Noninterferon-based adjuvant therapy for high-risk melanoma
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Review
Noninterferon-based adjuvant
therapy for high-risk melanoma
Lynn E Spitler
High-dose interferon is the only treatment approved by the FDA for adjuvant therapy of
melanoma. However, its efficacy in this setting is questionable and its administration is
associated with considerable toxicity. Many new agents are being tested clinically that
hold the promise of greater efficacy and less toxicity but none of these have yet shown
efficacy in controlled trials. These include biologics such as vaccines, cytokines,
monoclonal antibodies, gene transfer, cellular therapies and angiogenesis inhibitors as
CONTENTS well as chemotherapy combinations.
Melanoma staging Expert Rev. Anticancer Ther. 2(5), (2002)
Interferon
Melanoma staging This system represents an important
Alternative approaches
The American Joint Committee on Cancer advance in that it identifies significant prog-
Levamisole
(AJCC) Melanoma Staging Committee pro- nostic variables in patients with melanoma
Expert opinion posed a new staging system for melanoma and and validates them in an analysis of 17,600
Five-year view the final version and validation of the new stag- patients making it possible to precisely deter-
Key issues
ing system were published in 2001 [1]. The new mine the patient’s chance for survival. Under
staging system was approved by the AJCC Exec- the new staging system, survival curves corre-
References
utive Committee, the International Union late well with stage of disease (FIGURE 1) and
Affiliation Against Cancer (UICC) TNM Committee, the subgroupings within stage allow further
World Health Organization Melanoma Pro- refinement of prognosis (TABLE 1).
gram and the European Organization for There has not been consensus or agreement
Research and Treatment of Cancer (EORTC) as to which patients with melanoma represent
Melanoma Group. It went into effect in 2002 candidates for adjuvant therapy. In the USA,
with the publication of the Sixth Edition of the high-dose interferon (HDI) is approved for
AJCC Cancer Staging Manual [2]. patients with Stage II (T4) and Stage III dis-
Features of the new staging system include ease, although many patients refuse this ther-
the following changes: apy after being informed of the risk/benefit
• Incorporates ulceration of the primary as an ratio. There is no approved adjuvant therapy
adverse prognostic indicator in patients with for patients in other categories, so such
Stage I, II or III disease patients can receive standard therapy (obser-
vation) following surgery, participate in a
• Merges satellites and in-transit metastases
clinical trial or receive off-label treatment.
into a single staging entity that is grouped
Northern California Melanoma Clinical trials of adjuvant therapy for
into Stage III
Center, 900 Hyde Street, melanoma have focused mainly on patients
San Francisco, CA 94109 USA • Incorporates the number of metastatic with Stage III disease, probably because these
Tel.: +1 415 435 9861 lymph nodes and whether or not they are patients have a poor prognosis (Spitler
E16847
1.0 Two hundred and eighty intent-to-treat (ITT) patients (252 eligi-
0.9 ble) were treated with HDI or observation. The 5-year survival was
Stage I (n = 9175)
0.8 46% in patients on HDI versus 37% in patients randomized to
Proportion surviving
0.7 observation. This difference was of borderline statistical signifi-
0.6 cance (p = 0.237, one-sided as presented in the manuscript and p =
Stage II (n = 5739) 0.06, two-sided, as presented by the FDA) [101]. Furthermore, the
0.5
most important prognostic indicator, number of positive nodes,
0.4 Stage III (n = 528) was not recorded. Therefore, the reader cannot be sure the treat-
0.3 ment arms were balanced. Recent long-term follow-up data at a
0.2 median follow-up of 145 months shows no OS benefit with 95
0.1 Stage IV (n = 1158) deaths in the control arm and 93 deaths in the HDI arm (p = 0.09,
0.0 one-sided) [8]. Toxicity was considerable; 67% of the patients had
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 severe (Grade III) toxicity and 9% had life-threatening toxicity and
Survival (years) there were two deaths due to hepatotoxicity.
