ARTICLE
Auteur(s) : FJ
Lejeune, C Rüegg
Centre hospitalier universitaire Vaudois (CHUV)
Clinical Associate, Ludwig Institute for Cancer Research, BH15-701,
rue du Bugnon 46, CH 1011 Lausanne, Suisse
Cancer growth depends on tumour angiogenesis, which is promoted by
angiogenic factors secreted by tumour cells [1]. It has recently
been suggested that using agents destroying intratumoural vessels
could constitute a new strategy that has the advantage of not being
restricted by tumour histology.Tumour necrosis factor (TNF) is a
major player in both innate and specific acquired immunity. It has
pleiotropic properties, among which the ability to cause apoptosis
of tumour-associated endothelial cells, that can result in the
complete destruction of the tumour vasculature. Lloyd old’s team
discovered [2-4] that the serum from BCG- and endotoxin-challenged
mice induced massive haemorrhagic necrosis when injected to
tumour-bearing mice, hence the name tumour necrosis factor. The
same authors gave evidence that the tumour-associated vessels were
the primary target of TNF and were selectively destroyed. TNF is a
transmembrane protein which, upon cleavage by the metalloproteinase
TACE, produces a soluble trimer of 157 amino acids [5]. Both
isoforms of TNF (membrane and soluble TNF) bind two distinct
receptors that are ubiquitous, p55 or TNF-R1 and p75 or TNF-R2 [6].
Intracellular signalling of TNF-R1 has been partly deciphered. Two
opposite pathways were evidenced in endothelial cells: an apoptotic
pathway initiated by clustering of death domain-containing proteins
[7, 8] leading to caspase activation [9] and a proliferation and
survival pathway involving activation of nuclear factor (NFκB)
[10-12]. Activation of p55/TNFR-1 is essential for the apoptotic
pathway [13]. The mouse [14] and the human TNF genes were cloned
and recombinant TNF was produced in Escherichia coli. The crystal
structure was then solved a few years later [15]. The availability
of recombinant TNF paved the way to extensive studies in animals,
which revealed that TNF not only has antitumour properties but also
strong haemodynamic effects. Indeed it was found that TNF is an
important mediator of septic shock [16], although later Toll like
receptor 4 (TLR4) was also found to play a critical role in the
initiation of septic shock [17]. The clinical phase I and II
studies confirmed that the dose limiting toxicity of TNF is
vasoplegia, a pathological condition leading to multiorgan failure,
the “septic shock like syndrome”. Most phase I studies reported a
maximum tolerable dose (MTD) of 30 to 200 μg/m2 when
injected daily for 5 days; protracted infusion of 24 hours allowed
to reach a MTD of 200 to 545 μg/m2[18-22]. In phase II
studies, doses of 350 to 400 μg/m2 produced rare and
minimal tumour responses [23, 24]. Most tumour models including
human xenografts in nude mice have shown that TNF alone is not
sufficient to effectively suppress tumour growth, and that
definitive cure in animals could be only obtained by combining TNF
either with chemotherapeutic agents or with interferon-gamma
(IFNγ). It was then shown that TNF synergizes with IFNγ [25-28],
with several chemotherapeutic agents and hyperthermia, to induce
antitumour responses [29-33]. The mechanisms responsible for these
synergisms are still not fully understood, and, in the eighties,
only few clinical studies have evaluated these synergisms. In
addition, clinical investigators who were performing the phase II
studies were correcting vasoplegia only when it appeared during
therapy. In other words, no protocol included active measures to
prevent side effects, especially the “septic shock like syndrome”,
also known as “systemic inflammatory response” [34, 35].
Furthermore, vasoplegia immediately leads to poor vascular
exchanges and poor drug biodistribution [36, 37], including of TNF
itself. It is therefore not surprising that, in 1986-87, the
projects for further clinical evaluation of TNF were abandoned due
to the excessive systemic toxicity and lack of interesting clinical
antitumour effects.
