W. S. Kim, S. J. Kim, D. H. Yoon, H. W. Cho, S. E. Yoon, D. H. Yang, H. Shin, H. S. Eom, E. Y. Lee, J. M. Byun, Y. I. Koh, D. Y. Shin, J. Hong, H. W. Lee, J. H. Jung, S. S. Yoon, G. Y. Song, D. Y. Kim
{"title":"治疗复发/难治性大b细胞淋巴瘤（crc01-01）的抗肿瘤素（pd-1和tigit敲低cd19 car-t）","authors":"W. S. Kim, S. J. Kim, D. H. Yoon, H. W. Cho, S. E. Yoon, D. H. Yang, H. Shin, H. S. Eom, E. Y. Lee, J. M. Byun, Y. I. Koh, D. Y. Shin, J. Hong, H. W. Lee, J. H. Jung, S. S. Yoon, G. Y. Song, D. Y. Kim","doi":"10.1002/hon.70094_319","DOIUrl":null,"url":null,"abstract":"<p><b>Introduction:</b> Anbal-cel is CD19 CAR-T with PD-1, TIGIT knockdown to reduce the negative impact on response. This approach is expected to exert a stronger and more sustained effect on tumor cells.</p><p><b>Methods:</b> In this multicenter, phase 2 trial, we enrolled adult patients with relapsed or refractory large B-cell lymphomas including DLBCL-NOS, HGBL, PMBCL, FL3B. Lymphodepletion was performed with cyclophosphamide 500 mg/m<sup>2</sup> and fludarabine 30 mg/m<sup>2</sup>, administered for three days (-5, -4, -3 days). The median dose was 2.2 ×10<sup>6</sup>cells/kg (range, 0.2–2.61 (×10<sup>6</sup>cells/kg)). The primary endpoint is ORR by independent review committee. The secondary endpoints are PFS, OS and safety.</p><p><b>Results:</b> Between January 2022 and September 2023, 91 patients underwent leukapheresis to manufacture and 79 patients received anbal-cel. Most patients were DLBCL, NOS (94.9%) and 65 years or older accounted for 53.2%. The patients who had received up to second-line chemotherapy was 70.9%. The IPI score was distributed as follows: low in 31.6%, low-intermediate in 25.3%, high-intermediate in 34.2%, high in 8.9%. The median SPD was 1858 mm<sup>2</sup> (range, 150–13,724), and the median TMTV was 63.3 ml (range, 0–3603). 26.3% of patients had GCB phenotype, and 61.8% were classified as double expressors.</p><p>73 patients included in an efficacy analysis set. The ORR was 75.3% and CR rate was 67.1%. The median f/u time was 8.5 months (range, 0.2–22.6). The median PFS was 6.0 months (95% CI: 4.3–16.5 months), with 12-month and 18-month PFS rates of 41.1% and 35.2%, respectively. The median OS was not reached, and the 12-month and 18-month OS rates were 66.6% and 57.3%, respectively. Regarding CAR-T cell expansion, the responder group exhibited a significantly higher peak expansion (median C<sub>max</sub>: 22,281 copies/µg) compared to the non-responder group (median C<sub>max</sub>: 9781 copies/µg).</p><p>We categorized patients into long-term responders (LR) and non-long-term responders (non-LR) based on whether they maintained CR at 6 months. FACS analysis showed that PD-1 and TIGIT expression on anbal-cel was significantly lower in the LR group compared to the non-LR group, with this difference persisting at days 14. Additionally, CAR-T cells in the LR group displayed a less activated memory phenotype, characterized by lower expression of CD39 and Tim-3 and higher expression of CD127, compared to those in the non-LR group. Consistent with this, the non-LR group exhibited an increased frequency of terminally differentiated and functionally senescent CAR-T cells, marked by the expression of CD57, CD38, and HLA-DR.</p><p>CRS and neurologic events occurred in 57.0% and 13.9%, respectively. Grade 3 CRS occurred in 8.9% with no cases of grade 4. Neurologic events of grade 3 or higher were reported in 3.8%. The rate of serious infections was 25%, prolonged cytopenia was reported in 44% of patients.</p><p><b>Conclusions:</b> Anbal-cel demonstrated PD-1 and TIGIT knockdown can contribute to long-term response with high CR rate and manageable safety profile.</p><p><b>Keywords:</b> cellular therapies; aggressive B-cell non-Hodgkin lymphoma</p><p><b>Potential sources of conflict of interest:</b></p><p><b>W. S. Kim</b></p><p><b>Other remuneration:</b> received grants from Sanofi, BeiGene, Boryong, Roche, Kyowa Kirin, Donga, outside the submitted work.