Figure 1. Survival by stage. Fifteen-year survival curves comparing
localized melanoma (Stages I and II), regional metastases (Stage III) and Table 1. Staging of malignant melanoma.
distant metastases (Stage IV). The numbers in parentheses are patients
from the AJCC melanoma staging database used to calculate the survival Stage Characteristics Five-year
rates. The differences between the curves are significant (p < 0.0001) [1]. survival
(%)
in which thousands of patients have participated in clinical I No nodal or distant metastases and
trials. There is a desperate need to identify therapies that have A Primary tumor £1 mm in thickness without 95
greater efficacy and less toxicity than HDI as adjuvant therapy ulceration
for patients with melanoma. B Primary tumor £1 mm in thickness with 90
ulceration or level IV or V or primary tumor
1.01–2 mm in thickness without ulceration
Interferon
In the USA but not in other countries, HDI is approved for II No nodal or distant metastases and
A Primary tumor 1.01-2 mm in thickness with 78
adjuvant therapy of Stage II and Stage III melanoma. In con- ulceration or primary tumor 2.01 - 4 mm in
trast, the use of low-dose interferon (LDI) for patients with thickness without ulceration
Stage II melanoma has been approved by the European Medi- B Primary tumor 2.01-4 mm in thickness with 64
cine Evaluation Agency on the basis of two studies showing ulceration or primary tumor >4 mm in
benefit in disease-free survival (DFS) [5,6]. The US-approval of thickness without ulceration
C Primary tumor >4 mm in thickness with 45
HDI was based on a study by the Eastern Co-operative Oncol- ulceration
ogy Group (ECOG) [7] and has been followed by two addi-
tional randomized trials of this therapy by the same group. The III
results show that there is disease-free benefit but overall survival A 1–3 nodes with micrometastasis and no 67
ulceration of the primary tumor
(OS)OS benefit is marginal, if present at all. Moreover, toxicity B 1–3 nodes with micrometasis and ulceration 62
of this regimen is considerable. Nonetheless, in 2001, the FDA of the primary tumor or 1–3 nodes with
implemented a policy whereby patients with high-risk macrometastasis and no ulceration of the
melanoma who refused adjuvant therapy with HDI could not primary tumor or in transit met(s)/satellite(s)
participate in clinical trials of other agents. This policy precipi- without metastatic nodes with or without
ulceration of the primary
tated a review by the Oncologic Drugs Advisory Committee in 1–3 nodes with macrometastasis and
February 2002, at which time, the consensus of the members C ulceration of the primary tumor or 4 or more 27
seemed to be that [8]: nodes with micro- or macrometastasis with
or without ulceration of the primary tumor
• There is no compelling evidence that administration of or satellite or in-transit metastases with
HDI to melanoma patients in the adjuvant setting results in metastatic nodes with or without ulceration
clinical benefit of the primary
• With informed consent, patients should be allowed choice in IV
the therapy they undergo M1a Skin and/or sc. metastasis, normal LDH 19
M1b Lung metastasis, normal LDH 7
The results of the three pivotal trials by ECOG are summa- M1c Other visceral metastasis or any distant site 9
rized as follows. The patient population for all three trials of metastasis and elevated LDH
included patients with Stage II primary melanoma or Stage (Modified from J. Clin. Oncol. 19(16), 3635–3648 (2001)).
III disease.
90 Expert Rev. Anticancer Ther. 2(5), (2002)Adjuvant therapy for melanoma
E 1690 [9]: monitoring board due to a survival advantage found by a
Six hundred and forty two ITT patients (608 eligible) were ran- predetermined interim analysis.
domized to HDI, LDI, or observation. The results demonstrate Two additional trials of HDI [13,14] and three trials of LDI16-
that the OS was the same in all three arms (p = 0.99). 18 in patients with high-risk Stage II and Stage III have not
demonstrated a survival advantage associated with this therapy.
