Journal of Cancer Therapy, 2010, 1, 205-213
doi:10.4236/jct.2010.14032 Published Online December 2010 (http://www.scirp.org/journal/jct)
Copyright © 2010 SciRes. JCT
205
Immuno-Chemotherapy Using Repeated Vaccine
Treatment Can Produce Successful Clinical
Responses in Advanced Metastatic Melanoma
Brendon J. Coventry1, Peter Hersey2, Anne-Marie Halligan1, Antonio Michele3
1Discipline of Surgery, University of Adelaide, Royal Adelaide Hospital, Adelaide, Australia; 2Newcastle Melanoma Unit, Calvary
Mater Newcastle and Medical Oncology and Immunology Unit, University of Newcastle, New South Wales, Australia; 3Medical
Oncology, North Adelaide Oncology, Calvary Hospital, North Adelaide, Australia.
Email: brendon.coventry@adelaide.edu.au, Peter.Hersey@newcastle.edu.au, T.michele@naonc.com.au, Anne-Marie.Halligan
@health.sa.gov.au
Received August 16th, 2010; revised September 10th, 2010; accepted 17th, 2010.
ABSTRACT
Advanced Stage IV and IIIc melanoma has a dismal survival, with or without, standard chemotherapy. New therapies
are required to improve surviva l and redu ce mo rbid ity. Rep e ated va ccine do sing does not app ear to ha ve been explored,
so Vaccinia Melanoma Cell Lysate (VMCL) vaccine repetitive therapy was tested, either alone, or combined with che-
motherapy. 37 patients (31 Stage IV [M1a(6), b(7), c(18)] and 6 Stage IIIc) were studied using intra-dermal VMCL
vaccine therapy. If disease progressed, vaccine was continued with standard chemotherapy (DTIC and/or Fotemustine).
Overall survival was assessed and clinical responses were also recorded. From vaccine commencement, median overall
follow-up was 10 months. Survivals ranged from 4 to 73 months. Median (mean) overall survival was 10 (23.5) months;
overall survival at 1, 2 and 3 years was 40.5%, 21.6% and 10.8% respectively. CR and PR occurred in 18.9% (7) and
18.9% (7) of patients; these were durable for up to 6.1 years in 4 patients. Stable disease was noted in a further 17 pa-
tients (45.9%). In 6 patients (16.2%) no response to therap y was apparent. Repeated vaccinatio ns with or without che-
motherapy produced strong, durable clinical responses with overall survival > 23 months occurring in nearly 25% of
advanced melanoma patients. The overall disease control rate (CR, PR and SD) was 83.7%, including CR in very ad-
vanced cases. These results, in a largely unselected population of advanced metastatic melanoma patients, compare
very favourably with other regimens, and notably were associated with minimal, if any, toxicity. Further analysis of this
approach appears warranted.
Keywords: Vaccine Therapy, Combined Immuno-Chemotherapy, Repetitive Do sing, Advanced Melanoma, Clinical Re
sponses, Prolonged Survival
1. Introduction
Current therapies for advanced disseminated melanoma
or locally advanced disease remain seriously inadequate
with typically poor clinical responses, high failure rates
even when responses do occur, and options for any sub-
sequent therapy are severely limited. Immunotherapy
using vaccines has been used previously, but most stud-
ies have not persisted with continued vaccinations when
disease progression has occurred, and especially when
chemotherapy is administered, typically using either
Dacarbazine (DTIC) or Fotemustine, which are consid-
ered as the standard treatment agents. These standard
chemotherapy agents are often regarded as essentially
palliative for ameliorating symptoms from metastases,
but to our knowledge have seldom been tested with con-
current vaccine or other immunotherapies, apart from the
interferons. Despite trials and comparisons with a variety
of other chemotherapeutic and biologic agents and com-
binations of agents, little i mprovement has been possible
upon standard agents. However, progression free surviv-
als are usually less than 2 months with median overall
survival from 6-9 months, with any form of systemic
therapy. Percent survivals at 1-year in response to DTIC
and a variety of agents is approximately 25% [1], how-
ever this reduces substantially to < 2% at 2-5 years [2].