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70094_319","citationCount":"0","resultStr":"{\"title\":\"ANBALCABTAGENE AUTOLEUCEL (PD-1 AND TIGIT KNOCKDOWN CD19 CAR-T) FOR RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA (CRC01-01)\",\"authors\":\"W. S. Kim, S. J. Kim, D. H. Yoon, H. W. Cho, S. E. Yoon, D. H. Yang, H. Shin, H. S. Eom, E. Y. Lee, J. M. Byun, Y. I. Koh, D. Y. Shin, J. Hong, H. W. Lee, J. H. Jung, S. S. Yoon, G. Y. Song, D. Y. Kim\",\"doi\":\"10.1002/hon.70094_319\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><b>Introduction:</b> Anbal-cel is CD19 CAR-T with PD-1, TIGIT knockdown to reduce the negative impact on response. This approach is expected to exert a stronger and more sustained effect on tumor cells.</p><p><b>Methods:</b> In this multicenter, phase 2 trial, we enrolled adult patients with relapsed or refractory large B-cell lymphomas including DLBCL-NOS, HGBL, PMBCL, FL3B. Lymphodepletion was performed with cyclophosphamide 500 mg/m<sup>2</sup> and fludarabine 30 mg/m<sup>2</sup>, administered for three days (-5, -4, -3 days). The median dose was 2.2 ×10<sup>6</sup>cells/kg (range, 0.2–2.61 (×10<sup>6</sup>cells/kg)). The primary endpoint is ORR by independent review committee. The secondary endpoints are PFS, OS and safety.</p><p><b>Results:</b> Between January 2022 and September 2023, 91 patients underwent leukapheresis to manufacture and 79 patients received anbal-cel. Most patients were DLBCL, NOS (94.9%) and 65 years or older accounted for 53.2%. The patients who had received up to second-line chemotherapy was 70.9%. The IPI score was distributed as follows: low in 31.6%, low-intermediate in 25.3%, high-intermediate in 34.2%, high in 8.9%. The median SPD was 1858 mm<sup>2</sup> (range, 150–13,724), and the median TMTV was 63.3 ml (range, 0–3603). 26.3% of patients had GCB phenotype, and 61.8% were classified as double expressors.</p><p>73 patients included in an efficacy analysis set. The ORR was 75.3% and CR rate was 67.1%. The median f/u time was 8.5 months (range, 0.2–22.6). The median PFS was 6.0 months (95% CI: 4.3–16.5 months), with 12-month and 18-month PFS rates of 41.1% and 35.2%, respectively. The median OS was not reached, and the 12-month and 18-month OS rates were 66.6% and 57.3%, respectively. Regarding CAR-T cell expansion, the responder group exhibited a significantly higher peak expansion (median C<sub>max</sub>: 22,281 copies/µg) compared to the non-responder group (median C<sub>max</sub>: 9781 copies/µg).</p><p>We categorized patients into long-term responders (LR) and non-long-term responders (non-LR) based on whether they maintained CR at 6 months. FACS analysis showed that PD-1 and TIGIT expression on anbal-cel was significantly lower in the LR group compared to the non-LR group, with this difference persisting at days 14. Additionally, CAR-T cells in the LR group displayed a less activated memory phenotype, characterized by lower expression of CD39 and Tim-3 and higher expression of CD127, compared to those in the non-LR group. Consistent with this, the non-LR group exhibited an increased frequency of terminally differentiated and functionally senescent CAR-T cells, marked by the expression of CD57, CD38, and HLA-DR.</p><p>CRS and neurologic events occurred in 57.0% and 13.9%, respectively. Grade 3 CRS occurred in 8.9% with no cases of grade 4. Neurologic events of grade 3 or higher were reported in 3.8%. The rate of serious infections was 25%, prolonged cytopenia was reported in 44% of patients.</p><p><b>Conclusions:</b> Anbal-cel demonstrated PD-1 and TIGIT knockdown can contribute to long-term response with high CR rate and manageable safety profile.</p><p><b>Keywords:</b> cellular therapies; aggressive B-cell non-Hodgkin lymphoma</p><p><b>Potential sources of conflict of interest:</b></p><p><b>W. S. 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ANBALCABTAGENE AUTOLEUCEL (PD-1 AND TIGIT KNOCKDOWN CD19 CAR-T) FOR RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA (CRC01-01)
Introduction: Anbal-cel is CD19 CAR-T with PD-1, TIGIT knockdown to reduce the negative impact on response. This approach is expected to exert a stronger and more sustained effect on tumor cells.
