Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

Tomoyasu Jo^{1

2}, Satoshi Yoshihara^{3

4}, Yoshiki Okuyama⁵, Keiko Fujii⁶, Tomoko Henzan⁷, Kaoru Kahata⁸, Rie Yamazaki⁹, Wataru Takeda¹⁰, Yoshihiro Umezawa¹¹, Kentaro Fukushima¹², Takashi Ashida¹³, Minami Yamada-Fujiwara¹⁴, Ryo Hanajiri¹⁵, Noboru Yonetani¹⁶, Yuma Tada¹⁷, Yuji Shimura¹⁸, Hidekazu Nishikii¹⁹, Norio Shiba²⁰, Naoya Mimura²¹, Jun Ando²², Takayuki Sato²³, Yasuhiro Nakashima²⁴, Junko Ikemoto⁴, Keita Iwaki¹⁴, Shin-Ichiro Fujiwara²⁵, Masaki Ri²⁶, Tokiko Nagamura-Inoue²⁷, Ryuji Tanosaki⁸, Yasuyuki Arai^{1

2}

Affiliations

¹ Department of Clinical Laboratory Medicine and Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan.
² Department of Hematology and Oncology, Kyoto University Hospital, Kyoto, Japan.
³ Department of Transfusion Medicine and Cell Therapy, Hyogo Medical University Hospital, Nishinomiya, Japan.
⁴ Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Japan.
⁵ Division of Transfusion and Cell Therapy, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
⁶ Division of Transfusion, Okayama University Hospital, Okayama, Japan.
⁷ Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
⁸ Department of Hematology, Hokkaido University, Faculty of Medicine, Sapporo, Japan.
⁹ Center for Transfusion Medicine and Cell Therapy, Keio University School of Medicine, Tokyo, Japan.
¹⁰ Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.
¹¹ Department of Hematology, Tokyo Medical and Dental University, Tokyo, Japan.
¹² Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
¹³ Division of Hematology and Rheumatology, Department of Internal Medicine, Kindai University Hospital, Osakasayama, Japan.
¹⁴ Division of Blood Transfusion and Cell Therapy, Tohoku University Hospital, Sendai, Japan.
¹⁵ Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹⁶ Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
¹⁷ Department of Hematology, Osaka International Cancer Institute, Osaka, Japan.
¹⁸ Department of Blood Transfusion, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.
¹⁹ Department of Hematology, University of Tsukuba, Tsukuba, Japan.
²⁰ Department of Division of Blood Transfusion and Cell Therapy, Yokohama City University, Yokohama, Japan.
²¹ Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan.
²² Department of Cell Therapy and Transfusion Medicine, Juntendo University School of Medicine, Tokyo, Japan.
²³ Department of Haematology and Oncology, Kurashiki Central Hospital, Kurashiki, Japan.
²⁴ Department of Hematology, Osaka Metropolitan University Hospital, Osaka, Japan.
²⁵ Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Tochigi, Japan.
²⁶ Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
²⁷ Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

PMID: 37096915
DOI: 10.1111/bjh.18831

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

Tomoyasu Jo et al. Br J Haematol. 2023 Jul.

. 2023 Jul;202(2):256-266.

doi: 10.1111/bjh.18831. Epub 2023 Apr 25.

Authors

Affiliations

¹ Department of Clinical Laboratory Medicine and Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan.
² Department of Hematology and Oncology, Kyoto University Hospital, Kyoto, Japan.
³ Department of Transfusion Medicine and Cell Therapy, Hyogo Medical University Hospital, Nishinomiya, Japan.
⁴ Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Japan.
⁵ Division of Transfusion and Cell Therapy, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
⁶ Division of Transfusion, Okayama University Hospital, Okayama, Japan.
⁷ Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
⁸ Department of Hematology, Hokkaido University, Faculty of Medicine, Sapporo, Japan.
⁹ Center for Transfusion Medicine and Cell Therapy, Keio University School of Medicine, Tokyo, Japan.
¹⁰ Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.
¹¹ Department of Hematology, Tokyo Medical and Dental University, Tokyo, Japan.
¹² Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
¹³ Division of Hematology and Rheumatology, Department of Internal Medicine, Kindai University Hospital, Osakasayama, Japan.
¹⁴ Division of Blood Transfusion and Cell Therapy, Tohoku University Hospital, Sendai, Japan.
¹⁵ Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹⁶ Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
¹⁷ Department of Hematology, Osaka International Cancer Institute, Osaka, Japan.
¹⁸ Department of Blood Transfusion, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.
¹⁹ Department of Hematology, University of Tsukuba, Tsukuba, Japan.
²⁰ Department of Division of Blood Transfusion and Cell Therapy, Yokohama City University, Yokohama, Japan.
²¹ Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan.
²² Department of Cell Therapy and Transfusion Medicine, Juntendo University School of Medicine, Tokyo, Japan.
²³ Department of Haematology and Oncology, Kurashiki Central Hospital, Kurashiki, Japan.
²⁴ Department of Hematology, Osaka Metropolitan University Hospital, Osaka, Japan.
²⁵ Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Tochigi, Japan.
²⁶ Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
²⁷ Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

PMID: 37096915
DOI: 10.1111/bjh.18831

Abstract

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10⁴ /μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 10⁵ /μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients.

Keywords: chimeric antigen receptor T cell therapy; manufacturing failure; tisagenlecleucel.

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References

REFERENCES

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Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

Affiliations

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

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Research Materials