Download the ESMO 2012 Abstract Book - Oxford Journals

abstracts
molecular targets in malignant
lymphomas: from basic science
to clinical practice
64IN NEW ANTIBODIES IN THE POST-RITUXIMAB-ERA: ANOTHER
BREAKTHROUGH?
P. Johnson
Cancer Research UK Centre, University of Southampton, Southampton,
UNITED KINGDOM
Monoclonal antibodies (mAb) are one of the successes of modern cancer medicine,
with rituximab the first to enter widespread clinical application following the
demonstration of significant activity as a single agent, and superior results when
combined with chemotherapy for a variety of CD20+ lymphoma types. In parallel to
extensive clinical studies, we continue to uncover novel aspects of biology of the
lymphoid cell surface. The molecules to which mAb have been targeted were
identified several decades ago and few new ones have emerged recently, but there is
now increasing interest in effector mechanisms, selective delivery of radionuclides or
toxins, and bispecific molecules to target T- or NK- cells. Once thought of as a
comparatively inert component of the cell membrane, CD20 is in fact a dynamic
molecule. It can undergo rapid redistribution, and different mAb cause different
effects: those like Rituximab (“type I”) elicit redistribution into lipid-rich rafts,
mediate complement fixation and antibody-directed cell-mediated cytotoxicity
(ADCC). In contrast, those like the first anti-B-cell mAb characterised, B1 (“type II”)
do not cause redistribution into rafts but mediate homotypic cell adhesion and
programmed cell death. These differences have important therapeutic results, and we
have found that in lymphomas expressing the CD32 antigen (Fcgamma-R2b), type
ImAb mediate rapid internalization of CD20 with lysosomal consumption, while
type II do not. This has potential consequences for the therapeutic effect, as does the
avidity with which mAb with different sugar groups bind to various Fc receptors. As
well as radioconjugates, we are also returning to previously discarded approaches
such as immunotxins, which have benefitted from advances in linker chemistry to
improve their therapeutic ratio. Problems of toxin liberation and systemic toxicity
have been largely overcome, and a new generation of conjugates is finding
application in lymphoma therapy. Finally, the capacity to generate bispecific
constructs that allow targeting of T-cells to the malignant cell surface holds the
promise of harnessing cellular as well as humoral immunity. The initial promise of
antibody therapy for lymphoma is already being fulfilled, and the next generation of
compounds holds exciting challenges and great potential.
Disclosure: P. Johnson: Advisory Boards for Pfizer, Millenium Takeda, Roche,
Boehringer Ingelheim. Research funding from Janssen-Cilag.
65IN MTOR INHIBITORS AND BEYOND: TARGETING A CRITICAL
PATHWAY
M.H. Dreyling
Department of Medicine Iii, University of Munich, Munich, GERMANY
Upregulation of the PI3K/AKT/mTOR signal pathway has been detected in
numerous lymphoma subtypes including mantle cell lymphoma (MCL). Accordingly,
the mTOR inhibitor Temsirolimus has been registered in EU based on a prospective
randomized trial in 162 patients with relapsed MCL. In comparison to
monochemotherapy, Temsirolimus achieved significantly higher response rates (22%
vs 2%) and longer progression-free survival (4.8 vs. 1.9 months). Moreover, the
efficacy of the mTOR inhibitor was confirmed not only in MCL, but also follicular
and diffuse large B-cell lymphoma in numerous phase II studies. Based on in vitro
studies current trials investigate the combination with chemotherapy. Thus, all 12
initial patients with relapsed MCL responded to a
Bendamustin-Rituximab-Temsirolimus combination (BeRT). Recent research has
confirmed the critical role of the B-cell receptor pathway upstream of mTOR in the
molecular pathogenesis of malignant lymphoma. This pathway represents the
physiological survival signal for maturating lymphocytes in the germinal center.
Accordingly, small molecules attacking this pathway displayed high efficacy in
various lymphoma subtypes even in monotherapy. Thus, a SYK inhibitor has been
shown to be effective in patients with relapsed diffuse large cell lymphoma. Especially
both, an inhibitor of the PI3K delta isoform (GS-1101, formally Cal-101) only
expressed in lymphoid cells and the BTK inhibitor ibrutinib showed high efficacy in
relapsed mantle cell lymphoma (response rate about 70%) as well as CLL (response
Annals of Oncology 23 (Supplement 9): ix44–ix45, 2012
doi:10.1093/annonc/mds382
rate between 70–90% in relapsed or previously untreated disease). In contrast,
response rates were lower in follicular lymphoma presumely indicating the different
survival signal of the constitutive BCL-2 overexpression in this lymphoma subtype.
