Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy
Patients with refractory or recurrent B-lineage hematologic malignancies have less than 50% of chance of cure despite intensive therapy and innovative approaches are needed. We hypothesize that gene modification of haematopoietic stem cells (HSC) with an anti-CD19 chimeric antigen receptor (CAR) wil...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-05-01
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| Series: | Human Vaccines & Immunotherapeutics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/21645515.2016.1268745 |
| _version_ | 1797674557110222848 |
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| author | Sarah M. Larson Laurel C. Truscott Tzu-Ting Chiou Amie Patel Roy Kao Andy Tu Tulika Tyagi Xiang Lu David Elashoff Satiro N. De Oliveira |
| author_facet | Sarah M. Larson Laurel C. Truscott Tzu-Ting Chiou Amie Patel Roy Kao Andy Tu Tulika Tyagi Xiang Lu David Elashoff Satiro N. De Oliveira |
| author_sort | Sarah M. Larson |
| collection | DOAJ |
| description | Patients with refractory or recurrent B-lineage hematologic malignancies have less than 50% of chance of cure despite intensive therapy and innovative approaches are needed. We hypothesize that gene modification of haematopoietic stem cells (HSC) with an anti-CD19 chimeric antigen receptor (CAR) will produce a multi-lineage, persistent immunotherapy against B-lineage malignancies that can be controlled by the HSVsr39TK suicide gene. High-titer third-generation self-inactivating lentiviral constructs were developed to deliver a second-generation CD19-specific CAR and the herpes simplex virus thymidine kinase HSVsr39TK to provide a suicide gene to allow ablation of gene-modified cells if necessary. Human HSC were transduced with such lentiviral vectors and evaluated for function of both CAR and HSVsr39TK. Satisfactory transduction efficiency was achieved; the addition of the suicide gene did not impair CAR expression or antigen-specific cytotoxicity, and determined marked cytotoxicity to ganciclovir. NSG mice transplanted with gene-modified human HSC showed CAR expression not significantly different between transduced cells with or without HSVsr39TK, and expression of anti-CD19 CAR conferred anti-tumor survival advantage. Treatment with ganciclovir led to significant ablation of gene-modified cells in mouse tissues. Haematopoietic stem cell transplantation is frequently part of the standard of care for patients with relapsed and refractory B cell malignancies; following HSC collection, a portion of the cells could be modified to express the CD19-specific CAR and give rise to a persistent, multi-cell lineage, HLA-independent immunotherapy, enhancing the graft-versus-malignancy activity. |
| first_indexed | 2024-03-11T22:00:44Z |
| format | Article |
| id | doaj.art-887cdfad0888415ebc477955b5429788 |
| institution | Directory Open Access Journal |
| issn | 2164-5515 2164-554X |
| language | English |
| last_indexed | 2024-03-11T22:00:44Z |
| publishDate | 2017-05-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Human Vaccines & Immunotherapeutics |
| spelling | doaj.art-887cdfad0888415ebc477955b54297882023-09-25T11:00:55ZengTaylor & Francis GroupHuman Vaccines & Immunotherapeutics2164-55152164-554X2017-05-011351094110410.1080/21645515.2016.12687451268745Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapySarah M. Larson0Laurel C. Truscott1Tzu-Ting Chiou2Amie Patel3Roy Kao4Andy Tu5Tulika Tyagi6Xiang Lu7David Elashoff8Satiro N. De Oliveira9David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLAWestern University of Health SciencesDavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLAPatients with refractory or recurrent B-lineage hematologic malignancies have less than 50% of chance of cure despite intensive therapy and innovative approaches are needed. We hypothesize that gene modification of haematopoietic stem cells (HSC) with an anti-CD19 chimeric antigen receptor (CAR) will produce a multi-lineage, persistent immunotherapy against B-lineage malignancies that can be controlled by the HSVsr39TK suicide gene. High-titer third-generation self-inactivating lentiviral constructs were developed to deliver a second-generation CD19-specific CAR and the herpes simplex virus thymidine kinase HSVsr39TK to provide a suicide gene to allow ablation of gene-modified cells if necessary. Human HSC were transduced with such lentiviral vectors and evaluated for function of both CAR and HSVsr39TK. Satisfactory transduction efficiency was achieved; the addition of the suicide gene did not impair CAR expression or antigen-specific cytotoxicity, and determined marked cytotoxicity to ganciclovir. NSG mice transplanted with gene-modified human HSC showed CAR expression not significantly different between transduced cells with or without HSVsr39TK, and expression of anti-CD19 CAR conferred anti-tumor survival advantage. Treatment with ganciclovir led to significant ablation of gene-modified cells in mouse tissues. Haematopoietic stem cell transplantation is frequently part of the standard of care for patients with relapsed and refractory B cell malignancies; following HSC collection, a portion of the cells could be modified to express the CD19-specific CAR and give rise to a persistent, multi-cell lineage, HLA-independent immunotherapy, enhancing the graft-versus-malignancy activity.http://dx.doi.org/10.1080/21645515.2016.1268745carcancer immunotherapygene therapyhscsuicide gene |
| spellingShingle | Sarah M. Larson Laurel C. Truscott Tzu-Ting Chiou Amie Patel Roy Kao Andy Tu Tulika Tyagi Xiang Lu David Elashoff Satiro N. De Oliveira Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy Human Vaccines & Immunotherapeutics car cancer immunotherapy gene therapy hsc suicide gene |
| title | Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy |
| title_full | Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy |
| title_fullStr | Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy |
| title_full_unstemmed | Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy |
| title_short | Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy |
| title_sort | pre clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy |
| topic | car cancer immunotherapy gene therapy hsc suicide gene |
| url | http://dx.doi.org/10.1080/21645515.2016.1268745 |
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