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Anti-CD19 chimeric antigen receptor T-cell (CAR-T) is the current treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, transformed follicular lymphoma (FL) , standard of care for primary mediastinal large B-cell lymphoma and mantle cell lymphoma
.
Although CAR-T cell therapy is effective in many patients, only 30%-40% of patients with DLBCL achieve long-term remission, and only 60% of patients with relapsed or refractory FL Long-term relief can be obtained
.
Therefore, there is still a need for effective treatments for lymphoma patients who have failed or relapsed after CD19 CAR-T cell therapy
.
Studies have shown that in patients who do not respond to CAR-T cell therapy, the baseline levels of immune checkpoint-related proteins (PD-L1, LAG3) in tumor and tumor microenvironment cells are higher
.
Clinically, a subset of patients with progressive lymphomas have been observed to respond to immune checkpoint blockade after CAR-T cell therapy
.
Pembrolizumab is a novel humanized monoclonal antibody that binds to programmed cell death receptor 1 (PD-1) to block the immunosuppressive response mediated by the PD-1 pathway, thereby exerting tumor immunity
.
Based on this, the researchers launched a single-center, phase 1/2a prospective study of pembrolizumab for the treatment of patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T cell therapy.
Clinical efficacy of bolizumab
.
Research methods A total of 12 patients with relapsed/refractory B-cell lymphoma who received CAR-T cell therapy between June 1, 2016 and June 4, 2018 were enrolled in this study
.
Eligible patients: RBC transfusion duration > 7 days with platelet count ≥ 50,000/µL, absolute neutrophil count ≥ 1,000/µL, and hemoglobin ≥ 8 g/dL
.
Enrolled patients received pembrolizumab 200 mg IV every 3 weeks for 1 year or until disease progression, treatment-limiting toxicity, or optional regimen discontinuation
.
Patients who achieved a CR could discontinue treatment if they had received at least 8 pembrolizumab treatments and completed at least two cycles of treatment after a documented complete response (CR)
.
Before pembrolizumab treatment, 24-72 hours after the first pembrolizumab infusion (weeks 1 to 6, collected weekly), before the start of each pembrolizumab treatment cycle, and after the end of treatment, Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients
.
The primary endpoint was safety, secondary endpoints included clinical outcomes (best overall response rate [ORR], 3-month ORR, progression-free survival [PFS], and overall survival [OS]), and studies related to T cell biology
.
Results of the study>>>>Characteristics of enrolled patients Among the enrolled patients, there were 11 patients with DLBCL and 1 patient with grade 1-2 FL.
The detailed patient characteristics are shown in Table 1
.
10 of 12 patients (83%) developed biopsy-proven lymphoma after CAR-T cell therapy, and all showed PET/CT-measurable disease and Deauville score >4 after CAR-T cell therapy
.
Nine patients (75%) showed refractory to CAR-T cell therapy, and three patients (25%) relapsed after CAR-T cell therapy
.
Table 1 Patient characteristics For all patients, the median PFS after CAR-T cell therapy was 2.
8 months (range: 0.
4-35.
2 months), and the median PFS after CAR-T cell infusion into the first pembrolizumab-treated Bit time was 3.
3 months (range: 0.
4-42.
8 months)
.
For patients refractory to CAR-T cell therapy, median PFS after CAR-T cell therapy was 2.
7 months (range: 0.
4-4.
5 months) and median time to first pembrolizumab therapy was 3.
2 months months (range: 0.
4-4.
6 months)
.
For patients who relapsed after CAR-T cell therapy, the median PFS after CAR-T cell therapy was 26.
2 months (range: 19.
0-35.
2 months) and the median time to first pembrolizumab was 27.
1 months months (range: 20.
2-42.
8 months)
.
The median number of doses of pembrolizumab treatment was 2 (range: 1-9)
.
Before pembrolizumab treatment, CD19 was detected by biopsy in 9 patients after CAR-T cell therapy, and the immunohistochemical results of 7/9 patients showed that the expression of PD-L1 reached more than 5%, see Table 2
.
Ten of the 12 patients did not receive any cortisol therapy, and none received tocilizumab at a similar time to pembrolizumab
.