Immunotherapy with dendritic cell vaccines has been
effective in a number of small studies, but results have
Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful
Clinical Responses in Advanced Metastatic Melanoma
Copyright © 2010 SciRes. JCT
206
generally not justified the complex and expensive pro-
duction procedures. Immunotherapy with traditional
vaccines has received limited evaluation, and those
available have results at least as effective as those with
DTIC (reviewed by Hersey 2004) [3]. Surgery for iso-
lated metastases may be an option in highly selected pa-
tients with localised Stage IV or Stage IIIc melanoma,
but this option is usually unavailable or ineffective for
treatment of widespread metastatic disease.
Vaccinia Melanoma Cell Lysate (VMCL) vaccine
therapy, consisting of a vaccinia virus lysed, allogeneic
melanoma cell line, has been previously described [4,5]
and was used in a previous Australian randomised clini-
cal trial for earlier-stage, completely resected high-risk
melanoma [6]. Although no statistically apparent overall
survival benefit (p = 0.068) could be shown for the
VMCL vaccine treated group over the untreated controls
in Stage IIb and III melanoma patients, the survival of
vaccine treated patients remained above that of the
non-treated patients, indicating a possible ‘positive ef-
fect’ in some patients. The VMCL vaccine was shown to
be very safe and demonstrated low or no toxicity in over
700 patients given the vaccine for 2 years [6]. However,
no formal studies had been done in patients with residual
advanced disease, so a pilot study was done in patients
with advanced surgically non-resectable stage IV/ IIIc
metastatic melanoma (some after prior chemotherapy), to
examine whether immunotherapy with this vaccine may
be of benefit in this patien t group; and whether combina-
tion with DTIC or Fotemustine may further improve its
efficacy. The main aim in the study was to investigate
the feasibility of use of sustained, repeated dosing of the
VMCL vaccine for potential therapy in patients with
advanced unresectable melanoma to observe if any effect
appeared to be present, and if disease progression oc-
curred, vaccine would be continued during added che-
motherapy. Endpoints were primarily measurement of
overall survival, but morbidity and toxicity were also
recorded, and in addition response rates were noted sec-
ondarily.
2. Methods
2.1. Patient Characteristics
The median age of the thirty-seven [37] patients enrolled
in the studies was 59 years, with a mean age of 61 and
age range of 35 to 97 years. All patients were evaluable
for follow-up from 4 to 73 months after commencement
of vaccine therapy, with a mean of 23.5 months fol-
low-up and a median 10 months. No patients were lost to
follow-up.
All patients had either advanced non-surgically re-
sectable AJCC 1) Stage IV disease or 2) extensive multi-
ple in-transit metastatic stage IIIc disease. In these studies,
67.5% (25) of patients had extensive disease, with in-
volvement of internal organs; the remainder having ad-
vanced non-resectable subcutaneous metastatic disease of
the limb or trunk (Table 1).
2.2. Treatment Type
Vaccine therapy was administered alone in 18 (48.6%)
patients and Vaccine was combined and continued with
chemotherapy, typically with either DTIC, Fotemustine
or both sequentially in 19 (51.4%) of the 37 patients. 4
of the chemotherapy patients received Isolated Limb
Infusion (ILI) chemotherapy using melphalan (7.5 mg
per litre of limb tissue) and Actinomycin-D (50.0 g per
litre of limb tissue) and 2 patients received only 1 dose of
chemotherapy, terminated due to side-effects. CR’s oc-
curred in 7 patients: These occurred in 4 patients treated
with VMCL vaccine alone, 2 patients treated with prior
ILI chemotherapy and 1 patient treated with systemic
chemotherapy after commencement of the vaccine.
2.3. Patients and Inclusion/Exclusion Criteria
Informed patient consent, Human Ethics Committee ap-
proval and trial registration with the Australian Clinical
Trials Registry [ACTRN126 05000425695] was obtained.
