CD38 as a multifaceted immunotherapeutic target in CLL

References

• Malavasi F, Deaglio S, Funaro A, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88(3):841–886.
   PubMed Web of Science ®Google Scholar
• Tarrago MG, Chini CCS, Kanamori KS, et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD(+). Cell Metab. 2018;27(5):1081–1095.e10.
   PubMed Web of Science ®Google Scholar
• Chini CCS, Peclat TR, Warner GM, et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD(+) and NMN levels. Nat Metab. 2020;2(11):1284–1304.
   PubMedGoogle Scholar
• Camacho-Pereira J, Tarrago MG, Chini CCS, et al. CD38 dictates Age-Related NAD decline and mitochondrial dysfunction through an SIRT3-Dependent mechanism. Cell Metab. 2016;23(6):1127–1139.
   PubMed Web of Science ®Google Scholar
• Ceni C, Pochon N, Brun V, et al. CD38-dependent ADP-ribosyl cyclase activity in developing and adult mouse brain. Biochem J. 2003;370(Pt 1):175–183.
   PubMedGoogle Scholar
• Mizuguchi M, Otsuka N, Sato M, et al. Neuronal localization of CD38 antigen in the human brain. Brain Res. 1995;697(1-2):235–240.
   PubMed Web of Science ®Google Scholar
• Ceni C, Muller-Steffner H, Lund F, et al. Evidence for an intracellular ADP-ribosyl cyclase/NAD+-glycohydrolase in brain from CD38-deficient mice. J Biol Chem. 2003;278(42):40670–40678.
   PubMed Web of Science ®Google Scholar
• Young LJ. Regulating the social brain: a new role for CD38. Neuron. 2007;54(3):353–356.
   PubMed Web of Science ®Google Scholar
• Randall TD, Lund FE, Howard MC, et al. Expression of murine CD38 defines a population of long-term reconstituting hematopoietic stem cells. Blood. 1996;87(10):4057–4067.
   PubMed Web of Science ®Google Scholar
• Konopleva M, Rissling I, Andreeff M. Andreeff M: CD38 in hematopoietic malignancies. Chem Immunol. 2000;75:189–206.
   PubMedGoogle Scholar
• Morabito F, Mangiola M, Stelitano C, et al. Peripheral blood CD38 expression predicts time to progression in B-cell chronic lymphocytic leukemia after first-line therapy with high-dose chlorambucil. Haematologica. 2002;87(2):217–218.
   PubMed Web of Science ®Google Scholar
• Deaglio S, Capobianco A, Bergui L, et al. CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells. Blood. 2003;102(6):2146–2155.
   PubMed Web of Science ®Google Scholar
• Deaglio S, Vaisitti T, Serra S, et al. CD38 in chronic lymphocytic leukemia: from bench to bedside? Mini Rev Med Chem. 2011;11(6):503–507.
   PubMed Web of Science ®Google Scholar
• Albeniz I, Demir-Coskun O, Turker-Sener L, et al. CD38 expression as response of hematopoietic system to cancer. Oncol Lett. 2011;2(4):659–664.
   PubMed Web of Science ®Google Scholar
• Liao S, Xiao S, Zhu G, et al. CD38 is highly expressed and affects the PI3K/akt signaling pathway in cervical cancer. Oncol Rep. 2014;32(6):2703–2709.
   PubMed Web of Science ®Google Scholar
• Chmielewski JP, Bowlby SC, Wheeler FB, et al. CD38 inhibits prostate cancer metabolism and proliferation by reducing cellular NAD(+) pools. Mol Cancer Res. 2018;16(11):1687–1700.
   PubMed Web of Science ®Google Scholar
• Chen L, Diao L, Yang Y, et al. CD38-Mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov. 2018;8(9):1156–1175.
   PubMed Web of Science ®Google Scholar
• Zupo S, Isnardi L, Megna M, et al. CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis. Blood. 1996;88(4):1365–1374.