There was no difference in the safety and efficacy of pembrolizumab in patients treated with murine and human CAR-T cells
.
Table 2 Tumor biopsy before and after pembrolizumab treatment >>>> Safety Pembrolizumab is generally well tolerated, and the adverse events associated with pembrolizumab during treatment are detailed Table 3
.
Neutropenia was the most common grade 3-4 adverse event (n=3, 25%), but was relieved by granulocyte-colony stimulating factor
.
Neutropenic patients experienced neutropenic relapse after pembrolizumab after neutropenic growth
.
No febrile neutropenia occurred
.
Three patients (25%) developed grade 1-2 fever after the first infusion of pembrolizumab
.
One patient experienced a grade 2 infusion-related reaction 10 minutes after the first pembrolizumab infusion and 96 days after the CAR-T cell infusion
.
The patient developed grade 2 cytokine release syndrome (CRS) 1 day after the first pembrolizumab infusion and was treated with supportive care
.
Also observed were elevated transaminases (n=2, 17%), synovitis (n=1, 8%), hematuria (n=1, 8%), pleural effusion (n=1, 8%), All were relieved after pembrolizumab treatment
.
Grade 1 fatigue was reported in 1 patient (8%)
.
Cytomegalovirus (CMV) infection (unrelated to pembrolizumab, grade 4) was found in 1 patient with grade 3 hyperbilirubinemia (possibly related to pembrolizumab), which ultimately led to treatment discontinuation
.
Table 3 Adverse events related to pembrolizumab >>>> Efficacy A total of 12 patients were evaluated for clinical response, and the best ORR after pembrolizumab treatment was 25% (1 CR, 2 partial remissions) [PR]) (Fig.
1)
.
The 3-month ORR was 25% (1 CR, 2 PR)
.
The 3-month clinical benefit rate was 33% (1 CR, 2 PR, 1 stable disease [SD])
.
FL patients do not respond to pembrolizumab
.
2 of 9 patients (22%) refractory to CAR-T cell therapy responded to pembrolizumab, and 1 of 3 patients (33%) who relapsed after CAR-T cell therapy responded to pembrolizumab Responds to benzumab
.
Eight patients had disease progression (PD) while receiving pembrolizumab
.
One patient had pseudoprogression
.
One patient had an enlarged tumor 2 months after the first dose of pembrolizumab, but biopsy showed that the tumor was mainly composed of T cells, and achieved PR after continuing treatment
.
The biopsy results of all responders showed CD3+ tumor-infiltrating lymphocytes, and the total expression of PD-L1 was between 10% and 50% (Table 2)
.
One of the four clinically benefited patients had PD-1 expression ≥5% (Table 2)
.
Figure 1 Clinical results before and after pembrolizumab treatment>>>>Effect of pembrolizumab on anti-CD19 CAR-T cells The CAR-T cells were re-expanded, and patients who achieved CR experienced multiple re-expansion of CAR-T cells
.
Among patients with clinical benefit, CAR-T cells tended to increase after pembrolizumab treatment, and the proportion of CAR-T cells in patients who did not respond to pembrolizumab treatment remained stable or decreased after pembrolizumab treatment
.
By comparing the pre- and post-treatment samples of CAR-T cell therapy responders and non-responders, it was found that after CAR-T cell therapy, patients who responded to CAR-T cell therapy had CAR-T cell therapy after pembrolizumab treatment.
Activation and proliferation of T cells increased and markers of exhaustion decreased
.
Potential differences exist between non-CAR-T cells from non-responders as well as from responders
.
Conclusions This study confirmed that pembrolizumab treatment at 0.
4 months after CAR-T cell infusion was safe and well tolerated
.
There are potential differences in cell biology between patients who respond and those who do not respond to CAR-T cell therapy, and this difference affects the clinical efficacy of PD-1 blockade
.
Reference source: Elise A.
Chong, Cécile Alanio, Jakub Svoboda, et al.
Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy.
Blood 2022; 139(7): 1026–1038.
doi : https://doi.
org/10.
1182/blood.
2021012634.