E 1694/S9512/C5098111 A systematic review was conducted of randomized controlled
Eight hundred and eighty ITT patients (774 eligible for efficacy trials of interferon as adjuvant therapy for malignant melanoma
analysis) were randomized to HDI or to the GM2/KLH vaccine [18]. It is clear that interferon represents an imperfect solution
with QS 21 (called GMK). The results demostrated that patients for adjuvant therapy of melanoma and that alternatives are des-
receiving the HDI experienced benefit in OS (p = 0.009) and perately needed.
DFS as compared with patients who received the vaccine. The
study has been criticized for several reasons: Alternative approaches
• There was no control group given observation alone Investigational products under Investigational New Drug
applications (INDs) in 2002 for the adjuvant treatment of
• The difference in the OS in the two arms was not great (78% melanoma include vaccines, gene transfer, monoclonal anti-
for interferon-α-2b and 73% for GMK) bodies, cytokines and cellular therapies. Of these, vaccines are
• The vaccine regimen might have had a detrimental effect due by far the most widely studied, comprising over 50% of the
to the development of ‘blocking’ antibodies INDs, whereas the other approaches each constituteSpitler
Vaccines lipid A and mycobacterial cell wall skeleton. The allogeneic
Vaccinia melanoma oncolysate melanoma cell lines constituting the lysate contain many of
Mark Wallack devoted over 20 years to the preclinical and clin- the known melanoma-associated antigens, including tyrosi-
ical development of this vaccine that consists of four allogeneic nase, gp 100, MART-1, TRP-1, transferrin, transferrin
melanoma cell lines that are infected with live vaccinia virus receptor, S-100, ganglioside GD2, ganglioside GD3,
causing lysis of the cells. Phase I/II trials showed that the vac- MAGE-1, MAGE-2, MAGE-3 and high-molecular-weight
cine was safe and induced immune responses to melanoma chondroitin sulfate. They also contain human leukocyte
antigens when administered in higher doses and, furthermore, antigen (HLA) Class I and HLA Class II. The pioneering
these immune responses correlated with improved DFS. On trials of this vaccine conducted by Mitchell and coworkers
the basis of these observations, a Phase III, randomized, dou- demonstrated that the vaccine was safe and appeared to have
ble-blind, multicenter trial was initiated. Patients were rand- antitumor activity. The vaccine induced an increase in pre-
omized to receive VMO or vaccinia alone. The patient popula- cursors of cytolytic T-cells and objective responses in some
tion included 250 patients with Stage III melanoma (ITT), of patients with advanced melanoma. Mitchell further analyzed
whom 217 met eligibility criteria. There was no difference in the HLA Class I expression of patients with advanced
the DFS or OS [19]. Results may have been obscured by use of melanoma participating in the trials and reported that there
vaccinia as placebo, since this could have had activity. was an association between antitumor efficacy and the host
expression of two or three of the following Class I antigens:
Vaccinia melanoma cell lysate HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3,
In Australia, Peter Hersey devoted similar effort to the devel- collectively called M5.
opment of another vaccine made from a single allogeneic On the basis of these observations, The Southwest Oncology
melanoma cell line infected with vaccinia. In a Phase II trial, Group (SWOG) conducted a trial (SWOG-9035), a rand-
80 patients treated with VMCL following surgical excision of omized trial of Melacine® versus observation in patients with
regional lymph node metastases of melanoma had improved Stage II melanoma (nodes negative by clinical or pathological
survival compared with that of a historical control group of examination) with primary tumors 1.5–4.0 mm in thickness or
151 patients and a concurrent nonrandomized group of 55 Clark’s level IV if thickness was unknown [22]. The trial
patients. In a second Phase II trial, survival of 102 patients included 689 patients (ITT) of whom 600 met eligibility crite-
treated with VMCL plus low-dose cyclophosphamide was ria (300 randomized to Melacine and 300 randomized to obser-
superior to that of the historical control group but not to vation). The results show that there is no difference in the DFS
that of the group treated with VMCL alone. On the basis of rates in the treatment arms. Statistical analysis of OS was not
these observations, a prospective randomized control Phase conducted for this publication because the authors stated the
III trial was initiated to evaluate the efficacy of VMCL versus study had not reached the predetermined level of maturity for
observation in patients with Stage IIB and III melanoma. this analysis. In its presentation to the FDA on February 27,
The trial was initially projected for 400 patients but was sub- 2002, Corixa included an analysis of survival for patients who
sequently expanded to include 700 patients because of a had HLA phenotyping but did not include an analysis of OS
lower event rate than expected with better OS for the control for the ITT or eligible patient population [101].