   PubMed Web of Science ®Google Scholar
• Zupo S, Massara R, Dono M, et al. Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD. Blood. 2000;95(4):1199–1206.
   PubMed Web of Science ®Google Scholar
• Morabito F, Mangiola M, Oliva B, et al. Peripheral blood CD38 expression predicts survival in B-cell chronic lymphocytic leukemia. Leuk Res. 2001;25(11):927–932.
   PubMed Web of Science ®Google Scholar
• Deaglio S, Vaisitti T, Aydin S, et al. In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia. Blood. 2006;108(4):1135–1144.
   PubMed Web of Science ®Google Scholar
• D'Arena G, Tarnani M, Rumi C, et al. Prognostic significance of combined analysis of ZAP-70 and CD38 in chronic lymphocytic leukemia. Am J Hematol. 2007;82(9):787–791.
   PubMed Web of Science ®Google Scholar
• Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840–1847.
   PubMed Web of Science ®Google Scholar
• Manna A, Aulakh S, Jani P, et al. Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2019;25(13):3974–3985.
   PubMed Web of Science ®Google Scholar
• Horenstein AL, Faini AC, Morandi F, et al. The circular life of human CD38: from basic science to clinics and back. Molecules. 2020;25(20):4844.
   Web of Science ®Google Scholar
• Malavasi F, Deaglio S, Damle R, et al. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011;118(13):3470–3478.
   PubMed Web of Science ®Google Scholar
• Chanan-Khan A, Porter CW. Immunomodulating drugs for chronic lymphocytic leukaemia. Lancet Oncol. 2006;7(6):480–488.
   PubMed Web of Science ®Google Scholar
• Chanan-Khan AA. New treatments for chronic lymphocytic leukemia. Curr Oncol Rep. 2007;9(5):353–360.
   PubMedGoogle Scholar
• Masood A, Sher T, Paulus A, et al. Targeted treatment for chronic lymphocytic leukemia. Onco Targets Ther. 2011;4:169–183.
   PubMed Web of Science ®Google Scholar
• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.
   PubMed Web of Science ®Google Scholar
• Jelinek DF, Tschumper RC, Geyer SM, et al. Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukaemia. Br J Haematol. 2001;115(4):854–861.
   PubMed Web of Science ®Google Scholar
• Durig J, Naschar M, Schmucker U, et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia. 2002;16(1):30–35.
   PubMed Web of Science ®Google Scholar
• Del Poeta G, Maurillo L, Venditti A, et al. Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood. 2001;98(9):2633–2639.
   PubMed Web of Science ®Google Scholar
• Domingo-Domenech E, Domingo-Claros A, Gonzalez-Barca E, et al. CD38 expression in B-chronic lymphocytic leukemia: association with clinical presentation and outcome in 155 patients. Haematologica. 2002;87:1021–1027.
   PubMed Web of Science ®Google Scholar
• Ibrahim S, Keating M, Do KA, et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood. 2001;98(1):181–186.
   PubMed Web of Science ®Google Scholar
• Deaglio S, Vaisitti T, Billington R, et al. CD38/CD19: a lipid raft-dependent signaling complex in human B cells. Blood. 2007;109(12):5390–5398.
   PubMed Web of Science ®Google Scholar
• Vaisitti T, Aydin S, Rossi D, et al. CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells. Leukemia. 2010;24(5):958–969.
   PubMed Web of Science ®Google Scholar
• Vaisitti T, Audrito V, Serra S, et al. NAD+-metabolizing ecto-enzymes shape tumor-host interactions: the chronic lymphocytic leukemia model. FEBS Lett. 2011;585(11):1514–1520.
   PubMed Web of Science ®Google Scholar
• Vaisitti T, Audrito V, Serra S, et al. The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting. Leukemia. 2015;29(2):356–368.