These data also confirm the crucial role of the micromilieu in lymphoid diseases
which are hampered by the inhibition of the B-cell receptor pathway. Finally, recent
in vitro data suggest some synergism of different members of the B-cell receptor
pathway in combination with mTOR inhibition. Such molecular targeted strategies
have therefore the potential to become part of the new treatment strategies in a broad
spectrum of lymphoid neoplasias.
Disclosure: M.H. Dreyling: Pfizer (Temsirolimus): scientific advisory board, speaker\
\\’s honoraria Janssen (Ibrutinib): scientific advisory board, support of IITs, speaker\\
\’s honoraria
66IN PROTEASOME INHIBITORS: REALLY A TARGETED THERAPY?
D. Colomer 1 , P. Perez-Galan 2 , G. Roué 2
1 Hematopathology Unit, Hospital Clínic, Institut d’ Investigacions Biomèdiques
August Pi i Sunyer (IDIBAPS), Barcelona, SPAIN, 2 Hematology-oncology. Cek,
Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona,
SPAIN
Bortezomib is the first-in-class proteasome inhibitor that targets the critical process
of intracellular protein modification and degradation. In 2006, bortezomib was
approved for the treatment of relapsed or refractory MCL. The mechanisms of
proteasome inhibition are very complex as they affect many pathways. The Initial
rationale for bortezomib use was inhibition of NF-kB activity. However, bortezomib
does not block constitutive NF-kB activity in MCL and induces oxidative and
endoplasmic reticulum (ER) stress. This cellular stress leads to the activation of a
cytoprotective response called Unfolded Protein Response (UPR), that tries to aliviate
ER stress and rescue the cell by different adaptive mechanisms. However under
conditions of prolonged stress, apoptosis is activated. Apoptosis commitment starts
with the transcriptional activation of the propapoptotic BH3-only protein Noxa,
leading to mitochondrial apoptosis. However, half of MCL cases fail to respond, and
resistance often appears after initial treatment. By gene expression analysis it has
been reported that MCL bortezomib-resistant cell lines showed partial plasmacytic
differentiation, including increased expression of IRF4 and its target genes, and of the
cell-surface markers CD38 and CD138. Tumors from patients with inferior clinical
responses to bortezomib also had high IRF4 and CD38 expression, identifying
possible clinical markers of bortezomib resistance. Also, a correlation between loss of
sensitivity to bortezomib and up-regulation of the prosurvival chaperone BiP/Grp78
controlling ER homeostasis has been observed. BiP/Grp78 forms a large multiprotein
complex with other ER molecular chaperones, including HSP90. Combination of
bortezomib with IPI-504, a HSP90 inhibitor that displace the client proteins and
target them for destruction by the proteasome system, prevented BiP/Grp78
accumulation, thereby promoting apoptosis and inhibiting the growth of
bortezomib-resistant tumor xenotransplants. In summary, targeting the
ubiquitin-proteasome pathway with bortezomib represents a potent arsenal in the
treatment of MCL, although we need to find new combinations and specific
biomarkers that may help us to recognize which cases will be benefit from each
specific treatment.
Disclosure: All authors have declared no conflicts of interest.
67IN IMIDS: MULTIPLE PATHWAYS BUT DOES IT REALLY WORK?
G. Morgan, C. Pawlyn, F. Davies
Division of Molecular Pathology, The Institute of Cancer Research, London,
UNITED KINGDOM
The mechanism of action of IMiD® compounds has been the subject of much recent
research which has highlighted the dual effects of these drugs, with both direct
tumoricidal effects and immunomodulatory activity. Lenalidomide exerts its
tumoricidal effects through a number of mechanisms, including decreased
production of cytokine and growth factors causing disruption of stromal support,
induction of tumor suppressor genes leading to cell cycle arrest and activation of
caspases triggering tumor cell apoptosis. A recent study showed that IMiD®
compounds increase p21 expression by a novel epigenetic mechanism. Lenalidomide
also provides sustained disease control by improving immune function, resulting in
continued tumour killing. Lenalidomide exerts immunomodulatory effects via
enhanced antigen-specific CD8+ T-cell cytolysis and by increasing natural killer
(NK)-cell expression of death effector molecules. Lenalidomide and pomalidomide
have greater tumoricidal effects than thalidomide. Lenalidomide also has a more
potent effect on the immune system. Both thalidomide and pomalidomide have
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com