patients than originally anticipated. After a median follow- A further analysis of this study was done, based on the
up of 8 years, the median OS of eligible patients (n = 675) patients’ HLA type [22]. Human leukocyte antigen typing
was 88 months in the control arm and 151 months in the was performed on 553 (80%) of the ITT patient population
treated patients (p = 0.068) [20]. Thus, the difference in (294 randomized to vaccine and 259 randomized to obser-
median survival was large and the fact that the study did not vation). There were 97 vaccine-treated patients and 78
detect such a large difference as significant suggests that the observation patients whose HLA type matched two of the
study was underpowered. The percentage of patients surviv- M5 HLA Class I antigens and these vaccine-treated patients
ing at 5 years was 54.8 for controls and 60.6 for treated enjoyed a significantly better relapse-free survival than did
patients. Median relapse-free survival was 43 months in the the observation patients (5-year relapse-free survival 83 vs.
control group compared with 83 months in the treated group 59%; p = 0.0002). Human leukocyte antigen-A2 was the
(p = 0.28). It was concluded that immunotherapy with most common of the five candidate antigens, expressed by
VMCL was associated with a nonsignificant trend for 46% of the patients and HLA-C3 was the next most com-
improvement in overall and relapse-free survival as compared mon, expressed by 29% of the patients; a total of 58% of the
with observations in control subjects. patients expressed either HLA-A2, or HLA-C3 or both.
These two antigens constituted the major components of
Melacine the beneficial effect; relapse-free survival was significantly
This vaccine was developed by Ribi ImmunoChem Research better for vaccinated patients who were HLA-A2 positive
Inc., MT, USA and is now owned by Corixa Corp. It consists and/or HLA-C3 positive than for control patients of this
of lysed cells from two human melanoma cell lines combined HLA type (p = 0.004) [22] and these subjects similarly
with an adjuvant, Detox™ that consists of monophosphoryl enjoyed an OS benefit (p = 0.003) [101].
92 Expert Rev. Anticancer Ther. 2(5), (2002)Adjuvant therapy for melanoma
Table 3. Noninterferon agents investigated as adjuvant therapy for malignant melanoma: agents in Phase III trials.
Agent Phase Patient selection Primary end-points
CancerVax + BCG vs. placebo + III Node-positive Stage III melanoma Disease-free survival; survival.
BCG
CancerVax + BCG vs. placebo + III Stage IV melanoma, surgically excised Disease-free survival; survival.
BCG
HLA-A2-positive: Multiepitope III Locoregional recurrence of melanoma after prior Disease-free survival; survival.
