CAR-T CELL THERAPY IN LARGE B CELL LYMPHOMA CAR-T; Large B Cell Lymphoma; Salvage Therapy,

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Ugo Testa
Dr. Germana Castelli
Giuseppe Leone
Elvira Pelosi
Dr. Germana Castelli
Prof. Hohaus


CAR-T, Large Cell B-Lymphoma, Salvage therapy


Large B-cell lymphomas (LBCLs) are among the most frequent (about 30%) non-Hodgkin’s lymphoma. Despite the aggressive behavior of these lymphomas, more than 60% of patients can be cured with first-line chemoimmunotherapy using the R-CHOP regimen. Patients with refractory or relapsing disease show a poor outcome even when treated with second-line therapies.

CD19-targeted chimeric antigen receptor (CAR) T-cells are emerging as an efficacious second-line treatment strategy for patients with LBCL.  Three CD19-CAR-T-cell products received FDA and EMA approval. The use of CAR-T cell therapy has also been explored for the treatment of high-risk LBCL patients in the first-line setting and for patients with central nervous system involvement.

Although CD19-CAR-T therapy has transformed the care of refractory/relapsed LBCL, about 60% of these patients will ultimately progress or relapse following CD19-CAR-T: therefore, it is fundamental to identify predictive criteria of response to CAR-T therapy and to develop salvage therapies for patients relapsing after CD19-CAR-T therapies. Moreover, ongoing clinical trials are evaluating bispecific CAR-T cells targeting both CD19 and CD20 or CD19 and CD22 as a tool to improve the therapeutic efficacy and to reduce the number of refractory/relapsing patients.


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Fig.1 Schematic representation of CD19-CAR constructs currently available commercially and used for the therapy of DLBCL patients. All these products have a second-generation CAR construct, consisting of an antigen-binding domain, a hinge region, a transmembrane region, a co-stimulatory domain and a T-cell activation domain.

Fig. 2: Patients DCBL Disease-free Survival and Overall Survival of the three randomized trials of 19-CAR T-cell vs. Standard Care: BELINDA, Engl J Med 2022, 386(7): 629-639; ZUMA-7, N Engl J Med 2023, 2023 Jul 13;389(2):148-157; TRANSFORM, Blood 2023; 141(14): 1675-1684. No differences in the Belinda trial; significant differences in the two other trials, mostly evident for Disease free survival.