Isolated limb perfusion allows the regional administration of
TNF
The efficient antitumour dose of TNF in mice is approximately 50
mg/kg. If translated in human dose, this is 10-fold higher than the
dose i.e. 400 μg/m2 that was found toxic in human with
only anecdotal tumour responses [38]. In 1988, we designed a
protocol for the application of TNF by isolated limb perfusion
(ILP) [39-41]. ILP is a method originally designed for
administering high doses of chemotherapy in limbs affected by
locally advanced tumours. This method consists in surgically
isolating the vessels irrigating the limb affected by the tumour,
to canulate and connect them to a heart-lung machine to maintain
perfusion and oxygenation. The resulting extra-corporeal
circulation, under tourniquet, receives high dose chemotherapy,
reaching up to 30-fold the levels obtained by systemic
administration. Systemic toxicity is abolished, depending upon the
efficiency of the isolation. ILP with high-dose single chemotherapy
agent melphalan was found to produce a complete response (CR) rate
of around 50% in unexcised in-transit melanoma metastases but had
minimal effect on soft tissue sarcomas of the limbs [42, 43]. This
treatment modality allows administering high drug doses without or
with minimal systemic toxicity. It was therefore interesting to
investigate the combination of TNF to chemotherapy with the aim to
improve the results obtained with chemotherapy alone.
As previously mentioned, preclinical data indicated that TNF
cytoxicity to tumours could be enhanced when combined with other
treatment modalities:
- – with alkylating agents;
- – with IFNγ;
- – with hyperthermia.
Based on these data, we then decided to test TNF in a series of
feasibility studies: TNF as a single agent or in combination to
IFNγ, in ILP for melanoma in-transit metastases. In this pilot
study of TNF alone or in combination to IFNγ, we observed only
minimal or no tumour response [44]. Next, we designed a triple
combination protocol: high dose TNF, low dose IFNγ and high dose
melphalan [39]( (figure
1) ). TNF dosage was 10-fold the MTD, with perfusate
concentration reaching 2-7 μg/ml and melphalan peak concentrations
of 20-60 μg/ml [41]. Continuous radionuclide-based monitoring of
the leakage allowed to dose perfusion pressure/volume to avoid
leakage and major side effects [45].
There are oncological conditions where tumour spreads
extensively and exclusively for a time in a limb. This can be the
case in melanoma where in-transit metastases occur in 6 to 10% of
the patients, and in soft tissue sarcomas of the limbs that can be
inextirpable in 10% of the cases Indeed, multiple and recurrent
in-transit melanoma metastases and inextirpable soft tissue
sarcomas are conditions where surgery is either inefficient or
produces severe functional sequellae. Some cases, especially
sarcomas, are indications for limb amputation.
Efficacy of TNF-based isolated limb perfusion in melanoma
The results of the first single institution pilot study on melanoma
and sarcoma were impressive [40]: there was fast and intensive
tumour necrosis, similar to the one reported in animal models, with
virtually no severe systemic toxicity. An overall response rate of
100%, with 89% complete responses and 11% partial responses (table
1( Table 1 )).
Several phases II studies were undertaken in Europe and in the
United States (table 2( Table 2 )).
Although different phases II cannot be compared, it seems that the
triple combination of TNF, IFNγ and melphalan gave the highest
rates of CRs. The role of IFNγ was questioned in a randomized phase
II study (table 2). Omitting IFNγ resulted in a 10% CR rate
decrease, but the design of this study did not reach the
statistical power to confirm that this difference was significant.
Although no control melphalan arm was included, a comparison of the
two TNF arms with matched cases from a databank confirmed that ILP
with melphalan only resulted in a 52% CR rate.
One phase III randomized study aiming at comparing
TNF-containing ILP (TIM-ILP) to melphalan-only ILP (M-ILP) was
undertaken in the USA (table 2). Although a not significant trend
for higher CR rate was found in the TIM arm, the latter was
followed by 67% CR in bulky melanoma metastases 17% CR in non bulky
disease.
TIM-ILP is the treatment which gives the most dramatic response
of in-transit melanoma metastases. Within 1 to 7 days, collapses
and softening of skin tumours are apparent. This is similar to the
first observations reported by Old et al. in experimental models.
This potent effect is especially observed in bulky tumours, and to
a lesser extent in small tumours (figures 2, 3).