peptide vaccine, GM-CSF, adjuvant interferon therapy, local recurrence after
multiepitope peptide vaccine + adequate surgical excision of the primary, mucosal
GM-CSF, placebo melanoma, Stage IV melanoma, medically unfit for
HLA-A2-negative: GM-CSF vs. HDI, satellite or intransit disease, Stage III disease
placebo with gross extracapsular extension, recurrence in a
previously resected nodal basin, 4 or more
involved lymph nodes, matted lymph nodes, or an
ulcerated primary melanoma and any involved
lymph nodes
GMK vaccine vs. placebo.91 III Stage II melanoma Time to distant metastases,
survival
Melacine vs. observation III 700 patients who are HLA-A2-positive and/or Disease-free survival; survival
HLA-C3-positive, have had sentinel node sampling
that was negative and have Stage IIA (T2b and
T3a) or IIB (T3b) cutaneous malignant melanoma
(primary tumor thickness 1.01-4.0 mm)
Melacine + LDI vs. HDI III Stage III melanoma Disease-free survival; survival
Biochemotherapy (CVD, III Patients with melanoma metastatic to lymph Disease-free survival; survival
IL-2 and IFN-α) vs. HDI nodes, surgically resected
TriGem + HDI vs. HDI III Stage III melanoma Disease-free survival; survival
On the basis of these observations, Corixa Corp. has pro- GMK vaccine
posed a second randomized pivotal trial of Melacine as adju- Livingston has studied vaccines for therapy of melanoma based
vant therapy for Stage II melanoma (TABLE 3) [101]. The patient on gangliosides derived from bovine brain. These gangliosides
population will include a total of 700 patients who are are over-represented on melanoma cells and thus can be used in
HLA-A2-positive and/or HLA-C3-positive, have had senti- a vaccine in an effort to stimulate an immune response to
nel node sampling that was negative and have Stage IIA melanoma. One of these, called GM2, was selected for further
(T2b and T3a) or IIB (T3b) cutaneous malignant study. A double-blind randomized trial was conducted of a
melanoma (primary tumor thickness 1.01–4.0 mm, with or GM2 ganglioside vaccine, administered with bacillus Calmette-
without ulceration). Patients will be stratified by stage, gen- Guerin (GM2/BCG) versus BCG alone as adjuvant therapy in
der and site of primary and will be randomized to receive 122 patients with Stage III melanoma. The results showed
three cycles, each consisting of ten injections of Melacine, or improved survival in patients with GM2 antibodies as com-
observation. Efficacy end-points include relapse-free and pared with patients who did not have these antibodies. In a
OS. Melacine is also being evaluated in a Phase III rand- subsequent Phase I trial, it was demonstrated that conjugating
omized multicenter trial of Melacine and LDI versus HDI as the GM2 ganglioside with keyhole limpet hemocyanin and
adjuvant therapy for patients with Stage III melanoma administering it the QS-21 as adjuvant resulted in serological
(Study #6875-01) [101]. responses against GM2 that were strikingly superior, quantita-
In summary, although the studies described above failed tively and qualitatively, to any seen with previously tested GM2
to demonstrate a survival benefit in the treated patients, the vaccines. These results formed the basis for a prospectively ran-
data suggest that there is promise in the approach of cell domized trial of the GM2/KLH vaccine with QS 21 versus
lysate vaccines. The data from the VMCL trial demon- HDI as surgical adjuvant treatment for patients with high-risk
strated a large difference in survival in the treated patients, melanoma [10]. This was conducted in a combined intergroup
although it did not reach the level of statistical significance. protocol by three co-operative groups (E1694/S9512/C50981).
The data in the trial of Melacine suggest benefit in a sub- The results, described above, showed that patients receiving the
population of specified HLA type and forms the basis for a HDI enjoyed benefit in OS and DFS as compared with
further study. patients who received the vaccine.
