Nowadays, All Therapies Are Targeted-Understanding
Biology Improves Disease Management
Jean-François
Rossi
Jean-François
Rossi, CHU Montpellier,
Department of Clinical Haematology, Montpellier, F-34295 France ; INSERM U1040,
Institut de Recherche en Biothérapie, Montpellier, F-34295 and University of
Montpellier I, UFR Médecine, Montpellier, F-34967 France
Correspondence to: Jean-François Rossi, MD, PhD, CHU Montpellier,
Department of Clinical Haematology, Montpellier, F-34295 France; INSERM U1040,
Institut de Recherche en Biothérapie, Montpellier, F-34295 and University of
Montpellier I, UFR Médecine, Montpellier, F-34967, France.
Email: jeanfrancoisrossi@me.com
Telephone: +33-467338079
Fax:
+33-467338373
Received: December 25,
2014
Revised: January 25, 2015
Accepted: January 25, 2015
Published online: April 30, 2015
ABSTRACT
Several decades
ago, chemotherapy was the first observed efficient therapy for cancers,
particularly for hematological malignancies. It was the time of case reports
and short series, when the balance between efficacy and toxicity was evaluated
on a patient per patient basis. This was considered as an empiric therapy, just
basic clinical research supported by an intuitive and creative medical
approach, inherited from medical history. Then, with the emergence of more and
more drugs, methodologies and rules for clinical research were implemented with
two goals: protect patients and rationalize empiric thinking. It was the time
of large cohorts of patients, the time of the p value. Some progress was
made as less empiricism and more science facilitated medical decision. With the
development of clinical protocols, classifications, prognostic indexes and
other relevant tools, including patients in clinical trials became most often
the only objective for physicians and other health professionals, with the aim
of raising the right questions and creating new protocols.
© 2015 ACT. All
rights reserved.
Key words: Targeted therapy; Personalized medicine
Rossi JF.
Nowadays, All Therapies Are Targeted-Understanding Biology Improves Disease
Management. International Journal of Hematology Research 2015; 1(1): 1-3
Available from: URL: http://www.ghrnet.org/index.php/ijhr/article/view/995
INTRODUCTION
Several decades ago, chemotherapy was the first
observed efficient therapy for cancers, particularly for hematological malignancies.
It was the time of case reports and short series, when the balance between
efficacy and toxicity was evaluated on a patient per patient basis. This was
considered as an empiric therapy, just basic clinical research supported by an
intuitive and creative medical approach, inherited from medical history. Then,
with the emergence of more and more drugs, methodologies and rules for clinical
research were implemented with two goals: protect patients and rationalize
empiric thinking. It was the time of large cohorts of patients, the time of the
p value. Some progress was made as less empiricism and more science
facilitated medical decision. With the development of clinical protocols,
classifications, prognostic indexes and other relevant tools, including
patients in clinical trials became most often the only objective for physicians
and other health professionals, with the aim of raising the right questions and
creating new protocols.
Today, we get
into a new period with too many tools, too many drugs, too many targets,
leading to personalized medicine plans[1,2]. Biology has become
extremely complex because only a single piece of the puzzle or a single
technique, a single result or a single target, are considered. As clinicians we
tend to forget the patient, the organ, the tissue where cells are present and
interact. By asking right and simple questions, creativity may come back. A
targeted therapy is generally viewed as the association of a specific drug
designed for a specific biological target. In fact, targeted therapy is just
the better use of our knowledge to treat patients. When used appropriately all
therapies are targeted. It is time to merge all pieces of the extraordinary
biological knowledge to simplify what we need to optimize patient’s management.
Some
illustrations are obvious
Tyrosine kinase
inhibitors (ITK)
Tyrosine kinase inhibitors (ITK) are the most cited successful examples
of targeted therapies: one disease, one biological target, one specific drug
resulting in the best clinical outcome. Since the alternative is the allogenic
transplantation, the comparison in terms of balance between benefit and risk is
simple and evident. There are additional targets for ITK, including signaling
pathways involved in the chronic myeloid leukemia cancer stem cell survival[3].
Different immune consequences can be observed, depending of the drug, depending
of the patients[4]. Dasatinib increases the number of circulating
large granular lymphocytes, i.e. Natural Killer (NK) and NKT cells[5].
Which cell response for which type of drug and which type of patients
represents the opening way for immune therapy in order to get a better control
of residual disease.
CD20 molecule
The case of the CD20 molecule, a cell surface molecule not restricted
to tumor cell is another success story. A synergy with chemotherapy and an
optimal balance between benefit and risk was observed in B-cell malignancies
with rituximab, the first developed anti-CD20 monoclonal antibody (MAb)[6].
In addition, the partial blockade of B-cells was associated with a clinical
benefit in dysimmune diseases, despite they were considered as T-cell mediated
disorders. This empiric or intuitive thinking was in fact a good idea because
of the good safety and tolerance of the CD20 molecule observed in cancer
patients and because of the need for new drugs after the failure of the
anti-Tumor Necrosis Factor (TNF) therapy[7]. Clinical results
underlying mechanisms were explained thanks to progresses in biological
research.
This success
was not the end of the story. Due to the forthcoming rituximab loss of patent,
the marketing authorization holder (MAH) built a new scientific and positioning
strategy. First, a subcutaneous (SC) form of rituximab (SCR) likely to prolong
the use of the molecule by simplifying its administration was developed[8].
