Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma
Multiple rodent and primate preclinical studies have advanced CAR T cells into the clinic. However, no single model accurately reflects the challenges of effective CAR T therapy in human cancer patients. To evaluate the effectiveness of next-generation CAR T cells that aim to overcome barriers to du...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2019.1676615 |
| _version_ | 1819000996085366784 |
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| author | M. Kazim Panjwani Matthew J. Atherton Martha A. MaloneyHuss Kumudhini P. Haran Ailian Xiong Minnal Gupta Irina Kulikovsaya Simon F. Lacey Nicola J. Mason |
| author_facet | M. Kazim Panjwani Matthew J. Atherton Martha A. MaloneyHuss Kumudhini P. Haran Ailian Xiong Minnal Gupta Irina Kulikovsaya Simon F. Lacey Nicola J. Mason |
| author_sort | M. Kazim Panjwani |
| collection | DOAJ |
| description | Multiple rodent and primate preclinical studies have advanced CAR T cells into the clinic. However, no single model accurately reflects the challenges of effective CAR T therapy in human cancer patients. To evaluate the effectiveness of next-generation CAR T cells that aim to overcome barriers to durable tumor elimination, we developed a system to evaluate CAR T cells in pet dogs with spontaneous cancer. Here we report on this system and the results of a pilot trial using CAR T cells to treat canine diffuse large B cell lymphoma (DLBCL). We designed and manufactured CD20-targeting, second-generation canine CAR T cells for functional evaluation in vitro and in vivo using lentivectors to parallel human CAR T cell manufacturing. A first-in-species trial of five dogs with DLBCL treated with CAR T was undertaken. Canine CAR T cells functioned in an antigen-specific manner and killed CD20+ targets. Circulating CAR T cells were detectable post-infusion, however, induction of canine anti-mouse antibodies (CAMA) was associated with CAR T cell loss. Specific selection pressure on CD20+ tumors was observed following CAR T cell therapy, culminating in antigen escape and emergence of CD20-disease. Patient survival times correlated with ex vivo product expansion. Altering product manufacturing improved transduction efficiency and skewed toward a memory-like phenotype of canine CAR T cells. Manufacturing of functional canine CAR T cells using a lentivector is feasible. Comparable challenges to effective CAR T cell therapy exist, indicating their relevance in informing future human clinical trial design. |
| first_indexed | 2024-12-20T22:42:11Z |
| format | Article |
| id | doaj.art-d7afee87aa414d559adb4c116f51da3a |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-20T22:42:11Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-d7afee87aa414d559adb4c116f51da3a2022-12-21T19:24:26ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2019.16766151676615Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphomaM. Kazim Panjwani0Matthew J. Atherton1Martha A. MaloneyHuss2Kumudhini P. Haran3Ailian Xiong4Minnal Gupta5Irina Kulikovsaya6Simon F. Lacey7Nicola J. Mason8University of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaMultiple rodent and primate preclinical studies have advanced CAR T cells into the clinic. However, no single model accurately reflects the challenges of effective CAR T therapy in human cancer patients. To evaluate the effectiveness of next-generation CAR T cells that aim to overcome barriers to durable tumor elimination, we developed a system to evaluate CAR T cells in pet dogs with spontaneous cancer. Here we report on this system and the results of a pilot trial using CAR T cells to treat canine diffuse large B cell lymphoma (DLBCL). We designed and manufactured CD20-targeting, second-generation canine CAR T cells for functional evaluation in vitro and in vivo using lentivectors to parallel human CAR T cell manufacturing. A first-in-species trial of five dogs with DLBCL treated with CAR T was undertaken. Canine CAR T cells functioned in an antigen-specific manner and killed CD20+ targets. Circulating CAR T cells were detectable post-infusion, however, induction of canine anti-mouse antibodies (CAMA) was associated with CAR T cell loss. Specific selection pressure on CD20+ tumors was observed following CAR T cell therapy, culminating in antigen escape and emergence of CD20-disease. Patient survival times correlated with ex vivo product expansion. Altering product manufacturing improved transduction efficiency and skewed toward a memory-like phenotype of canine CAR T cells. Manufacturing of functional canine CAR T cells using a lentivector is feasible. Comparable challenges to effective CAR T cell therapy exist, indicating their relevance in informing future human clinical trial design.http://dx.doi.org/10.1080/2162402X.2019.1676615car t cellb cell lymphomacomparative oncology |
| spellingShingle | M. Kazim Panjwani Matthew J. Atherton Martha A. MaloneyHuss Kumudhini P. Haran Ailian Xiong Minnal Gupta Irina Kulikovsaya Simon F. Lacey Nicola J. Mason Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma OncoImmunology car t cell b cell lymphoma comparative oncology |
| title | Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma |
| title_full | Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma |
| title_fullStr | Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma |
| title_full_unstemmed | Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma |
| title_short | Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma |
| title_sort | establishing a model system for evaluating car t cell therapy using dogs with spontaneous diffuse large b cell lymphoma |
| topic | car t cell b cell lymphoma comparative oncology |
| url | http://dx.doi.org/10.1080/2162402X.2019.1676615 |
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