Editor: Wenting Reviewer: Quinta Typesetting: Quinta Execution: Quinta pokes "read the original text", we make progress together
.
Although CAR-T cell therapy is effective in many patients, only 30%-40% of patients with DLBCL achieve long-term remission, and only 60% of patients with relapsed or refractory FL Long-term relief can be obtained
.
Therefore, there is still a need for effective treatments for lymphoma patients who have failed or relapsed after CD19 CAR-T cell therapy
.
Studies have shown that in patients who do not respond to CAR-T cell therapy, the baseline levels of immune checkpoint-related proteins (PD-L1, LAG3) in tumor and tumor microenvironment cells are higher
.
Clinically, a subset of patients with progressive lymphomas have been observed to respond to immune checkpoint blockade after CAR-T cell therapy
.
Pembrolizumab is a novel humanized monoclonal antibody that binds to programmed cell death receptor 1 (PD-1) to block the immunosuppressive response mediated by the PD-1 pathway, thereby exerting tumor immunity
.
Based on this, the researchers launched a single-center, phase 1/2a prospective study of pembrolizumab for the treatment of patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T cell therapy.
Clinical efficacy of bolizumab
.
Research methods A total of 12 patients with relapsed/refractory B-cell lymphoma who received CAR-T cell therapy between June 1, 2016 and June 4, 2018 were enrolled in this study
.
Eligible patients: RBC transfusion duration > 7 days with platelet count ≥ 50,000/µL, absolute neutrophil count ≥ 1,000/µL, and hemoglobin ≥ 8 g/dL
.
Enrolled patients received pembrolizumab 200 mg IV every 3 weeks for 1 year or until disease progression, treatment-limiting toxicity, or optional regimen discontinuation
.
Patients who achieved a CR could discontinue treatment if they had received at least 8 pembrolizumab treatments and completed at least two cycles of treatment after a documented complete response (CR)
.
Before pembrolizumab treatment, 24-72 hours after the first pembrolizumab infusion (weeks 1 to 6, collected weekly), before the start of each pembrolizumab treatment cycle, and after the end of treatment, Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients
.
The primary endpoint was safety, secondary endpoints included clinical outcomes (best overall response rate [ORR], 3-month ORR, progression-free survival [PFS], and overall survival [OS]), and studies related to T cell biology
.
Results of the study>>>>Characteristics of enrolled patients Among the enrolled patients, there were 11 patients with DLBCL and 1 patient with grade 1-2 FL.
The detailed patient characteristics are shown in Table 1
.
10 of 12 patients (83%) developed biopsy-proven lymphoma after CAR-T cell therapy, and all showed PET/CT-measurable disease and Deauville score >4 after CAR-T cell therapy
.
Nine patients (75%) showed refractory to CAR-T cell therapy, and three patients (25%) relapsed after CAR-T cell therapy
.
Table 1 Patient characteristics For all patients, the median PFS after CAR-T cell therapy was 2.
8 months (range: 0.
4-35.
2 months), and the median PFS after CAR-T cell infusion into the first pembrolizumab-treated Bit time was 3.
3 months (range: 0.
4-42.
8 months)
.
For patients refractory to CAR-T cell therapy, median PFS after CAR-T cell therapy was 2.
7 months (range: 0.
4-4.
5 months) and median time to first pembrolizumab therapy was 3.
2 months months (range: 0.
4-4.
6 months)
.
For patients who relapsed after CAR-T cell therapy, the median PFS after CAR-T cell therapy was 26.
2 months (range: 19.
0-35.
2 months) and the median time to first pembrolizumab was 27.
1 months months (range: 20.
2-42.
8 months)
.
The median number of doses of pembrolizumab treatment was 2 (range: 1-9)
.
Before pembrolizumab treatment, CD19 was detected by biopsy in 9 patients after CAR-T cell therapy, and the immunohistochemical results of 7/9 patients showed that the expression of PD-L1 reached more than 5%, see Table 2
.
Ten of the 12 patients did not receive any cortisol therapy, and none received tocilizumab at a similar time to pembrolizumab
.
There was no difference in the safety and efficacy of pembrolizumab in patients treated with murine and human CAR-T cells
.