   PubMed Web of Science ®Google Scholar
• Petrucci MT, Vozella F. The anti-CD38 antibody therapy in multiple myeloma. Cells. 2019;8(12):1629.
   PubMed Web of Science ®Google Scholar
• Martin TG, Corzo K, Chiron M, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with isatuximab. Cells. 2019;8(12):1522.
   PubMed Web of Science ®Google Scholar
• Hambach J, Riecken K, Cichutek S, et al. Targeting CD38-expressing multiple myeloma and burkitt lymphoma cells in vitro with Nanobody-Based chimeric antigen receptors (Nb-CARs). Cells. 2020;9(2):321.
   Web of Science ®Google Scholar
• Chari A, Lonial S, Mark TM, et al. Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma. Cancer. 2018;124(22):4342–4349.
   PubMed Web of Science ®Google Scholar
• Abdallah N, Kumar SK. Daratumumab in untreated newly diagnosed multiple myeloma. Ther Adv Hematol. 2019;10:2040620719894871.
   Web of Science ®Google Scholar
• Weisel K, Spencer A, Lentzsch S, et al. Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hematol Oncol. 2020;13(1):115.
   PubMed Web of Science ®Google Scholar
• Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754–766.
   PubMed Web of Science ®Google Scholar
• Malavasi F, Faini AC. Mechanism of action of a new anti-CD38 antibody: enhancing myeloma immunotherapy. Clin Cancer Res. 2019;25(10):2946–2948.
   PubMed Web of Science ®Google Scholar
• Dhillon S. Isatuximab: first approval. Drugs. 2020;80(9):905–912.
   PubMed Web of Science ®Google Scholar
• Adams HC III, Stevenaert F, Krejcik J, et al. High-Parameter mass cytometry evaluation of relapsed/refractory multiple myeloma patients treated with daratumumab demonstrates immune modulation as a novel mechanism of action. Cytometry A. 2019;95(3):279–289.
   PubMed Web of Science ®Google Scholar
• Manna A, Kellett T, Aulakh S, et al. Targeting CD38 is lethal to breg-like chronic lymphocytic leukemia cells and tregs, but restores CD8+ T-cell responses. Blood Adv. 2020;4(10):2143–2157.
   PubMed Web of Science ®Google Scholar
• Paulus A, Manna A, Akhtar S, et al. Targeting CD38 with daratumumab is lethal to waldenstrom macroglobulinaemia cells. Br J Haematol. 2018;183(2):196–211.
   PubMed Web of Science ®Google Scholar
• Ferrero E, Saccucci F, Malavasi F. The making of a leukocyte receptor: origin, genes and regulation of human CD38 and related molecules. Chem Immunol. 2000;75:1–19.
   PubMedGoogle Scholar
• Ferrero E, Saccucci F, Malavasi F. The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene. Immunogenetics. 1999;49(7-8):597–604.
   PubMed Web of Science ®Google Scholar
• Ferrero E, Malavasi F. Human CD38, a leukocyte receptor and ectoenzyme, is a member of a novel eukaryotic gene family of nicotinamide adenine dinucleotide+-converting enzymes: extensive structural homology with the genes for murine bone marrow stromal cell antigen 1 and aplysian ADP-ribosyl cyclase. J Immunol. 1997;159(8):3858–3865.
   PubMed Web of Science ®Google Scholar
• Lee HC. Structure and enzymatic functions of human CD38. Mol Med. 2006;12(11-12):317–323.
   PubMed Web of Science ®Google Scholar
• Liu Q, Kriksunov IA, Graeff R, et al. Crystal structure of human CD38 extracellular domain. Structure. 2005;13(9):1331–1339.
   PubMed Web of Science ®Google Scholar
• Liu Q, Kriksunov IA, Graeff R, et al. Structural basis for formation and hydrolysis of the calcium messenger cyclic ADP-ribose by human CD38. J Biol Chem. 2007;282(8):5853–5861.
