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A Phase 1 Dose Escalation Trial of Third Generation Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed and Refractory B-Cell Non Hodgkin Lymphoma

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thesis
posted on 08.12.2021, 22:06 by Philip GeorgePhilip George

Anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy is shifting the treatment paradigm internationally for selected patients with relapsed and refractory B-cell Non- Hodgkin Lymphoma. Despite high response rates with durable responses achieved in a significant proportion of patients, over 50% of patients will have progressed at one year following treatment with the currently licensed anti-CD19 CAR T-cell therapies. This modality of therapy is also associated with acute and potentially life-threatening toxicities, requiring strict risk mitigation strategies.  In this thesis, the design, preparation and implementation of a new third generation anti-CD19 CAR T-cell Phase 1 trial entitled ENABLE, for patients with relapsed and refractory B-cell Non-Hodgkin Lymphoma, is described in detail. Following a literature review of CAR T-cell therapy in patients with B-cell Non-Hodgkin Lymphoma, the rationale for the ENABLE trial design is discussed, along with regulatory and clinical requirements for setting up CAR T-cell therapy in New Zealand. The importance of international collaboration to inform aspects of study design, CAR T-cell product manufacturing and developing CAR T-cell toxicity management protocols, has been demonstrated.  The early clinical experience on the ENABLE trial is presented along with provisional safety, pharmacokinetic and efficacy data from the first participant treated. This is the first time that CAR T-cell therapy has been administered in New Zealand, demonstrating CAR T-cell expansion in vivo; but also highlighting the complexities of the CAR T-cell product manufacturing process and the importance of evaluating feasibility of CAR T-cell manufacturing, as a key secondary endpoint of the study. Further clinical experience on the ENABLE trial is crucial to develop the potential for CAR T-Cell therapy to be a safe, feasible and effective option for selected New Zealand patients in the future.

History

Copyright Date

01/01/2020

Date of Award

01/01/2020

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Clinical Research

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Masters

Degree Name

Master of Clinical Research

Victoria University of Wellington Unit

Malaghan Institute for Medical Research

ANZSRC Type Of Activity code

3 APPLIED RESEARCH

Victoria University of Wellington Item Type

Awarded Research Masters Thesis

Language

en_NZ

Victoria University of Wellington School

School of Biological Sciences

Advisors

Weinkove, Robert