Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer
B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autolog...
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| Published in | Molecular therapy Vol. 28; no. 11; pp. 2367 - 2378 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
04.11.2020
American Society of Gene & Cell Therapy |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1525-0016 1525-0024 1525-0024 |
| DOI | 10.1016/j.ymthe.2020.07.017 |
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| Abstract | B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7–10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence.
[Display omitted]
This study examined the safety/feasibility of administering two separate infusions of CART cells recognizing (1) mesothelin, a tumor-associated antigen, and (2) CD19 to deplete B cells. Treatment was well-tolerated in patients with pancreatic cancer and depleted peripheral B cells but did not improve CART cell anti-tumor activity or persistence. |
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| AbstractList | B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m
cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 10
/m
) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 10
/m
). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence. B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m 2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 10 7 /m 2 ) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 10 7 /m 2 ). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7–10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence. This study examined the safety/feasibility of administering two separate infusions of CART cells recognizing (1) mesothelin, a tumor-associated antigen, and (2) CD19 to deplete B cells. Treatment was well-tolerated in patients with pancreatic cancer and depleted peripheral B cells but did not improve CART cell anti-tumor activity or persistence. B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence.B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence. B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7–10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence. [Display omitted] This study examined the safety/feasibility of administering two separate infusions of CART cells recognizing (1) mesothelin, a tumor-associated antigen, and (2) CD19 to deplete B cells. Treatment was well-tolerated in patients with pancreatic cancer and depleted peripheral B cells but did not improve CART cell anti-tumor activity or persistence. |
| Author | Chang, Renee B. Levine, Bruce L. Ko, Andrew H. Fong, Lawrence Tooker, Evan Jordan, Alexander C. Damon, Lloyd Melenhorst, J. Joseph June, Carl H. Tempero, Margaret Li, Yan Lacey, Simon F. Venook, Alan P. O’Hara, Mark H. Plesa, Gabriela Beatty, Gregory L. |
| Author_xml | – sequence: 1 givenname: Andrew H. surname: Ko fullname: Ko, Andrew H. organization: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA – sequence: 2 givenname: Alexander C. surname: Jordan fullname: Jordan, Alexander C. organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 3 givenname: Evan surname: Tooker fullname: Tooker, Evan organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 4 givenname: Simon F. surname: Lacey fullname: Lacey, Simon F. organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 5 givenname: Renee B. surname: Chang fullname: Chang, Renee B. organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 6 givenname: Yan surname: Li fullname: Li, Yan organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 7 givenname: Alan P. surname: Venook fullname: Venook, Alan P. organization: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA – sequence: 8 givenname: Margaret surname: Tempero fullname: Tempero, Margaret organization: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA – sequence: 9 givenname: Lloyd surname: Damon fullname: Damon, Lloyd organization: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA – sequence: 10 givenname: Lawrence surname: Fong fullname: Fong, Lawrence organization: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA – sequence: 11 givenname: Mark H. surname: O’Hara fullname: O’Hara, Mark H. organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 12 givenname: Bruce L. surname: Levine fullname: Levine, Bruce L. organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 13 givenname: J. Joseph surname: Melenhorst fullname: Melenhorst, J. Joseph organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 14 givenname: Gabriela surname: Plesa fullname: Plesa, Gabriela organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 15 givenname: Carl H. surname: June fullname: June, Carl H. organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA – sequence: 16 givenname: Gregory L. surname: Beatty fullname: Beatty, Gregory L. email: gregory.beatty@uphs.upenn.edu organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32730744$$D View this record in MEDLINE/PubMed |
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| Copyright | 2020 The American Society of Gene and Cell Therapy Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved. 2020 The American Society of Gene and Cell Therapy. 2020 The American Society of Gene and Cell Therapy |
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| Keywords | pancreatic cancer chimeric antigen receptor B cells CD19 mesothelin |
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| Snippet | B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we... B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we... |
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| SubjectTerms | Antigens, CD19 - immunology B cells CD19 chimeric antigen receptor GPI-Linked Proteins - antagonists & inhibitors Humans Immunotherapy, Adoptive - adverse effects Immunotherapy, Adoptive - methods Lymphocyte Depletion - methods Mesothelin Neoplasm Metastasis Neoplasm Staging Original pancreatic cancer Pancreatic Neoplasms - immunology Pancreatic Neoplasms - pathology Pancreatic Neoplasms - therapy Pilot Projects Receptors, Chimeric Antigen - immunology T-Lymphocytes - immunology T-Lymphocytes - metabolism Treatment Outcome |
| Title | Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer |
| URI | https://dx.doi.org/10.1016/j.ymthe.2020.07.017 https://www.ncbi.nlm.nih.gov/pubmed/32730744 https://www.proquest.com/docview/2429779315 https://pubmed.ncbi.nlm.nih.gov/PMC7647666 |
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