Patient withdrawal could occur at any stage, and data
Table 1. Patient baseline characteristics.
Parameter VMCL Treated
(n = 37)
Age
(years)
Mean 61
Median 59
Range 35-97
< 55 14
55 - < 65 8
65+ 15
Gender
Male 19
Female 18
ECOG UICC
0 34 0 34
1 2 1 1
Perform-
ance Status
2 1 2 2
M Classi-
fication
IIIc 6
M1a 6
M1b 7
M1c 18
Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful
Clinical Responses in Advanced Metastatic Melanoma
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207
confidentiality was preserved. ECOG and UICC quality
of life/functional status scores were measured. Ophthal-
mological testing (for possible melanoma associated
retinopathy/iritis) and CT scans of the head, chest and
abdomen were done at entry and repeated each 6 and 3
months, respectively. In all, 37 stage IV/ IIIc melanoma
patients were enrolled in these studies for the primary
aim (see statistical information). Inclusion Criteria: Pa-
tients over 18 years; with ECOG 0-2; evaluable metas-
tases; primary cutaneous melanoma; advanced
non-surgically resectable AJCC Stage IV or Stage IIIc;
tumour volume < 20 cm diameter or < 70% of organ
replacement; +/- post-surgical treatment of brain metas-
tases; able to give informed consent. Exclusion Criteria
were presence of another primary invasive cancer (not
BCC, SCC or resected in-situ malignancy), untreated
brain metastases, extremely extensive disease, bone me-
tastases only, high-dose oral steroid therapy; pregnancy
or lactation; severe atopia; severe cachexia; immunode-
ficiency, HIV, Hepatitis B or C positive. 3 patients were
screened and found to have inoperable brain metastases
and were excluded. Apart from the latter, all screened
patients participated in the study.
Most patients were offered therapy provided their dis-
ease was advanced and not amenable to surgical resec-
tion.
2.4. VMCL Vaccinations
Vaccinations were at regular 2-weekly intervals for 6
months; then monthly for 6 months. If stabilisation/
complete response was obtained, then doses were given
3-monthly thereafter. Intra-dermal injection sites were
rotated between upper outer aspects of all 4 limbs, but
avoided in any limb where lymph node dissection was
performed, to avoid inducing any lymphoedema. 0.3 ml
of the re-suspended, sonicated, lysate was determined
as safe and practical from the previous studies of
VMCL vaccine [5]. Although only minimal skin reac-
tions were observed in previous Stage II/III melanoma
studies, precautionary resuscitation facilities were
available and patients were observed for 0.5-1 hour
after th e 1st and 2nd vacc in a t ions.
2.5. Skin DTH Testing & Responses
These were performed using the 1st and again at the 4th
VMCL vaccination dose (each read-out 48 hours later;
erythema and the induration responses were independ-
ently recorded in two directions perpendicular to each
other; > 10 mm was positive) at the vaccination sites,
after ensuring that no inflammatory response
pre-existed.
2.6. Chemotherapy
If the patien t showed melanoma d isease-progression dur-
ing vaccine therapy, the protocol allowed for addition of
standard chemotherapy with either Dacarbazine (DTIC)
(850 mg/ m2 at 3-weekly intervals intravenously), or Fo-
temustine (100 mg/ m2 weekly intravenously for 3 weeks,
followed by a 5 week break, then 3 weekly thereafter).
Vaccinations were maintained at 2-weekly intervals over
the chemotherapy period and during breaks in chemo-
therapy.
2.7. Clinical End-points
Primary End-point
Overall survival was the primary end-point assessed by
survival in months from the time of commencement of
vaccination to the date of analysis or death of the patient.
Secondary End-points
1) Toxicity and tolerability, in terms of local or sys-
temic reactions, was examined with each vaccination and
recorded.