Second, the afucosylated MAb, GA-101 or obinutuzumab, a more active form of
anti-CD20 MAb by amplifying Antibody-Dependent Cell Cytoxicity (ADCC), is close
to be marketed[9]. Therefore, both new anti-C20 MAbs are associated
with improved clinical efficacy. The SCR was developed by the MAH as an
equivalent drug of its IV formulation. However the MAH omitted the fact that
the target organ after SC administration is the lymph node compartment. Had
this been taken into account, one could predict a better activity and a better
clinical use of the drug. Similarly, GA-101 has a better activity particularly
on the lymphoid organs, with increased depletion on B-cell compartment,
including B-memory-cells-sharing CD20 molecules. This changes the therapeutic
strategy by avoiding the long-term therapy currently applied to rituximab.
Wrong clinical targeting would probably be associated with more infections or
less protection against standard and atypical infectious agents, with less
active vaccination against infectious pathogens[10]. Taking into
account biological and clinical targets is associated with an optimal
management of drugs.
Lenalidomide
Lenalidomide is another example that illustrates the need to consider
the biological target, present on both the tumor cells and the
micro-environment. This was not the case when the clinical development of
lenalidomide was initiated[11,12]. In such conditions, using
lenalidomide in Multiple Myeloma (MM) till disease progression as a maintenance
therapy may expose to unexpected clinical consequences. The cautious attitude
we adopted was to stop therapy after a limited additional duration, when
obtaining an optimal response in MM. Such decision is just logic when
biomarkers of interest or biological targets are unknown, and now it is adapted
to the follow-up of the residual disease. No unexpected secondary malignancies
were observed in our experience. Since « maintenance therapy » is not
meaningful « control of the residual disease » should be preferred,
representing an example of multi-factorial dynamic targeted therapy.
Interleukin 6
Interleukin 6 (IL6) is a pleiotropic cytokine in both cancers and
dysimmune diseases.
In Castelman’s
disease, it has been shown to be the central factor explaining clinical and
biological symptoms. Applying two drugs (siltuximab as a MAb against IL6 and
tocilizumab as a MAb against soluble IL6-Receptor) on one key target resulted
in a major clinical efficacy with both drugs[13]. The story is quite
different in MM. Siltuximab has been used in different clinical research
programs, with no demonstration of major clinical effect such as significant
prolongation of progression free survival and/or overall survival. The reason
of this failure of clinical benefit is due (1) to a mistargeting of patients,
too late in the disease, with clonal evolution and presence of several tumoral
growth factors (BAFF, IGF-1, VEGF,…), and (2) to a wrong choice of chemotherapy
agents combined with siltuximab, as these drugs also have anti-IL6 effect[14].
This example is the illustration of a combination of two mistargetings. Now, it
is time to perform ibrutinib adequate targeting for this drug, probably by
combining anti-IL6 and ibrutunib in patients who overexpress Bruton Tyrosine
Kinase (BTK).
Chemotherapy
Chemotherapy is also a targeted therapy, particularly if we use these
drugs correctly, combined to newly designed drugs. Their biological targets are
well known (cell cycle, DNA repair, epigenetics, metabolism,…)[15].
For some of these effects, simple biological tests are available, particularly
for cell cycle or signal transduction pathways. One could better use these
drugs. As an example, high proliferating index (checked by plasma cell labeling
index or KI-67 marker) is a simple test that could guide their use[16].
Immune therapy
Immune therapy represents another aspect of the complexity of targeted
therapy. Recently, the knowledge in immunology has substantially progressed.
This better knowledge of biological mechanisms should improve the use of the
different available tools for an improved clinical efficacy. Such progress has
been obtained in different domains, including the tumor cell escape to the
immune surveillance and cell-cell communication. Bio-clinical aspects to be
considered are simple: target recognition, target accessibility of the effector
cells and its biological efficacy, mechanisms of blockade, mechanisms of
killing, specificity, consequences of targeting. However, the current
complexity of immune therapy is probably due to the race in fundamental
research to develop more sophisticated techniques and tools. Immune therapy is
now entering a mature phase, an « à la mode » i.e. fashionable therapy
supported by drug companies[17].
Supportive care
Supportive care is also a targeted therapy. Hematopoietic growth
factors are proposed if hemoglobin level is below a certain level depending
from other factors such as co-morbidities or iron balance. In addition, the
prescription must be evaluated and modulated according to the targeted
efficacy. Granulocyte growth factor, platelet receptor agonists have to be
similarly managed. Anti-thrombotic agents are also targeted therapies. Among
them, low-molecular–weight heparins have an anti-heparanase activity which is
not shared by new oral anticoagulants. In MM, heparanase produced by
osteoclasts has been shown to perform syndecan-1 shedding from plasma cell
surface in the tumor micro-environment and by the way contributing to the
accumulation of growth factors in the tumor niche[18]. Therefore,
blocking heparanase may contribute to limit tumor growth, which may represent
an additional targeted clinical activity[19].
conclusion
Progress in biology and technology makes possible to improve clinical
efficacy. A new era is emerging, with less empiricism and more science. Efforts
have to be made to improve cost-effectiveness of new drugs despite the fact
that the direct costs for both developing and approving new drugs largely
increased[20]. Thus, decision is now based on evaluation of
different parameters, including an incremental cost-effectiveness ratio (ICER)
and the cost per life-year gained (LYG)[21]. There is a need to
create optimal conditions for such new therapeutic age, including dynamic
methodologies, bio-clinicians talking and taking care of the patients in the
context of real life.
ACKNOWLEDGMENTS
The authors thank Dr. Vidal Benatar for manuscript corrections.
CONFLICT OF INTERESTS
The author has no conflicts of interest to declare.
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Peer reviewer: Jo Caers, Department of
Clinical Hematology, CHU de Liège Domaine Universitaire du Sart Tilman Bâtiment
B 35, B-4000 Liège, Belgium.
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