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Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma.

ABSTRACT: 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.

SUBMITTER: Panjwani MK

PROVIDER: S-EPMC6959441 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma.

Panjwani M Kazim MK Atherton Matthew J MJ MaloneyHuss Martha A MA Haran Kumudhini P KP Xiong Ailian A Gupta Minnal M Kulikovsaya Irina I Lacey Simon F SF Mason Nicola J NJ

Oncoimmunology 20191023 1

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 ca ...[more]

PMID: 32002286

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Project description:BackgroundChimeric antigen receptor (CAR) T-cell therapy is a novel cell therapy for treating non-Hodgkin lymphoma. The development of CAR T-cell therapy has transformed oncology treatment by offering a potential cure. However, due to the high cost of these therapies, and the large number of eligible patients, decision makers are faced with difficult funding decisions. Our objective was to assess the cost-effectiveness of tisagenlecleucel for adults with relapsed/refractory diffuse large B-cell lymphoma in Canada using updated survival data from the recent JULIET trial.MethodsWe developed an individual-simulated discrete event simulation model to assess the costs and quality-adjusted life-years (QALY) of tisagenlecleucel compared with salvage chemotherapy. Survival estimates were obtained from a published clinical trial and retrospective analysis. If patients remained progression free for 5 y, they were assumed to be in long-term remission. Costing and utility data were obtained from reports and published sources. A Canadian health care payer perspective was used, and outcomes were modeled over a lifetime horizon. Costs and outcomes were discounted at 1.5% annually, with costs reported in 2021 Canadian dollars. A probabilistic analysis was used, and model parameters were varied in 1-way sensitivity analyses and scenario analyses.ResultsAfter we incorporated the latest clinical evidence, tisagenlecleucel led to an additional cost of $503,417 and additional effectiveness of 2.48 QALYs, with an incremental cost-effectiveness ratio of $202,991 compared with salvage chemotherapy. At a willingness-to-pay threshold of $100,000/QALY, tisagenlecleucel had a 0% likelihood of being cost-effective.ConclusionsAt the current drug price, tisagenlecleucel was not found to be a cost-effective option. These results heavily depend on assumptions regarding long-term survival and the price of CAR T. Real-world evidence is needed to reduce uncertainty.HighlightsFor patients with diffuse large B-cell lymphoma who failed 2 or more lines of systemic therapy, CAR T was not found to be a cost-effective treatment option at a willingness-to-pay threshold of $100,000.These results heavily depend on the expected long-term survival. The uncertainty in the model may be improved using real-world evidence reported in the future.

Dataset Information

Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma.

Publications

Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma.

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