2) Tumour response rates were also recorded, assessed
by the WHO [7] criteria. Observable subcutaneous le-
sions were assessed using two perpendicular direct size
measurements using calipers or a ruler, and internal me-
tastases were assessed using CT scans at 3-monthly in-
tervals or as clinically otherwise determined, and where
appropriate using ultrasound, MRI or Positron Emission
Tomographic (PET) scans.
2.8. Statistical Analysis
This was performed using standard means and median
calculations, Kaplan-Meier analysis and time-series
analysis with the assistance of our statistician and
mathematician (NB; AC). All analyses were set at a sig-
nificance level of 0.05 in the initial analyses.
3. Results Clinical Outcomes
3.1. Primary Endpoint-Overall Survival
Statistical analysis was performed on data collected to
the end of 2006, with a median overall follow-up at this
time (to either death or date of analysis) of 10 months.
Overall survival for all 37 patients ranged from ranged
from 4 to 73 months with a mean survival of 23.5
months and median survival of 10 months. Nine (9) of
the 37 (24.3%) patients survived greater than 23 months,
ranging from 1.9 – 6.1 years. The characteristics of these
9 patients are shown in Table 2. Organ and/ or lymph
node metastases in 7 of 9 patients (78%), and multiple
subcutaneous metastases alone were present in 2 of 9
Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful
Clinical Responses in Advanced Metastatic Melanoma
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208
Figure 1. Bar-chart for the 37 patients indicating the survival duration time-lines; showing also the period of vaccination
(red), and where used chemotherapy (blue), for each patient. (The green line indicates the comparative survival line calcu-
lated from the Korn 2008 paper data1).
patients (22%).
For the entire group, at the end of the survey period 9
(24.3%) patients were alive and well, and 28 (75.7%)
had died. The median survival time of the 9 patients
still alive was 25 months from vaccine commencement,
and in 5 of these patients the median survival time was
45 months. The survival times for the individual 37 pa-
tients along with the treatments given and the timing of
these treatments are shown as a bar-chart in Figure 1.
Nearly half the patients (15) survived beyond 12
months and 9 patients survived for longer than 23
months. More detailed description of the patients surviv-
ing to the 2-year time-point or beyond is given in Table
3. This showed that 3 had M1c, 1 M1b and 5 M1a stage
melanoma and most had failed prior radiotherapy (1),
surgical metastatectomy (6), biological therapy (2) and
ILI chemotherapy (1), two had received no prior therapy.
A Kaplan-Meier analysis was performed which dem-
onstrated an overall survival at 1, 2, and 5 years was
40.5%, 21.6% and 10.8% respectively. These survivals
compare vary favourably with the 1- and 2-year survivals
of 25% and 10% [1] and 30% and 11% [2] respectively,
in previous studies [1,2,8; see Table 3]. 5-year survivals
are uniformly low at < 2% in most studies.
3.2. Duration of Survival
The survival times of patients from the time of commence-
ment of vaccination until either death, or the time
of evaluation were analyzed by stratification into 6-
Table 2. Clinical outcomes for patients surviving > or = 23
months including survival time in months, disease sites and
current status.
Survival
(Months) ID Sites Past
Tx Status
73 015s/c; LN S Alive; Fully
functional
69 002lung; LN S, B AWD; Fully
functional
45 010s/c; LN S, ILI Alive; Fully
functional
44 008s/c Alive; Fully
functional
28 021s/c; LN S AWD; Fully
functional
26 006s/c S Died
25 023GB; s/c; lung;
LN S, B Alive; Fully
functional
24 017lung; liver;
spleen none Died
23 009bone; s/c; lung S, R Died
Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful
Clinical Responses in Advanced Metastatic Melanoma
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Figure 2. Kaplan-Meier survival curve for the VMCL ± Chemotherapy Treated Patients (n = 37).
monthly survival time groups for convenience and ease
of evaluation. Survival < 6 Month was 3 pati ent s (8. 1% );
6-12 Months 19 patients (51.4%); 12-18 Months 6 pa-
tients (16.2%); > 18 Months 9 patients (24.3%); and > 44
Months 4 patients (10.8%). Cumulative Survival, from
commencement of vaccination to either death or analysis
was: < 6 Months 3 patients (8.1%); > 6 Months 34 pa-
tients (91.9%); > 12 Months 15 patients (40.5%); > 18
Months 9 patients (24.3%); > 44 Months 4 patients
(10.8%).