This is in opposition to the paradigm of cancer chemotherapy:
the smaller the tumour, the better the response. It seems that
vascularization in large tumours is more elaborated than in small
tumours and results from a progressive process triggered by tumour
growth. In addition, bulky tumours are often heterogeneous, with
areas of necrosis. It can therefore be hypothesised that two
phenomena could be responsible for the better response of bulky
tumours:
- – destruction of elaborated vascularization;
- – improved drug penetration into poorly vascularized
regions of the tumour.
A strong support for this hypothesis was given by in vivo animal
studies (see section “Evidence for two distinct effects of TNF on
tumour associated vessels”). As the major effect of TNF is exerted
on tumour-associated vessels, there is no limitation to tumour
histology. The same efficacy can be obtained in extensive skin
spindle cell carcinomas (( figure 3 ), case 3).
Table 1 First pilot/phase II study of TNF-based
isolated limb perfusion in melanoma and soft tissue sarcoma
|
Regimen
|
Reference
|
CR%
|
PR%
|
ORR%
|
|
TIM-ILP
|
[40]
|
89%
|
11%
|
100%
|
Table 2 Phases II and III of TNF-based isolated limb
perfusion in melanoma
|
Study
|
Regimen
|
References
|
CR%
|
PR%
|
ORR%
|
|
Phase II, multicentric
|
TIM-ILP
|
[82]
|
90
|
10
|
100
|
|
Phase II, monocentric
|
TIM-ILP
|
[83]
|
76
|
16
|
92
|
|
Various phases II
|
TM-ILP
|
[84, 46, 48]
|
65-70
|
80-100
|
|
|
Randomised phase II
|
TIM-ILP
|
[47]
|
78
|
22
|
100
|
|
TM-ILP
|
|
69
|
22
|
91
|
|
Randomised phase III
|
TIM-ILP
|
[85]
|
80 (67*)
|
|
|
|
M-ILP
|
|
61(17*)
|
|
|
Duration of response to TNF ILP and survival in melanoma
Typically, ILP is a one-course procedure that cannot easily be
repeated because of difficult vascular access after previous ILP.
In addition, tissue fibrosis can impair limb function and is a
rather common side-effect, mainly due to melphalan, and multiple
ILPs can further worsen it. Time to recurrence was found to range
from 6 to 16 months. Despite the very high response rate, this
treatment is a regional treatment and as such it was not expected
to have impact on survival. Indeed, in melanoma, survival curves
from patients treated with TNF-containing ILP were identical to
melphalan alone ILP and the median survival ranged from 2.5 years
to 5 years [42, 46-48]. These results show that survival was
rather long in spite of local progression. This suggests that
in-transit melanoma metastases are indeed a different disease where
the tumour restricts its extension to an area of the body several
years before producing distant metastases. This is an argument that
reinforces the indication of ILP for in-transit melanoma
metastases.
TNF-based isolated limb perfusion is a limb-sparing
neo-adjuvant treatment in inextirpable soft tissue sarcoma
Soft tissue sarcomas (STS) of large volume or recurrent are usually
found to be invading several anatomical compartments, involving
neuro-vascular bundles and/or articular capsule, a clinical
situation leading to the indication of amputation or
disarticulation in 5 to 10% of all limb STS. However, survival
rates of STS patients treated with limb salvage surgery seem to be
similar to those obtained after mutilating surgery [49, 50]. This
observation suggested that any regional treatment that increases
limb salvage would not be detrimental to life expectancy of the
patients. Attempts to increase the local operability of soft tissue
sarcoma have been made using systemic neo-adjuvant chemotherapy.
The literature showed that the overall response rate is in the
range of 38 to 47%, with few complete responses. ILP with melphalan
with or without other drugs gives a 5 to 10% complete response of
short duration (reviewed in [43]). The first single center study
which included melanoma and soft tissue sarcomas [40] indicated
that TNF-containing ILP could be used in a neo-adjuvant setting,
rendering inextirpable tumours removable without major mutilation (
(figure 4) ).
The surgical procedure aims at removing the tumour remnants
without mutilating surgery. In other words, when classical broad
surgery could create a serious limb function impairment, narrow
margins are taken, considering tumour necrosis and tumour vascular
destruction resulting from perfusion; this can be evaluated by MRI
( (figure 5) )
and ultrasound Doppler.
