STTT Huazhong University of Science and Technology Huang Liang/Zhou Jianfeng Discovers Better Potential Treatment for TP53 Altered Aggressive B-Cell Lymphoma

Genetic alterations in iNatureTP53 lead to poor prognosis in refractory/relapsed aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL)
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On April 11, 2022, Huang Liang and Zhou Jianfeng of Huazhong University of Science and Technology jointly published a paper entitled "Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone in Signal Transduction and Targeted Therapy (IF=18)" or in combination with ASCT", which evaluated eligibility for two trials evaluating anti-CD19 and anti-CD22 embedded combined antigen receptor (CAR19/22) T-cell cocktail therapy or in combination with autologous stem cell transplantation (ASCT)
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TP53 alterations were screened in 123 enrolled patients and confirmed in 60 patients
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This study found that CAR19/22 T-cell therapy was effective in TP53-altered relapsed aggressive B-NHL
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Combining CAR-T cell administration with ASCT further improved long-term outcomes for these patients
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Patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL) in a primary refractory or relapsed state have a poor prognosis
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Salvage high-dose chemotherapy (HDT) and subsequent autologous stem cell transplantation (ASCT) are considered standard treatment options for rituximab-sensitive cases
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However, the role of ASCT in the setting of chemoresistance remains controversial, and this salvage regimen has shown no additional benefit, indicating the need for more effective treatments
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Recently, chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented responses in r/r B-NHL
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In ZUMA-1, axicabtagene ciloleucel (Axi-cel), a first-in-class CD19-targeted CAR (CAR19) T cell product, achieved in r/r aggressive B-NHL following ≥2 lines of systemic therapy An objective response rate (ORR) of 82% and a median overall survival (OS) of greater than 2 years
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After a median follow-up of 55.
1 months, the median OS time and 4-year OS rate were 25.
8 months and 44%, respectively
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Especially in high-risk cases, CAR T-cell therapy offers a potential solution
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In ZUMA-12, Axi-cel is used as first-line therapy in patients with high-risk large B-cell lymphoma (LBCL), approximately 60% of whom have double or triple hit lymphoma (DHL/THL)
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The interim analysis demonstrated that Axi-cel had significant clinical benefit in these disadvantaged patients, with high treatment response rates and a manageable safety profile
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However, in TP53-disrupted B-cell malignancies, CAR T-cell therapy has produced controversial results
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The efficacy of CAR-T cell therapy, especially CAR-T with a dual-targeting strategy, in TP53-altered r/r B-NHL cases remains unclear and requires systematic studies
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The evolutionarily conserved TP53 gene, also known as the "guardian of the genome," represents a key tumor suppressor gene that regulates cell cycle arrest, DNA repair pathways, apoptosis, senescence, and autogenesis under stressful conditions.
devour
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In humans, TP53 is the most frequently disrupted gene in malignant disease, altered in 20-25% of individuals with aggressive B-NHL
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A higher incidence of TP53 mutations may be found in r/r B-NHL
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Meanwhile, genomic instability caused by alterations in TP53 induces chemoresistance and progression of cancer
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Disruption of TP53 has been linked to lymphomagenesis and treatment resistance in multiple reports, and is increased at relapse in diffuse large B-cell lymphoma (DLBCL) and other lymphoid malignancies
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Mutation spectrum of TP53 alterations (figure from Signal Transduction and Targeted Therapy) In DLBCL, TP53 gene alterations are detected in approximately 30-50% of patients
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However, even after high-dose therapy (HDT)/ASCT, the prognosis for these patients remains unfavorable
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In the multicenter, open-label, randomized, phase 3 DLCL04 trial, HDT/ASCT was combined as first-line therapy in untreated individuals with high-risk DLBCL
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As a result, the 5-year OS rates for wild-type (TP53wt) and mutant (TP53mut) TP53 cases were 81% and 33%, respectively
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The 5-year failure-free survival (FFS) rate was 73% for TP53wt patients and 19% for TP53mut patients
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Attempts to manage these patients were futile due to the poor outcomes of TP53 alterations
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In this study, the safety and efficacy of two clinical studies examining CAR19/22 T cells alone (Trial A) or in combination with ASCT (Trial B) in B-cell malignancies were examined
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To assess the prognostic effect of TP53 gene disruption and develop therapeutic strategies for these patients, this work systematically assessed the efficacy and safety of both regimens in this patient population, increasing the sample size and follow-up time
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The study evaluated 257 patients with r/r B-NHL from September 2016 to September 2020 for eligibility in two trials evaluating anti-CD19 and anti-CD22 chimeric antigen receptor (CAR19/22) T Cell cocktail therapy or in combination with autologous stem cell transplantation (ASCT)
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TP53 alterations were screened in 123 enrolled patients and confirmed in 60 patients
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The study found that administration of CAR19/22 T cells resulted in optimal objective (ORR) and complete (CRR) response rates of 87.
1% and 45.
2%, respectively, in patients with TP53 alterations
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After a median follow-up of 16.
7 months, the median progression-free survival (PFS) was 14.
8 months, and the 24-month overall survival (OS) was estimated to be 56.
3%
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Comparable ORR, PFS, and OS were determined in individuals with or without TP53 alterations and in individuals at different risk levels stratified by TP53 altered function
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 Combining CAR19/22 T-cell therapy with ASCT improved ORR, CRR, PFS, and OS, but reduced the incidence of severe CRS in this patient population, even in individuals who exhibited stable or progressive disease prior to transplantation
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The best ORR and CRR in TP53-altered patients were 92.
9% and 82.
1%, respectively
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After a median follow-up of 21.
2 months, the 24-month PFS and OS rates in patients with TP53 alterations were estimated to be 77.
5% and 89.
3%, respectively
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In multivariate analysis, this combined strategy predicted improvement in OS
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In conclusion, CAR19/22 T-cell therapy is effective in TP53-altered relapsed aggressive B-NHL
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Combining CAR-T cell administration with ASCT further improved long-term outcomes for these patients
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Note: On March 27, 2022, Professor Zhou Jianfeng died in Wuhan at the age of 57 due to ineffective treatment
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