl.3002.
   PubMedGoogle Scholar
• Tang K, Wu YH, Song Y, Yu B. 2021. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. J Hematol Oncol. 14(1):68.
   PubMed Web of Science ®Google Scholar
• Thakur A, Schalk D, Sarkar SH, Al-Khadimi Z, Sarkar FH, Lum LG. 2012. A Th1 cytokine–enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells. Cancer Immunol Immunother. 61(4):497–509.
   PubMed Web of Science ®Google Scholar
• Tham EL, Shrikant P, Mescher MF. 2002. Activation-induced nonresponsiveness: a Th-dependent regulatory checkpoint in the CTL response. J Immunol. 168(3):1190–97.
   PubMed Web of Science ®Google Scholar
• Thibodeaux SR, Barnett BB, Pandeswara S, Wall SR, Hurez V, Dao V, Sun L, Daniel BJ, Brumlik MJ, Drerup J, et al. 2021. IFNα augments clinical efficacy of regulatory T-cell depletion with denileukin diftitox in ovarian cancer. Clin Cancer Res. 27(13):3661–73.
   PubMed Web of Science ®Google Scholar
• Topp MS, Duell J, Zugmaier G, Attal M, Moreau P, Langer C, Krönke J, Facon T, Salnikov AV, Lesley R, et al. 2020. Anti–b-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma. J Clin Oncol. 38(8):775–83.
   PubMed Web of Science ®Google Scholar
• Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, et al. 2015. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 16(1):57–66.
   PubMed Web of Science ®Google Scholar
• Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, et al. 2012. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 120(26):5185–87.
   PubMed Web of Science ®Google Scholar
• Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, et al. 2014. Phase II trial of the anti-CD19 bispecific T cell–engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 32(36):4134–40.
   PubMed Web of Science ®Google Scholar
• Trinklein ND, Pham D, Schellenberger U, Buelow B, Boudreau A, Choudhry P, Clarke SC, Dang K, Harris KE, Iyer S, et al. 2019. Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies. MAbs. 11(4):639–52.
   PubMed Web of Science ®Google Scholar
• Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, et al. 2016a. CD19 CAR–T cells of defined CD4+:cD8+ composition in adult B cell ALL patients. J Clin Invest. 126(6):2123–38.
   PubMed Web of Science ®Google Scholar
• Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, Hawkins R, Chaney C, Cherian S, Chen X, et al. 2016b. Immunotherapy of non-hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells. Sci Transl Med. 8(355): 355ra116-355ra116. doi:10.1126/scitranslmed.aaf8621.
   PubMed Web of Science ®Google Scholar
• Uckun FM, Watts J, Mims AS, Patel P, Wang E, Shami PJ, Cull E, Lee C, Cogle CR, Lin TL. 2021. Risk, characteristics and biomarkers of cytokine release syndrome in patients with relapsed/refractory AML or MDS treated with CD3xCD123 bispecific antibody APVO436. Cancers (Basel). 13(21):5287.
   PubMed Web of Science ®Google Scholar
• Ueda T, Fukushima K, Kusakabe S, Yoshida K, Suga M, Nakai R, Koike M, Hino A, Akuta K, Toda J, et al. 2022. Inotuzumab ozogamicin and blinatumomab sequential therapy for relapsed/refractory Philadelphia Chromosome-positive acute lymphoblastic leukemia. Leukemia Res Rep. 17:100294.
   PubMedGoogle Scholar
• Usmani SZ, Garfall AL, van de Donk NWCJ, Nahi H, San-Miguel JF, Oriol A, Rosinol L, Chari A, Bhutani M, Karlin L, et al. 2021. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. The Lancet. 398(10301):665–74.
   PubMed Web of Science ®Google Scholar
• Uy GL, Aldoss I, Foster MC, Sayre PH, Wieduwilt MJ, Advani AS, Godwin JE, Arellano ML, Sweet KL, Emadi A, et al. 2021. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 137(6):751–62.
   PubMed Web of Science ®Google Scholar
• Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H, Sullivan AH, Viboch EJ, Patel T, Ibrahimova N, et al. 2020a. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Transl Med. 12(546):eaaz0463.
   PubMed Web of Science ®Google Scholar
• Vadakekolathu J, Yau TO, Church SE, Rettig MP, Aldoss I, Uy GL, Vey N, Emadi A, Sayre PH, Walter RB, et al. 2020b. Immune senescence and exhaustion correlate with response to flotetuzumab, an investigational CD123×CD3 bispecific dart® molecule, in acute myeloid leukemia. Blood. 136(Supp 1):26-28.