   PubMed Web of Science ®Google Scholar
• Lee HC, Aarhus R. ADP-ribosyl cyclase: an enzyme that cyclizes NAD + into a calcium-mobilizing metabolite. Cell Regul. 1991;2(3):203–209.
   PubMedGoogle Scholar
• De Flora A, Guida L, Franco L, et al. CD38 and ADP-ribosyl cyclase catalyze the synthesis of a dimeric ADP-ribose that potentiates the calcium-mobilizing activity of cyclic ADP-ribose. J Biol Chem. 1997;272(20):12945–12951.
   PubMed Web of Science ®Google Scholar
• Munshi C, Aarhus R, Graeff R, et al. Identification of the enzymatic active site of CD38 by site-directed mutagenesis. J Biol Chem. 2000;275(28):21566–21571.
   PubMed Web of Science ®Google Scholar
• Graeff R, Munshi C, Aarhus R, et al. A single residue at the active site of CD38 determines its NAD cyclizing and hydrolyzing activities. J Biol Chem. 2001;276(15):12169–12173.
   PubMed Web of Science ®Google Scholar
• Aksoy P, White TA, Thompson M, et al. Regulation of intracellular levels of NAD: a novel role for CD38. Biochem Biophys Res Commun. 2006;345(4):1386–1392.
   PubMed Web of Science ®Google Scholar
• Kellenberger E, Kuhn I, Schuber F, et al. Flavonoids as inhibitors of human CD38. Bioorg Med Chem Lett. 2011;21(13):3939–3942.
   PubMed Web of Science ®Google Scholar
• Horenstein AL, Quarona V, Toscani D, et al. Adenosine generated in the bone marrow niche through a CD38-Mediated pathway correlates with progression of human myeloma. Mol Med. 2016;22:694–704.
   PubMed Web of Science ®Google Scholar
• Morabito F, Mangiola M, Stelitano C, et al. Simultaneous expression of CD38 and its ligand CD31 by chronic lymphocytic leukemia B-cells: anecdotal observation or pathogenetic hypothesis for the clinical outcome? Haematologica. 2003;88(3):354–355.
   PubMed Web of Science ®Google Scholar
• Deaglio S, Morra M, Mallone R, et al. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J Immunol. 1998;160:395–402.
   PubMed Web of Science ®Google Scholar
• Deaglio S, Aydin S, Grand MM, et al. CD38/CD31 interactions activate genetic pathways leading to proliferation and migration in chronic lymphocytic leukemia cells. Mol Med. 2010;16(3-4):87–91.
   PubMed Web of Science ®Google Scholar
• Benkisser-Petersen M, Buchner M, Dorffel A, et al. Spleen tyrosine kinase is involved in the CD38 signal transduction pathway in chronic lymphocytic leukemia. PLoS One. 2016;11(12):e0169159.
   PubMed Web of Science ®Google Scholar
• Lund FE, Muller-Steffner HM, Yu N, et al. CD38 signaling in B lymphocytes is controlled by its ectodomain but occurs independently of enzymatically generated ADP-ribose or cyclic ADP-ribose. J Immunol. 1999;162(5):2693–2702.
   PubMed Web of Science ®Google Scholar
• Funaro A, De Monte LB, Dianzani U, et al. Human CD38 is associated to distinct molecules which mediate transmembrane signaling in different lineages. Eur J Immunol. 1993;23(10):2407–2411.
   PubMed Web of Science ®Google Scholar
• Morra M, Zubiaur M, Terhorst C, et al. CD38 is functionally dependent on the TCR/CD3 complex in human T cells. FASEB J. 1998;12(7):581–592.
   PubMed Web of Science ®Google Scholar
• Deaglio S, Zubiaur M, Gregorini A, et al. Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells. Blood. 2002;99(7):2490–2498.
   PubMed Web of Science ®Google Scholar
• Lee HT, Kim Y, Park UB, et al. Crystal structure of CD38 in complex with daratumumab, a first-in-class anti-CD38 antibody drug for treating multiple myeloma. Biochem Biophys Res Commun. 2021;536:26–31.