A series of prospective, multicentric phase II studies were
launched in Europe (table 3( Table 3 )).
As in melanoma, the triple combination, TNF, IFNγ and melphalan
(TIM-ILP) gave the highest CR rate ever obtained in STS treatment:
36% [51]. The ultimate achievement was limb salvage, which was
obtained in more than 85% of cases.
Melphalan is not a drug of choice for systemic chemotherapy of
sarcoma whilst doxorubicin as a single agent can produce up to 40%
responses. For this reason an Italian group has tried doxorubicin
alone with some promising results and it was followed by the
combination of doxorubicin with TNF with response rates rather
similar to the combination of melphalan and TNF, but apparently
with slightly less limb salvage rates (75%) [52].
ILP with recombinant human TNFα-1A (tasonermin) and melphalan
was registered in Europe for the indication of limb salvage in soft
tissue sarcoma and, in Switzerland, for both soft tissue sarcoma
and melanoma.
Table 3 Phases II of TNF-based isolated limb perfusion
in soft tissue sarcoma
|
Study
|
Regimen
|
References
|
CR%
|
ORR%
|
Limb salvage (%)
|
|
Phase II, multicentric
|
TIM-ILP
|
[51]
|
36
|
87
|
84
|
|
|
Multicentric, data grouping
|
TM-ILP
|
[86]
|
29
|
82
|
82
|
|
|
Various phases II
|
TM-ILP
|
[87-89]
|
37-70
|
80-92
|
85-90
|
|
|
Phase II, monocentric
|
TIM/TM-ILP
|
[90]
|
18
|
82
|
77
|
|
|
Phases I, multicentric
|
Doxo/TNF-ILP
|
[91]
|
|
|
75
|
|
|
Randomized phase II, multicentric
|
TM-ILP TNF dose:
|
|
|
|
|
|
0.5 mg
|
|
32
|
68
|
84
|
|
1 mg
|
|
40
|
56
|
80
|
|
2 mg
|
|
32
|
72
|
84
|
|
3-4 mg
|
|
40
|
64
|
92
|
What is the optimal TNF dosage for ILP?
Pharmacokinetics of TNF in ILP perfusate showed a plateau that
suggests a saturation of the perfused tissues [41]. The lowest dose
of TNF clinically efficient in ILP for soft tissue sarcoma (STS) is
not known. A relevant question is, therefore, whether doses lower
than the registered ones might be as efficient and less toxic.
Lowering TNF dosage could improve safety and reduce cost. There are
indeed some small series in the literature which suggest that lower
doses of TNF can be efficient but no comparative study was
available [53, 54].
A multicentric randomized phase II study was initiated to
compare four dosages of TNF in terms of complete response on MRI
[55]. The CR rates and the overall response rates (OSR) showed no
statistically significant differences as the study was designed to
detect a difference of 10% or more. Systemic toxicity was
significantly related to high doses TNF. The 2-year overall and
disease-free survival rates (95% CI) are 82% (73%-89%) and 49%
(39%-59%), respectively. Although the overall results are similar
to the ones obtained after high dose TNF, it cannot be definitively
concluded that lower doses are equal to high doses because this
study was not powered to prove it.
Toxicity of ILP with TNF and chemotherapy
Continuous monitoring of leakage from perfusate to systemic
circulation is of paramount importance. It was well established
that it permits to take action at any moment, mainly by reducing
pump flow rate that is directly correlated to perfusion pressure,
hence to imbalance between the two compartments [42, 56, 57].
Indeed, a 10% leakage means that the systemic MTD is reached. In
spite of this monitoring, suppressing leakage in some patients is
sometimes an unmet goal for peculiar anatomical/vascular reasons.
In the European experience, most side effects were mainly due to
TNF and they were all reversible with no sequellae [42]. An
important finding was that peak levels of bioactive TNF measured in
the plasma varied a lot, with a minimum at picograms level and a
maximum of hundreds of nanograms [58]. This very high TNF
concentration was not life-threatening in our patients. A tentative
explanation comes from studies on septic shock, where not only TNF,
but also Toll like receptor-4 (TLR-4) triggering by endotoxin, is
necessary to elicit a septic shock [17]. Patients treated with
TNF-based ILP had no infection and therefore were not exposed to
endotoxin. Interestingly, the haemodynamic changes that occurred,
especially the drop of peripheral vascular resistance, were rarely
correlated to the level of TNF in the systemic circulation [58].