   Web of Science ®Google Scholar
• Vafa O, Trinklein ND. 2020. Perspective: designing T-cell engagers with better therapeutic windows. Front Oncol. 10:446.
   PubMed Web of Science ®Google Scholar
• van Beijnum JR, Thijssen VL, Läppchen T, Wong TJ, Verel I, Engbersen M, Schulkens IA, Rossin R, Grüll H, Griffioen AW, et al. 2016. A key role for galectin-1 in sprouting angiogenesis revealed by novel rationally designed antibodies. Int J Cancer. 139(4):824–35.
   PubMed Web of Science ®Google Scholar
• Velas L, Brameshuber M, Huppa JB, Kurz E, Dustin ML, Zelger P, Jesacher A, Schütz GJ. 2021. Three-dimensional single molecule localization microscopy reveals the topography of the immunological synapse at isotropic precision below 15 nm. Nano Lett. 21(21):9247–55.
   PubMed Web of Science ®Google Scholar
• Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, Libicher M, Sayehli C, Stieglmaier J, et al. 2016. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 127(11):1410–16.
   PubMed Web of Science ®Google Scholar
• Viardot A, Hess G, Bargou RC, Morley NJ, Gritti G, Goebeler ME, Iskander K, Cohan D, Zhang A, Franklin J, et al. 2020. Durability of complete response after blinatumomab therapy for relapsed/refractory diffuse large B-cell lymphoma. Leukemia Lymphoma. 61(11):2767–70.
   PubMed Web of Science ®Google Scholar
• von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O’Brien MM, Brethon B, Bhojwani D, et al. 2016. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 34(36):4381–89.
   PubMed Web of Science ®Google Scholar
• Waite JC, Wang B, Haber L, Hermann A, Ullman E, Ye X, Dudgeon D, Slim R, Ajithdoss DK, Godin SJ, et al. 2020. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med. 12(549):eaba2325.
   PubMed Web of Science ®Google Scholar
• Wang S, Chen K, Lei Q, Ma P, Yuan AQ, Zhao Y, Jiang Y, Fang H, Xing S, Fang Y, et al. 2021. The state of the art of bispecific antibodies for treating human malignancies. EMBO Mol Med. 13(9):e14291.
   PubMed Web of Science ®Google Scholar
• Wang Q, Chen Y, Park J, Liu X, Hu Y, Wang T, McFarland K, Betenbaugh MJ. 2019. Design and production of bispecific antibodies. Antibodies (Basel). 8(3):43.
   PubMedGoogle Scholar
• Wang B, Maile R, Greenwood R, Collins EJ, Frelinger JA. 2000. Naive CD8+ T cells do not require costimulation for proliferation and differentiation into cytotoxic effector cells. J Immunol. 164(3):1216–22.
   PubMed Web of Science ®Google Scholar
• Wdowiak K, Francuz T, Gallego-Colon E, Ruiz-Agamez N, Kubeczko M, Grochoła I, Wojnar J. 2018. Galectin targeted therapy in oncology: current knowledge and perspectives. Int J Mol Sci. 19(1):210.
   PubMed Web of Science ®Google Scholar
• Webster J, Luskin MR, Prince GT, DeZern AE, DeAngelo DJ, Levis MJ, Blackford A, Sharon E, Streicher H, Luznik L, et al. 2018. Blinatumomab in combination with immune checkpoint inhibitors of PD-1 and CTLA-4 in adult patients with relapsed/refractory (R/R) CD19 positive B-cell acute lymphoblastic leukemia (ALL): preliminary results of a phase I study. Blood. 132(Supplement 1): 557-57. doi:10.1182/blood-2018-99-111845.
   Google Scholar
• Wei AH, Ribera JM, Larson RA, Ritchie D, Ghobadi A, Chen Y, Anderson A, Dos Santos CE, Franklin J, Kantarjian H. 2021. Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia. Leukemia. 35(8):2220–31.
   PubMed Web of Science ®Google Scholar
• Westervelt P, Cortes JE, Altman JK, Long M, Oehler VG, Gojo I, Guenot J, Chun P, Roboz GJ. 2019. Phase 1 first-in-human trial of AMV564, a bivalent bispecific (2:2) CD33/CD3 T-cell engager, in patients with relapsed/refractory acute myeloid leukemia (AML). Blood. 134(Supplement_1):134834.
