SCIENTIFIC PROGRAMME
SESSION I
THE GENOMIC AND
EPIGENOMIC LANDSCAPE
OF CLL AND CLINICAL
CONSEQUENCES
SESSION II
THE ROLE OF BCR
ACTIVATION AND
SIGNALLING FOR CLL
SESSION III
THERAPEUTIC OPTIONS
FOR CLL
SESSION IV
LONG TERM FOLLOW
UP OF CLINICAL TRIALS
VERSUS REAL WORLD
DATA (OUTSIDE CLINICAL
TRIALS DATA-OCT)
SESSION V
THE INCREASING ROLE
OF THE LEUKAEMIC
MICROENVIRONMENT
SESSION VI
THERAPEUTIC OPTIONS 2 :
THE USE OF CELLULAR
AND NON-CELLULAR
IMMUNOTHERAPIES IN
CLL
SESSION VII
EFFICACY THROUGH
SAFETY
SESSION VIII
CLONAL HETEROGENEITY,
CLONAL EVOLUTION AND
MECHANISMS OF DRUG
RESISTANCE
SESSION IX
CONTRASTING
THERAPEUTIC CONCEPTS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES
inferior at coordinating anti-tumor activity.9 Recent investigations suggest that ibrutinib
improves the T cell immune dysfunction associated with CLL. Niemann et al observed
decreases in chronic T cell activation and exhaustion,10 while Dubovsky et al demonstrated
a shift from Th2 to Th1 polarization with ibrutinib in a murine model.11 Ibrutinib has also
been shown to decrease frequency of immunosuppressive regulatory T cells in CLL.12, 13
Interestingly, the T-cell receptor (TCR) repertoire in patients with chronic lymphocytic
leukemia (CLL) is more clonal than in healthy individuals. Shared TCR clonotypes among
patients may reflect the expansion of T-cell clones that recognize common antigens. It is
unknown whether these antigens are tumor-antigens on CLL cells to which T cells react or
microbial or auto-antigens that promote expansion of both T cells and the leukemic clone. We
found that ibrutinib induced a more oligoclonal T-cell receptor (TCR) repertoire in CLL
patients. Using next generation sequencing, overrepresented TCRβ clonotypes were mostly
patient-specific and the degree of oligoclonal expansion correlated with CD8+ T-cell counts
(see also abstract submitted to this meeting by M.J. Baptista). Based on these observations,
we are currently testing the hypothesis that overrepresented clonotypes are CD8+ T cells that
respond to tumor antigens.
Additional observations suggest that ibrutinib could prime the CLL immune system for
immunotherapy. Notably, studies demonstrated improved CD19-directed chimeric antigen
receptor T (CAR-T) cell expansion, engraftment, and clinical activity in CLL patients treated
with ibrutinib.14, 15 In pre-clinical studies, we found that a CD19/CD3 bispecific antibody
engineered in a scFv-Fc format had considerable activity against CLL cells in vitro and in
patient-derived xenografts in vivo.16 Similar to observations with CAR-T cells, the bsAb
demonstrated superior anti-tumor activity against CLL cells from ibrutinib-treated patients
compared to cells obtained from treatment-naïve patients. Robust activity of the bsAb was
maintained against CLL cells from patients experiencing early disease progression with clones
harboring the classic BTK and/or PLCG2 mutations.16
In summary, BTK inhibitors modulate the immune microenvironment in ways that can
contribute to improved humoral and cellular immune function, reducing the risk of infections
and enhancing T cell mediated anti-CLL effects.
References
1. Hendriks, R.W., et al., Biology and novel treatment options for XLA, the most common
monogenetic immunodeficiency in man. Expert Opin Ther Targets, 2011. 15(8): p. 1003-21.
2. Sun, C., et al., Partial reconstitution of humoral immunity and fewer infections in patients with
chronic lymphocytic leukemia treated with ibrutinib. Blood, 2015. 126(19): p. 2213-9.
3. Byrd, J.C., et al., Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl
J Med, 2013. 369(1): p. 32-42.
4. Sun, C., et al., Seasonal Influenza Vaccination in Patients With Chronic Lymphocytic Leukemia
Treated With Ibrutinib. Jama Oncology, 2016. 2(12): p. 1656-1657.
5. Forconi, F. and P. Moss, Perturbation of the normal immune system in patients with CLL. Blood,
2015. 126(5): p. 573-581.
6. Riches, J.C. and J.G. Gribben, Understanding the immunodeficiency in chronic lymphocytic
leukemia: potential clinical implications. Hematol Oncol Clin North Am, 2013. 27(2): p. 207-35.