3.3. Clinical Disease Responses
Clinical responses were considered as secondary
end-points, as these were related to, but separate from,
overall survival. This was especially so for CRs, as ex
pected, but PRs were also observed to be associated with
marked clinical melanoma regression (Figure 3), devel-
Table 3. Summary of Overall Survival and Complete Re-
sponse comparisons for VMCL (± Chemotherapy) Trial
treated patients compared with standard chemo-therapy
treated patients derived from recent historical data
(adapted from [1,2,8]).
N = 37
Complete
Response
Rate
Median
(mths)
1-Year
Overall
Survival
3-Year
Overall
Survival
Median
Survival
Time
(months)
VMCL
Therapy
(± Chemo-
therapy)
18.9% 40% 10.8%
10 (23.5
mean)
Standard
Therapies 0.8-2.7% 25.5-30% 0.5-1.9% 6.2
opment of stable disease and prolonged survival in some
cases. Initial complete regression (CR) of all tumors, as
measured by clinical and radiological means, occurred in
18.9% (7) of patients. Complete Durable Regression be-
yond 18 months (Alive + CR) occurred in 10.8% (4) of
patients.
Any Clinically Measurable Response was demon-
strated in 83.7 % (31) of patients, detected by regression
of some or all melanoma lesions, either clinically for
directly observable lesions, or radiologically for internal
lesions. PR was demonstrated in 18.9% (7) of patients
during treatment with the vaccine. Stable Disease (SD)
occurred in 45.9% (17) of patients. No quantifiable re-
sponse was noted in 16.2 % (6) of patients, but 1 or 2
lesions in these patients showed mild erythema or minor
size reduction of some lesions, which were sometimes
short-lived (< 6 weeks), ho wever, th ese were not counted
as ‘responses’. Progressive Disease (PD) was the cause
of death in all 28 (75.7%) who had died at the end of the
study period. No patient died of non-melanoma related
causes.
3.4. Toxicity
Anaphylaxis or allergy was not observed. No local or sys-
temic toxicity was observed at any stage from the vaccina-
tions during the studies. Minor skin irritation or unex-
plained dizziness was rare. Chemotherapy toxicity was of
the same profile observed with standard chemotherapy for
metastatic melanoma, and unaffected by concomitant vac-
cination. Side-effects of chemotherapy were generally
mild with no grade 4 toxicity observed. Three patients
required dose delay because of grade 3 neutropenia. Two
Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful
Clinical Responses in Advanced Metastatic Melanoma
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210
(a) August 2005
(b) December 2005
Figure 3. Patient treated with VMCL vaccine alone from
August (before; a) to December 2005 (during; b). She was
able to walk after the therapy and the pain, odour and
self-care ability improved markedly.
patients stopped chemotherapy after one cycle due to dis-
ease progression and patient choice.
3.5. DTH Responses
No measurable DTH responses against VMCL were de-
tected at either of the time-points tested in any of the 37
patients in the studies.
3.6. Prior Failed Clinical Treatment Type
Of the 37 patients, 20 patients (54%) had failed previous
non-surgical treatments; 14 (37.8%) had failed previous
chemotherapies (DTIC, Fotemustine, ILI chemotherapy,
other biological therapies), and a further 6 (16.2%) had
failed Radiotherapy alone; refer to Table 4 and Figure 1.
Table 4. Previous (Failed) treatments (see also Figure 2).
