Exploring T cell mediated immunotherapy against therapy resistant leukemic stem cells
Lehander, Madeleine
2024-05-24
09.00
Erna Möllersalen, NEO, Karolinska Institutet, Flemingsberg
Inst för medicin, Huddinge / Dept of Medicine, Huddinge
The cancer stem cell (CSC) model suggests that cancers depend on continuous
replenishment from rare and distinct CSCs, but their existence has been
challenging to prove for many malignancies. The CSCs in myeloid leukemias,
known as leukemic stem cells (LSCs) have been well characterised and shown to
selectively escape treatment, thus representing the cellular source of relapse.
Relapse following initial periods of clinical remission represents the most
significant threat to leukemic patients as the available treatment options at this
stage are sparse due to the development of resistance. There is therefore a need
for strategies facilitating earlier detection of an impending relapse to initiate preemptive
treatments early, as well as for new targeted therapies to eliminate LSCs.
The cellular identity of LSCs was recently assigned to the hematopoietic stem cell
(HSC) compartment in patients with low to intermediate risk myelodysplastic
syndromes (MDS), for which the only curative treatment option is allogeneic stem
cell transplantation (allo-HSCT). Detailed characterisation of LSCs in terms of
phenotype, function, and treatment resistance is thus now possible, with the aim
to ultimately identify novel targets allowing for targeted elimination of LSCs. In
study I, we performed LSC-directed screening for measurable residual disease
(MRD) in patients with MDS after allo-HSCT. By flow cytometric purification of the
hematopoietic stem and progenitor cells, the MRD-sensitivity was enhanced 97-
fold compared to conventional screening methods on unfractionated bone
marrow cells. Consequently, in our patient cohort, targeted screening of the
leukemia initiating cells led to the detection of impending relapses on average ten
months before clinical diagnosis. In the clinic, this would allow for prescribing
preventative treatments earlier while disease burden remains low which could
improve outcome.
A potentially effective cancer treatment option is adoptive T cell therapy, using T
cells that carry cancer-specific T cell receptors (TCR). TCR T cells can, unlike
chimeric antigen receptor (CAR) T cells, recognise intracellular antigens but
despite the theoretical large range of targetable antigens, very few are
immunogenic. Consequently, no TCR T cell therapy is yet clinically approved for
treatment against hematological malignancies, highlighting the need for new
potential targets. In study II we showed that terminal deoxynucleotidyl
transferase (TdT), which is normally transiently expressed during early B and T cell
development and overexpressed in >80% of patients with B and T acute
lymphoblastic leukemia (ALL), is a promising target for TCR based immunotherapy
in context of HLA-A*02:01 (HLA-A2). T cells targeting TdT, identified through the
blood of healthy donors, showed very efficient elimination of TdT+ leukemic cells,
while sparing healthy hematopoietic stem and progenitor cells and mature
lymphocytes in clinically relevant mouse models. Thus, TdT TCR T cells are a novel
and promising immunotherapy option for patients with B- and T-ALL.
Myeloid leukemias are, to a greater extent than the lymphoid leukemias,
characterised by somatic recurrent mutations which generate cancer-specific
neoantigens representing a group of unique attractive therapeutic targets. In
study III, an HLA-A2 restricted TCR with high specificity against a recurrent
neoantigen generated from the FLT3-D835Y mutation in acute myeloid leukemia
(AML) was identified and shown to exhibit great anti-leukemic effect restricted to
the FLT3-D835Y mutated cells while non-mutated cells were spared. Interestingly,
the FLT3-D835Y TCR T cells also had the potential to eliminate the LSCs in vitro
as shown by loss of leukemia initiating formation in mice following co-cultures.
The results from study II and III revealed the therapeutic potential of TCR T cells,
therefore, in study IV we proposed TCR T cells as a targeted therapy against LSCs.
Identification of antigens that mediate specific elimination of all LSCs across many
patients has been challenging due to large inter- and intra-patient heterogeneity.
Myeloproliferative leukemia protein (MPL) has an important role in lifelong
maintenance of HSCs and is therefore expressed on all HSCs and consequently
also all LSCs in patients with low to intermediate risk MDS. We suggest TCR T cells
targeting MPL presented on HLA-A2 as an immunotherapeutic approach with
clinical relevancy to treat an impending relapse following an haploidentical allo-
HSCT. MPL TCR T cells would potentially also represent a novel research tool to
study the dependency of HSCs and LSCs in normal and malignant hematopoiesis.