Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma
| Autor: | M. Kazim Panjwani, Matthew J. Atherton, Minnal Gupta, Nicola J. Mason, Irina Kulikovsaya, Kumudhini Preethi Haran, Ailian Xiong, Martha A. MaloneyHuss, Simon F. Lacey |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
comparative oncology T-Lymphocytes Immunology Receptors Antigen T-Cell Immunotherapy Adoptive 03 medical and health sciences Mice 0302 clinical medicine Dogs Antigen In vivo medicine Immunology and Allergy Animals Humans B-cell lymphoma RC254-282 Original Research CD20 biology business.industry CAR T cell Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC581-607 medicine.disease Antigens CD20 In vitro B cell lymphoma 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Lymphoma Large B-Cell Diffuse Immunologic diseases. Allergy Antibody business Diffuse large B-cell lymphoma human activities Ex vivo |
| Zdroj: | Oncoimmunology OncoImmunology, Vol 9, Iss 1 (2020) |
| ISSN: | 2162-402X 2162-4011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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