Karattil, Rajesh; (2023) Novel approaches for restricting on-target off-tumour effects of AML CAR T cells. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text Raj PhD thesis.pdf - Other Download (6MB) | Preview

Abstract

Acute myeloid leukaemia (AML) is a life-threatening haematological malignancy characterised by infiltration of the bone marrow by blasts derived from abnormally differentiated myeloid cells. Conventional treatment for AML comprises cytarabine and anthracycline-containing regimens, followed by a haematopoietic stem cell transplant (HSCT). Despite the responses to these treatments, high rates of relapse occur due to chemoresistant leukaemic stem cells (LSC), making the 5-year survival of patients less than 30%. Therefore, therapeutic strategies to target the LSC are imperative to improve patient outcomes. The chimeric antigen receptor (CAR) T cell approach is a novel type of immunotherapy in which T cells are genetically modified to express CARs specific to a tumour antigen. CAR T cell immune therapy targeting CD19 has shown potential benefits for acute lymphoblastic leukaemia (ALL) and B cell lymphoma. However, this is challenging in AML due to the absence of AML-specific antigens, as AML antigens are co-expressed on normal haematopoietic stem/progenitor cells (HSPC), leading to intolerable myeloablation in patients, particularly where CAR T cells are potent and persist long term. The high expression of CD33 on both LSC and AML bulk cell population (>90%) make this antigen a highly promising candidate for the AML CAR T cell approach, even though novel strategies are needed to avoid myelotoxicity. My study investigated a novel strategy for reducing the CD33 cell surface expression in normal haematopoietic stem cells (HSCs) by combining a CD33 antibody fragment with an endoplasmic reticulum (ER) retention sequence known as KDEL. Cell transduction with this vector leads to expression of an antibody that binds to the CD33 molecule. Moreover, the KDEL signal on the vector binds to the KDEL receptor within the ER, preventing the secretion of the CD33 molecule to the cell surface, resulting in a reduction of cell surface CD33. This method was successfully validated on target cells expressing CD33 antigen. Even though my study found CD33 reduction with one HSC donor, this approach was failed to reduce CD33 cell surface expression of other HSC donors tested.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as XMLCSVJSON

Archive Staff Only

View Item