Treatment Number
Surgical Metastatectomy 21
Radiotherapy 11
Chemotherapy 6
ILI Chemotherapy 4
Biological Therapy 5
No Prior Therapy 10
4. Discussion
A possible innovative role for combined continued im-
muno-chemotherapy is suggested by these results in the
treatment of advanced non-resectable melanoma that has
(usually) failed surgery and/or other therapies. The re-
sults shown above indicate that repeated vaccine therapy,
with or without concomitant standard chemotherapy was
effective in inducing complete regression of advanced
melanoma in nearly 20% of patients and appeared to
slow melanoma growth in over 60% of patients with
mean survivals of 23.5 months and 1, 2 and 3 year sur-
vivals of 40.5, 21.6 and 10.5% respectively. An as yet
undefined mechanism appears to be operating to produce
these observations. The above findings compare fa-
vourably with the pooled results from the cooperative
group studies reported by Korn et al. [1], which appear to
have similar patient entry criteria. Our results were
unexpected, as many patients had failed (often multiple)
previous therapies and had extensive disease. Further-
more, one quarter of the patients (24.3%; 9) survived
over 23 months, since commencement of vaccination,
and long-term durable responses of between 4 and 6
years were obtained in 4 (10.8%) patients. Interestingly,
not all of these patients h ad CR’s to explain their clinical
course with repeated vaccination. At the end of the sur-
vey period, out of the 37 patients included in the study, 9
(24.3%) patients were alive and well, and 28 (75.7%) had
died. Almost half (46%; 17) of the patients were ob-
served to develop stable disease (SD), despite having
extensive disease. Somewhat predictably, overall sur-
vival was associated with clinical responses. This was
especially so for CRs, but surprisingly to us, PRs were
also observed to be associated with development of sta-
ble disease and prolonged survival, even in some patients
with high disease burden. This suggests some true effect
of repeated vaccination therapy, and possibly additional
chemotherapy enhancement, although the direction of the
effect (ie. which therapy is enhan cing which) is pr esently
unclear.
Although the results shown above are suggestive that
immunotherapy with VMCL ± chemotherapy may be of
benefit in extending the survival of some patients with
Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful
Clinical Responses in Advanced Metastatic Melanoma
Copyright © 2010 SciRes. JCT
211
melanoma, it is of course appreciated that interpreta-
tion in smaller uncontrolled studies may be con-
founded. However, the very fact that any patients
could demonstrate prolonged survivals was remarkable,
and that disease progression appeared to be halted, at
least for some considerable time in some patients. Al-
though inadvertent patient selection is difficult to
completely exclude, nevertheless, over 2/3 of patients
in the present study had much less favourable stage IV
M1b/c disease and included a spectrum of patients
with advanced disease. The importance of stage of
disease on metastatic melanoma is well reported, for
example in large patient groups, 1 and 2 year survivals
for M1a disease were 54% and 36% respectively
compared to 35% and 18% respectively for patients
with M1c disease [8]. In addition, some patients had
failed/ relapsed prior to entry and some had received
two or more forms of prior therapy as shown in Table 4,
where surgical metastatectomy included local and organ
metastatic disease resections; prior chemotherapy was
standard systemic therapy and/or ILI chemotherapy;
biological trial therapies included IL-18; Canvaxin;
NY-ESO-1; Interferon; and P-188 therapy.
The standard use of dacarbazine (DTIC) and Fote-
mustine, and in some countries multi-dose regimens,
have not been able to substantially alter the survival of
advanced metastatic melanoma, and are regarded as
essentially ‘palliative’. Despite hope that interleukins,
interferons and other bio-therapeutic agents would
improve outcome, this has not proved to be the case,
and are often limited by significant toxicity [9]. Prior
studies with both DTIC and Fotemustine alone have
reported response rates of 5-15%, and complete re-
sponse rates of 0.8-2.7% with median survival times of
5-8 months in patients with advanced melanoma. No
benefit was observed with multi-agent over single agent
chemotherapy [10-12]. Korn [1] in a me ta-an alysis of 42
phase 2 trials involving 2027 patients reported a me-
dian survival time of 6.2 months (95% CI; 5.9-6.5
months). Percent survival at 1-year was 25.5%. Be-
dikian [2] reported that DTIC induced a median sur-
vival of 7.8 months and approximately a 30% 1-year
survival. Overall response was 7.5% and a 0.8% com-
plete response rate in 395 patients. In the present
studies we observed that 15 patients (40.5%) survived
12 months or more. Our observed initial complete re-
sponse rate (CR) of all clinical and radiological tu-
mour was 18.9% (7) of patients. This remained durable
beyond 18 months (Alive + CR) in 10.8% (4) of pa-
tients. Any Clinically Measurable Response was
demonstrated in 83.7% (31) of patients despite many
of these patients had already failed standard (multiple)
therapies before entry to our study.