   PubMed Web of Science ®Google Scholar
• Ghose J, Viola D, Terrazas C, et al. Daratumumab induces CD38 internalization and impairs myeloma cell adhesion. Oncoimmunology. 2018;7(10):e1486948.
   PubMed Web of Science ®Google Scholar
• Moreno L, Perez C, Zabaleta A, et al. The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clin Cancer Res. 2019;25(10):3176–3187.
   PubMed Web of Science ®Google Scholar
• Malavasi F, Faini AC, Morandi F, et al. Molecular dynamics of targeting CD38 in multiple myeloma. Br J Haematol. 2021;193(3):581–591.
   PubMed Web of Science ®Google Scholar
• Ellis JH, Barber KA, Tutt A, et al. Engineered anti-CD38 monoclonal antibodies for immunotherapy of multiple myeloma. J Immunol. 1995;155(2):925–937.
   PubMed Web of Science ®Google Scholar
• Stevenson FK, Bell AJ, Cusack R, et al. Preliminary studies for an immunotherapeutic approach to the treatment of human myeloma using chimeric anti-CD38 antibody. Blood. 1991;77(5):1071–1079.
   PubMed Web of Science ®Google Scholar
• de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840–1848.
   PubMed Web of Science ®Google Scholar
• Zhu C, Song Z, Wang A, et al. Isatuximab acts through Fc-Dependent, independent, and direct pathways to kill multiple myeloma cells. Front Immunol. 2020;11:1771.
   PubMed Web of Science ®Google Scholar
• Matas-Cespedes A, Vidal-Crespo A, Rodriguez V, et al. The human CD38 monoclonal antibody daratumumab shows antitumor activity and hampers Leukemia-Microenvironment interactions in chronic lymphocytic leukemia. Clin Cancer Res. 2017;23(6):1493–1505.
   PubMed Web of Science ®Google Scholar
• Vidal-Crespo A, Matas-Cespedes A, Rodriguez V, et al. Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens. Haematologica. 2020;105(4):1032–1041.
   PubMed Web of Science ®Google Scholar
• Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384–394.
   PubMed Web of Science ®Google Scholar
• Casneuf T, Adams HC III, van de Donk N, et al. Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab. Leukemia. 2021;35(2):573–584.
   PubMed Web of Science ®Google Scholar
• DiLillo DJ, Weinberg JB, Yoshizaki A, et al. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. Leukemia. 2013;27(1):170–182.
   PubMed Web of Science ®Google Scholar
• Blair PA, Norena LY, Flores-Borja F, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129–140.
   PubMed Web of Science ®Google Scholar
• Alhakeem SS, McKenna MK, Oben KZ, et al. Chronic lymphocytic Leukemia-Derived IL-10 suppresses antitumor immunity. J Immunol. 2018;200(12):4180–4189.
   PubMed Web of Science ®Google Scholar
• Verma V, Shrimali RK, Ahmad S, et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance. Nat Immunol. 2019;20(9):1231–1243.
   PubMed Web of Science ®Google Scholar
• van de Donk NW, Janmaat ML, Mutis T, et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016;270(1):95–112.
   PubMed Web of Science ®Google Scholar
• Dima D, Dower J, Comenzo RL, et al. Evaluating daratumumab in the treatment of multiple myeloma: safety, efficacy and place in therapy. Cancer Manag Res. 2020;12:7891–7903.
   PubMed Web of Science ®Google Scholar
• Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34(7):1875–1884.
   PubMed Web of Science ®Google Scholar
• Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539–2549.
   PubMed Web of Science ®Google Scholar
• Solman IG, Blum LK, Hoh HY, et al. Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia. Leuk Res. 2020;97:106432.
   PubMed Web of Science ®Google Scholar
• Yin Q, Sivina M, Robins H, et al. Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia. J Immunol. 2017;198(4):1740–1747.