   Google Scholar
• Westervelt P, Roboz GJ, Cortes JE, Kantarjian HM, Lee S, Rettig MP, Han TH, Guenot J, Feldman EJ, DiPersio JF. 2018. Phase 1 first-in-human trial of AMV564, a bivalent bispecific (2x2) CD33/CD3 T-cell engager, in patients with relapsed/refractory acute myeloid leukemia (AML). Blood. 132(Suppl 1): 1455-55. doi: 10.1182/blood-2018-99-111529.
   Google Scholar
• Wong R, Pepper C, Brennan P, Nagorsen D, Man S, Fegan C. 2013. Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. Haematologica. 98(12):1930–38.
   PubMed Web of Science ®Google Scholar
• Wu Z, Cheung NV. 2018. T cell engaging bispecific antibody (T-BsAb): from technology to therapeutics. Pharmacol Ther. 182:182161–75.
   Web of Science ®Google Scholar
• Xia L, Tian E, Yu M, Liu C, Shen L, Huang Y, Wu Z, Tian J, Yu K, Wang Y, et al. 2022. RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers. J Exp Clin Cancer Res. 41(1):155.
   PubMed Web of Science ®Google Scholar
• Yang X, Chu Y, Wang Y, Zhang R, Xiong S. 2006. Targeted in vivo expression of IFN-gamma-inducible protein 10 induces specific antitumor activity. J Leukoc Biol. 80(6):1434–44.
   PubMed Web of Science ®Google Scholar
• Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R. 1998. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 188(12):2205–13.
   PubMed Web of Science ®Google Scholar
• Zamarin D, Hamid O, Nayak-Kapoor A, Sahebjam S, Sznol M, Collaku A, Fox FE, Marshall MA, Hong DS. 2020. Mogamulizumab in combination with durvalumab or tremelimumab in patients with advanced solid tumors: a phase I study. Clin Cancer Res. 26(17):4531–41.
   PubMed Web of Science ®Google Scholar
• Zhang P, Shi B, Gao H, Jiang H, Kong J, Yan J, Pan X, Li K, Zhang P, Yao M, et al. 2014. An EpCAM/CD3 bispecific antibody efficiently eliminates hepatocellular carcinoma cells with limited galectin-1 expression. Cancer Immunol Immunother. 63(2):121–32.
   PubMed Web of Science ®Google Scholar
• Zhang J, Stein MN, Kelly WK, Tsao CK, Falchook GS, Xu Y, Seebach FA, Lowy I, Mohan KK, Kroog G, et al. 2021. A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti–pd-1) in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 39(6_suppl): TPS174-TPS74. doi:10.1200/JCO.2021.39.6_suppl.TPS174.
   Web of Science ®Google Scholar
• Zhao Y, Aldoss I, Qu C, Crawford JC, Gu Z, Allen EK, Zamora AE, Alexander TB, Wang J, Goto H, et al. 2021b. Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL. Blood. 137(4):471–84.
   PubMed Web of Science ®Google Scholar
• Zhao Q, Jiang Y, Xiang S, Kaboli PJ, Shen J, Zhao Y, Wu X, Du F, Li M, Cho CH, et al. 2021a. Engineered TCR-T cell immunotherapy in anticancer precision medicine: pros and cons. Front Immunol. 12. doi:10.3389/fimmu.2021.658753
   Web of Science ®Google Scholar
• Zhao L, Liu Y, Zhang S, Wei L, Cheng H, Wang J, Wang J. 2022. Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer. Cell Death Dis. 13(4):378.
   PubMed Web of Science ®Google Scholar
• Zhou S, Liu M, Ren F, Meng X, Yu J. 2021. The landscape of bispecific T cell engager in cancer treatment. Biomarker Res. 9(1):38.
   PubMed Web of Science ®Google Scholar
• Zinkernagel RM. 2000. Localization dose and time of antigens determine immune reactivity. Semin Immunol 12(3):163–71. discussion 257-344.
   PubMed Web of Science ®Google Scholar
• Zonder JA, Richter J, Bumma N, Brayer J, Hoffman JE, Bensinger WI, Wu KL, Xu L, Chokshi D, Boyapati A, et al. 2021. Early, deep, and durable responses, and low rates of cytokine release syndrome with REGN5458, a BCMAxCD3 bispecific monoclonal antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 138(Supplement 1):138160. doi:10.1182/blood-2021-144921.
   Google Scholar
• Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, et al. 2015. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 126(24):2578–84.
   PubMed Web of Science ®Google Scholar