Table 2 Tumor biopsy before and after pembrolizumab treatment >>>> Safety Pembrolizumab is generally well tolerated, and the adverse events associated with pembrolizumab during treatment are detailed Table 3
.
Neutropenia was the most common grade 3-4 adverse event (n=3, 25%), but was relieved by granulocyte-colony stimulating factor
.
Neutropenic patients experienced neutropenic relapse after pembrolizumab after neutropenic growth
.
No febrile neutropenia occurred
.
Three patients (25%) developed grade 1-2 fever after the first infusion of pembrolizumab
.
One patient experienced a grade 2 infusion-related reaction 10 minutes after the first pembrolizumab infusion and 96 days after the CAR-T cell infusion
.
The patient developed grade 2 cytokine release syndrome (CRS) 1 day after the first pembrolizumab infusion and was treated with supportive care
.
Also observed were elevated transaminases (n=2, 17%), synovitis (n=1, 8%), hematuria (n=1, 8%), pleural effusion (n=1, 8%), All were relieved after pembrolizumab treatment
.
Grade 1 fatigue was reported in 1 patient (8%)
.
Cytomegalovirus (CMV) infection (unrelated to pembrolizumab, grade 4) was found in 1 patient with grade 3 hyperbilirubinemia (possibly related to pembrolizumab), which ultimately led to treatment discontinuation
.
Table 3 Adverse events related to pembrolizumab >>>> Efficacy A total of 12 patients were evaluated for clinical response, and the best ORR after pembrolizumab treatment was 25% (1 CR, 2 partial remissions) [PR]) (Fig.
1)
.
The 3-month ORR was 25% (1 CR, 2 PR)
.
The 3-month clinical benefit rate was 33% (1 CR, 2 PR, 1 stable disease [SD])
.
FL patients do not respond to pembrolizumab
.
2 of 9 patients (22%) refractory to CAR-T cell therapy responded to pembrolizumab, and 1 of 3 patients (33%) who relapsed after CAR-T cell therapy responded to pembrolizumab Responds to benzumab
.
Eight patients had disease progression (PD) while receiving pembrolizumab
.
One patient had pseudoprogression
.
One patient had an enlarged tumor 2 months after the first dose of pembrolizumab, but biopsy showed that the tumor was mainly composed of T cells, and achieved PR after continuing treatment
.
The biopsy results of all responders showed CD3+ tumor-infiltrating lymphocytes, and the total expression of PD-L1 was between 10% and 50% (Table 2)
.
One of the four clinically benefited patients had PD-1 expression ≥5% (Table 2)
.
Figure 1 Clinical results before and after pembrolizumab treatment>>>>Effect of pembrolizumab on anti-CD19 CAR-T cells The CAR-T cells were re-expanded, and patients who achieved CR experienced multiple re-expansion of CAR-T cells
.
Among patients with clinical benefit, CAR-T cells tended to increase after pembrolizumab treatment, and the proportion of CAR-T cells in patients who did not respond to pembrolizumab treatment remained stable or decreased after pembrolizumab treatment
.
By comparing the pre- and post-treatment samples of CAR-T cell therapy responders and non-responders, it was found that after CAR-T cell therapy, patients who responded to CAR-T cell therapy had CAR-T cell therapy after pembrolizumab treatment.
Activation and proliferation of T cells increased and markers of exhaustion decreased
.
Potential differences exist between non-CAR-T cells from non-responders as well as from responders
.
Conclusions This study confirmed that pembrolizumab treatment at 0.
4 months after CAR-T cell infusion was safe and well tolerated
.
There are potential differences in cell biology between patients who respond and those who do not respond to CAR-T cell therapy, and this difference affects the clinical efficacy of PD-1 blockade
.
Reference source: Elise A.
Chong, Cécile Alanio, Jakub Svoboda, et al.
Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy.
Blood 2022; 139(7): 1026–1038.
doi : https://doi.
org/10.
1182/blood.
2021012634.
Editor: Wenting Reviewer: Quinta Typesetting: Quinta Execution: Quinta pokes "read the original text", we make progress together