This observation clearly shows that haemodynamic sensitivity to TNF
varies tremendously among individual patients. As this is
unpredictable variable, careful monitoring of perfused patients is
mandatory during and after ILP.
Evidence for two distinct effects of TNF on tumour angiogenic
vessels
TNF has two distinct effects occurring at different time points:
- – an early effect within 30 minutes is the improved
penetration of anti-cancer agents;
- – a late effect 24 hours to a few days , the selective
destruction of the tumour-associated angiogenic vessels.
Improved penetration of anticancer agents
In vitro data on human umbilical vein endothelial cells (HUVECs)
and microvascular endothelial cells can explain why penetration of
drugs into tumours is enhanced by TNF and why tumour angiogenic
vessels are selectively destroyed by TNF-based ILP. TNF alone or in
combination to IFNγ at a concentration of 10 ng/ml strongly alters
the endothelial cell monolayer integrity [59]. From a confluent
cobblestone monolayer, treated cultures show spindle endothelial
cell morphology with interrupted confluence. An increased
permeability of endothelial cells and pericytes was evidenced in
vitro upon treatment with TNF [60].
In vivo, these gaps in the endothelial cell monolayer translate
into increased permeability of perfused microvessels. An increased
uptake of monoclonal antibody and chemotherapy drugs was found to
occur selectively in the tumours [61-63].
Selective destruction of angiogenic vessels
The initial work of Old et al. [2, 3] indicated that the rapid
necrosis of mouse tumours was the result of the selective
destruction of tumour-associated vessels. Moreover, the same group
showed that this effect was important when the tumours were grafted
in well-vascularized skin and negligible when they had been grafted
in poorly vascularized peritoneum cavity.
Indeed, in patients treated by TNF-ILP, angiograms performed on
sarcoma- or carcinoma-bearing limbs reproduced the early
disappearance of tumour-associated angiogenic vessels, whilst
bystander normal tissue vessels were spared [40, 64] (( figure 3 ), case 3). New
methods can provide an early evaluation of the effect of TNF-ILP on
tumour vasculature, namely magnetic resonance imaging (MRI) and
Doppler ultrasonography. A prospective comparison study was
undertaken at Institut Gustave-Roussy on soft tissue sarcomas.
According to MRI and histological analysis, 51% of patients were
good responders with tumour necrosis exceeding 90% and 49% were
poor responders. In contrast, as of day +1 the accuracy of DUPC
(Doppler ultrasonography with perfusion software and contrast agent
injection) in predicting tumour response was 82% (72% good
responders and 22/24 poor responders) increasing to 91% at day +7,
95% at day +15 and 96% at day +30. At day +15, DUPC was predictive
of a good response in 100% of the cases. DUPC is a simple
technique, allowing early prediction of tumour response after ILP
technique [65]. A direct way of assessing tumour viability is
positron emission tomography (PET) scan. It is especially useful
for the follow-up of patients with multiple in-transit melanoma
metastases.
We have demonstrated that TNF-induced endothelial cell death is
associated with the selective inhibition of integrin avb3, an
adhesion receptor highly expressed on angiogenesis endothelial
cells, but not, or to a lower level, on quiescent endothelial cells
[66, 67]. Integrins, indeed, promote physical cell adhesion to the
extracellular matrix, and deliver survival signals to the cell
[68]. Subsequently we have observed that activation of protein
kinase B (PKB, or Akt), together with NFκB, is essential for
endothelial cell survival on response to TNF. Importantly, PKB
activation, required integrin ligation to ECM, while NFκB does not
[Bieler et al., in preparation].
Local and systemic inflammatory response after TNF-based
ILP
After ILP, several soluble factors involved in inflammation are
secreted in the plasma and seem to result from the systemic effect
of TNF: there is a peak of IL-6 [69, 70], IL-8 [69, 71], increase
of C-reactive protein, release of tenascin-C [72] and of
phospholipase A2 [73]. Release in the plasma of soluble TNFR-1 and
TNFR-2 occurs within 30 minutes and does not correlate with the
amount of TNF leakage [70]. We found that the amount of receptors
was only able to neutralize picograms of TNF. At the tumour tissue
level, biopsies taken early after TIM-ILP and up to 60 days later
revealed that an intense inflammatory response takes place [74].