   PubMed Web of Science ®Google Scholar
• Patel MP, Masood A, Patel PS, et al. Targeting the bcl-2. Curr Opin Oncol. 2009;21(6):516–523.
   PubMed Web of Science ®Google Scholar
• Advani PP, Paulus A, Masood A, et al. Pharmacokinetic evaluation of oblimersen sodium for the treatment of chronic lymphocytic leukemia. Expert Opin Drug Metab Toxicol. 2011;7(6):765–774.
   PubMed Web of Science ®Google Scholar
• Soumerai JD, Ni A, Darif M, et al. Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: a retrospective, pooled cohort study with external validations. Lancet Haematol. 2019;6(7):e366–e374.
   PubMed Web of Science ®Google Scholar
• Held L, Siu C, Shadman M. Venetoclax as a therapeutic option for the treatment of chronic lymphocytic leukemia: the evidence so far. Expert Opin Pharmacother. 2021;22(6):655–665.
   PubMed Web of Science ®Google Scholar
• Bair SM, Porter DL. Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: the development and challenges of chimeric antigen receptor T-cell therapy for chronic lymphocytic leukemia. Am J Hematol. 2019;94(S1):S10–S17.
   PubMedGoogle Scholar
• Mihara K, Bhattacharyya J, Kitanaka A, et al. T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia. 2012;26(2):365–367.
   PubMed Web of Science ®Google Scholar
• Drent E, Groen RW, Noort WA, et al. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Haematologica. 2016;101(5):616–625.
   PubMed Web of Science ®Google Scholar
• Gao Z, Tong C, Wang Y, et al. Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells. J Genet Genomics. 2019;46(8):367–377.
   PubMed Web of Science ®Google Scholar
• An N, Hou YN, Zhang QX, et al. Anti-multiple myeloma activity of nanobody-Based anti-CD38 chimeric antigen receptor T cells. Mol Pharm. 2018;15(10):4577–4588.
   PubMedGoogle Scholar
• Drent E, Themeli M, Poels R, et al. A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther. 2017;25(8):1946–1958.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Lobato LG, Ganzetti M, Fernandez de Larrea C, et al. CAR T-Cells in multiple myeloma: state of the art and future directions. Front Oncol. 2020;10:1243.
   PubMed Web of Science ®Google Scholar
• Mihara K, Yoshida T, Takei Y, et al. T cells bearing anti-CD19 and/or anti-CD38 chimeric antigen receptors effectively abrogate primary double-hit lymphoma cells. J Hematol Oncol. 2017;10(1):116.
   PubMedGoogle Scholar
• Guo Y, Feng K, Tong C, et al. Efficiency and side effects of anti-CD38 CAR T cells in an adult patient with relapsed B-ALL after failure of bi-specific CD19/CD22 CAR T cell treatment. Cell Mol Immunol. 2020;17(4):430–432.
   PubMed Web of Science ®Google Scholar
• van der Schans JJ, van de Donk N, Mutis T. Dual targeting to overcome current challenges in multiple myeloma CAR T-Cell treatment. Front Oncol. 2020;10:1362.
   PubMed Web of Science ®Google Scholar
• Lejeune M, Kose MC, Duray E, et al. Bispecific, T-cell-recruiting antibodies in B-cell malignancies. Front Immunol. 2020;11:762.
   PubMed Web of Science ®Google Scholar
• Goebeler ME, Knop S, Viardot A, et al. 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. 2016;34(10):1104–1111.
   PubMed Web of Science ®Google Scholar
• Zuch de Zafra CL, Fajardo F, Zhong W, et al. Targeting multiple myeloma with AMG 424, a novel anti-CD38/CD3 bispecific T-cell-recruiting antibody optimized for cytotoxicity and cytokine release. Clin Cancer Res. 2019;25(13):3921–3933.
   PubMed Web of Science ®Google Scholar