Methods: In this multicenter, phase 2 trial, we enrolled adult patients with relapsed or refractory large B-cell lymphomas including DLBCL-NOS, HGBL, PMBCL, FL3B. Lymphodepletion was performed with cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2, administered for three days (-5, -4, -3 days). The median dose was 2.2 ×106cells/kg (range, 0.2–2.61 (×106cells/kg)). The primary endpoint is ORR by independent review committee. The secondary endpoints are PFS, OS and safety.
Results: Between January 2022 and September 2023, 91 patients underwent leukapheresis to manufacture and 79 patients received anbal-cel. Most patients were DLBCL, NOS (94.9%) and 65 years or older accounted for 53.2%. The patients who had received up to second-line chemotherapy was 70.9%. The IPI score was distributed as follows: low in 31.6%, low-intermediate in 25.3%, high-intermediate in 34.2%, high in 8.9%. The median SPD was 1858 mm2 (range, 150–13,724), and the median TMTV was 63.3 ml (range, 0–3603). 26.3% of patients had GCB phenotype, and 61.8% were classified as double expressors.
73 patients included in an efficacy analysis set. The ORR was 75.3% and CR rate was 67.1%. The median f/u time was 8.5 months (range, 0.2–22.6). The median PFS was 6.0 months (95% CI: 4.3–16.5 months), with 12-month and 18-month PFS rates of 41.1% and 35.2%, respectively. The median OS was not reached, and the 12-month and 18-month OS rates were 66.6% and 57.3%, respectively. Regarding CAR-T cell expansion, the responder group exhibited a significantly higher peak expansion (median Cmax: 22,281 copies/µg) compared to the non-responder group (median Cmax: 9781 copies/µg).
We categorized patients into long-term responders (LR) and non-long-term responders (non-LR) based on whether they maintained CR at 6 months. FACS analysis showed that PD-1 and TIGIT expression on anbal-cel was significantly lower in the LR group compared to the non-LR group, with this difference persisting at days 14. Additionally, CAR-T cells in the LR group displayed a less activated memory phenotype, characterized by lower expression of CD39 and Tim-3 and higher expression of CD127, compared to those in the non-LR group. Consistent with this, the non-LR group exhibited an increased frequency of terminally differentiated and functionally senescent CAR-T cells, marked by the expression of CD57, CD38, and HLA-DR.
CRS and neurologic events occurred in 57.0% and 13.9%, respectively. Grade 3 CRS occurred in 8.9% with no cases of grade 4. Neurologic events of grade 3 or higher were reported in 3.8%. The rate of serious infections was 25%, prolonged cytopenia was reported in 44% of patients.
Conclusions: Anbal-cel demonstrated PD-1 and TIGIT knockdown can contribute to long-term response with high CR rate and manageable safety profile.
期刊介绍：
Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged:
-Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders
-Diagnostic investigations, including imaging and laboratory assays
-Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases
-Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies
-Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems.
Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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