There is an up-regulation of the adhesion molecules E-selectin and
V-CAM on endothelial cells, with perivascular recruitment of PMNs.
This is followed by PMNs colonisation of tumours a few days later
by lymphocytes and macrophage infiltration after two weeks [74].
These results suggested that tumour destruction, with tumour
antigens shedding in the context of and inflammatory reaction, with
recruitment of antigen presenting cells and lymphocytes, could have
elicited some immune response. Previous unpublished data on
circulating CD8+ lymphocytes in HLA-A2 melanoma patients suggested
that CD8+ T cell activation had occurred after TIM-ILP. An ongoing
study at Ludwig Institute for Cancer Research, in Lausanne, aims at
evaluating CD8+ T cell response in melanoma patients after
TNF-based ILP, using HLA-A2 multimers against Melan-A/Mart-1
peptides.
TNF based ILP efficacy is due to dual targeting
Taken together, the clinical and experimental results suggest that
the synergism of the combination of TNF to melphalan is not limited
to a direct interaction but rather to a double and distinct
targeting: endothelial cells and tumour cells. TNF rapidly enhances
tumour vessel permeability, resulting in increased accumulation of
melphalan in the tumour, while, later on, it causes vascular
collapse, resulting in a complete shut-down of tumour perfusion and
acute tumour necrosis. An hypothetic model is presented in ( figure 6 ).
TNF targeting: a hope for a safe systemic administration in
humans?
The recent approach of using phage display libraries allowed the
discovery of new targets for anti-angiogenic strategies. It was
possible to isolate human antibody fragments that recognize altered
extracellular matrix proteins normally only expressed in oncofoetal
tissues and to find peptides that can bind receptors expressed by
angiogenic endothelial cells in tumours.
At least three recent studies indicate that it is possible to
target TNF to the tumour site. First, a human single chain (scFv)
recombinant antibody [75] recognizing the extradomain B+ (ED-B+)
isoform of fibronectin was fused with monomeric TNF. As this
fibronectin isoform is highly expressed in the basal membrane of
angiogenic vessels in malignant tumours, tumour accumulation after
intra-venous injection was obtained in an animal model. It
permitted a strong synergism with melphalan also injected
systemically [76]. Second, peptides containing the CNGRC motif bind
to an isoform of aminopeptidase N (CD13) extensively expressed by
angiogenic tumour vessels. When coupled to TNF (NGR-TNF),
doxorubicin penetration in tumours was improved and a strong
synergism was demonstrated, using picogram doses of NGR-TNF [77,
78]. Third, a single-chain Fv recognizing gp240 [79] a glycoprotein
expressed by more than 80% of melanoma cells [80] was found to
increase TNF cytotoxicity and to reduce cell resistance, when
coupled to TNF. Recent in vitro experiments showed some synergy
with chemotherapeutic agents [81].
Taken together, these three TNF targeting preclinical studies
indicate that it is possible to efficiently and safely administer
TNF systemically if it is targeted to angiogenic vessels or to
tumour cells. The efficiency clearly resides essentially in the
increased efficacy of chemotherapy because of improved
intratumoural penetration. However, it can also be hypothesized
that the intratumoural delivery of TNF might produce other
biological effects, such as the improvement of the immunological
response to the tumour, or inhibition of angiogenesis in case of
repeated administration.
Acknowledgements
Our clinical studies were supported in part by Boehringer Ingelheim
GmBh. Work in our laboratory is supported by funds from the
Molecular Oncology Program of the National Centre for Competence in
Research (NCCR), a research instrument of the Swiss National
Science Foundation, the Swiss Cancer League/Oncosuisse, the Swiss
National Science Foundation, the Fondazione San Salvatore, the
Leenaards Foundation, the Fondation de la Banque Cantonale
Vaudoise, the Roche Research Foundation, the Novartis Foundation
and by the Medic Foundation. We apologize to those colleagues whose
work could not be cited due to space limitations.
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