A potentially significant point of difference between
this and previous studies is that we chose to continue
regular vaccine administration for a long time period
irrespective of continued tumor growth [13]. Furthermore,
we also continued repeated VMCL vaccination during
any chemotherapy delivery, rather than stopping vacci-
nation entirely or even temporarily, as others have done
in the past.
Whether DTIC (or f ot emust ine) added subs t a nt ially to
the benefit of immunotherapy, or the reverse was true,
is not clear from this limited study, but it is our impres-
sion that combined vaccine and chemotherapy in pa-
tients with progressive disease enhanced the clinical
effectiveness and importantly was capable of producing
either CR or stable disease, with the net effect of pro-
longing overall survival. The combined additive effect
of vaccine and chemotherapy might be explained by
either increased antigen release due to chemotherapy, or
ablation of T-regulatory cells by chemotherapy or both
[14,15]. The timing of the administration of the VMCL
Vaccine and/ or chemotherapy may be of importance in
determining the clinical outcome and is the subject of
on-going studies [16,17]. Previous work has shown that
intra-tumoural dendritic cell (DC) numbers or poor DC
activation/ presentation may play a significant role in
directing the anti-tumor response and outcome [18-24],
perhaps through T-cell immunosuppression [25-28].
The T-effector cells and T-regulatory cell balance in the
tumour microenvironment is of likely critical impor-
tance in determining outcome in a variety of cancers
[29-34] and further studies are needed to examine these
aspects.
In summary, treatment with the VMCL Vaccine has
proven to be safe, with no or very low toxicity, and
appears to induce significant improvement in overall
survival in some 40% of patients with advanced mela-
noma. It is capable of inducing complete regression of
melanoma, and some of these are durable for long pe-
riods, extending to over 6 years. Stable disease can be
induced with or without partial responses in some le-
sions. If disease progresses, the VMCL vaccine can be
safely combined and continued with standard chemo-
therapy using DTIC or fotemusine, and this has added
to its effectiveness in a number of patients. The tu-
mour growth modulation producing resolution, regres-
sion, and stabilization of melanoma deposits in pa-
tients, is likely due to immunomodulation due to re-
peated dosing of vaccine continuously with or without
concurrent chemotherapy. Further evaluation of com-
bined vaccine and chemotherapy in a randomized trial
appears warranted.
Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful
Clinical Responses in Advanced Metastatic Melanoma
Copyright © 2010 SciRes. JCT
212
5. Acknowledgements
The authors would like to thank: Nancy Briggs and
Thomas Sullivan for statistical advice; Dr Andrew Coyle
for mathematical advice; Drs RG Morgan, R Hamilton,
D Kotasek, K Pitman, J Hokin, I Patterson for clinical
patient information and participation; Martin Ashdown
for reading the manuscript and helpful discussions; Pro-
fessor M James, for ethical advice and support. Mr Nick
Xenophon, for support and the donors and patients in
every way. Dr H Koga for some of the preliminary data
analysis.
6. Declaration of Conflicts of Interest
The authors declare no conflict of interest apart from the
development of the vaccine technology. A patent is ap-
plied for and held by the respective institutions. There
are currently no plans for commercialization of the vac-
cine.
7. Roles of Authors
BJC wrote the manuscript and conducted the studies with
assistance in the patient and data management by A-MH;
PH produced the vaccine and provided essential support
and advice; TM managed and coordinated the chemo-
therapy where used and provided advice.
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