TY - JOUR
T1 - CD19 occupancy with tafasitamab increases therapeutic index of CART19 cell therapy and diminishes severity of CRS
AU - Sakemura, R. Leo
AU - Manriquez Roman, Claudia
AU - Horvei, Paulina
AU - Siegler, Elizabeth L.
AU - Girsch, James H.
AU - Sirpilla, Olivia L.
AU - Stewart, Carli M.
AU - Yun, Kun
AU - Can, Ismail
AU - Ogbodo, Ekene J.
AU - Adada, Mohamad M.
AU - Bezerra, Evandro D.
AU - Kankeu Fonkoua, Lionel Aurelien
AU - Hefazi, Mehrdad
AU - Ruff, Michael W.
AU - Kimball, Brooke L.
AU - Mai, Long K.
AU - Huynh, Truc N.
AU - Nevala, Wendy K.
AU - Ilieva, Kristina
AU - Augsberger, Christian
AU - Patra-Kneuer, Maria
AU - Schanzer, Jürgen
AU - Endell, Jan
AU - Heitmüller, Christina
AU - Steidl, Stefan
AU - Parikh, Sameer A.
AU - Ding, Wei
AU - Kay, Neil E.
AU - Nowakowski, Grzegorz S.
AU - Kenderian, Saad S.
N1 - Publisher Copyright:
© 2024 American Society of Hematology
PY - 2024/1/18
Y1 - 2024/1/18
N2 - In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.
AB - In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.
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U2 - 10.1182/blood.2022018905
DO - 10.1182/blood.2022018905
M3 - Article
C2 - 37879074
AN - SCOPUS:85179702063
SN - 0006-4971
VL - 143
SP - 258
EP - 271
JO - Blood
JF - Blood
IS - 3
ER -