www.future-drugs.com 93Spitler
CancerVax receive vaccine (TABLE 4). In a more powerful analysis, 349
This vaccine was developed by Donald Morton at the John Wayne patients who received vaccine were matched on the basis of
Cancer Institute and consists of an irradiated live-cell preparation seven covariates defined by the AJCC Melanoma Staging Com-
of three allogeneic melanoma cell lines chosen for their high con- mittee with patients who did not receive the vaccine. The 5-
tent of immunogenic melanoma-associated and common tumor- year OS was 55% for patients treated with vaccine versus 38%
associated antigens, administered with Bacillus Calmette-Guerin for the matched controls (p = 0.0001). Similarly, the median
(BCG) as an adjuvant [23]. The vaccine in now owned by Cancer- survival was more than doubled (83.5 vs. 31.3 months). On the
Vax Corp. and has been renamed Canvaxin™. In Phase II clinical basis of the observation of survival advantage in patients receiv-
trials conducted worldwide, the vaccine has been administered to ing the vaccine, a multicenter Phase III trial of CancerVax ver-
over 1600 patients with advanced stage melanoma and results doc- sus HDI after resection of nodal metastases in patients with
ument the safety of the vaccine and potential efficacy as shown by Stage III melanoma was initiated in 1998. Following surgical
a significant increase in 5-year survival rates and in OS time when resection of the regional lymph nodes, patients were stratified
compared with historical controls. according to the number of nodes involved and clinical status
In 283 patients with surgically resected Stage III melanoma of the nodes (nonpalpable versus palpable) and then rand-
treated with CancerVax, the median survival was >80 months, omized to vaccine or HDI. After the results of ECOG trial,
whereas in 1474 historical control patients treated with surgery E1690 showed no survival advantage with LDI or HDI, the
followed by nonvaccine therapies, the median survival was control arm of the study was changed to BCG plus placebo.
24 months (p < 0.002). A subsequent analysis included these The study is still ongoing but patient accrual has been halted
patients, as well as additional patients treated subsequently. In based on the FDA’s recommendation while the production of
935 patients with surgically resected Stage III melanoma the vaccine is being moved to a new corporate facility. Patients
treated with the vaccine, the median OS and 5-year survival already entered into the study continue to be treated. The first
were significantly higher than in 1667 patients who did not interim analysis of this study is planned for this fall.
Table 4. Noninterferon agents investigated as adjuvant therapy for malignant melanoma: agents that have completed
Phase II trials.
Agent Patient selection Primary end-points Ref.
CancerVax 935 patients with surgically resected The median overall survival and 5-year survival were [92]
Stage III melanoma significantly higher than in 1667 patients who did not
receive vaccine
CancerVax 157 patients with surgically resected The median survival was 23 months as compared with 7.5 [93]
Stage IV melanoma months in 1521 historical controls treated with various
other therapies
Polyvalent, shed-antigen 38 patients with resected melanoma Significant prolongation of time-to-disease-progression but [34]
vaccine vs. placebo to regional nodes (Stage III) not of overall survival
Autologous tumor cells 77 patients who had regional nodal Survival rates appeared higher than those in patients treated [94]
conjugated to DNP plus BCG metastases = 3 cm diameter with surgery alone
Autologous tumor cells 214 patients who had regional nodal With a median follow-up time of 4.4 years, the overall 5- [36,37]
conjugated to DNP plus BCG metastases = 3 cm diameter year survival was 47% in patients treated with the vaccine,
felt comparable to the results obtained with HDI
GM-CSF 48 patients with Stage III disease at The overall survival and the disease-free survival were [41]
very high risk for recurrence or with significantly prolonged in patients who received GM-CSF
Stage IV disease, surgically excised compared with matched historical controls
TriGem. 69 patients with Stage III melanoma; At a median follow-up of 2 years, the data suggested a [54]
25 also received HDI clinical benefit of TriGem
Vindesine, vindesine-based 318 patients with Stage III melanoma Patients in the groups receiving the vindesine-based [78]
combinations, observation adjuvant treatments enjoyed statistically significant benefit
as compared with the untreated concurrent controls or the
AJCC Stage III patients enrolled in the Aim High trial, which
was conducted in the UK
Neoadjuvant biochemotherapy 48 patients with Stage III melanoma At a median follow-up of 31 months 38 or the 48 patients [82]
given before and after lymph (79%) were alive and 31 patients (65%) remained free of
node dissection disease progression
94 Expert Rev. Anticancer Ther. 2(5), (2002)Adjuvant therapy for melanoma
In 157 patients with surgically resected Stage IV melanoma A synthetic peptide was designed to increase the binding to
treated with CancerVax, the median survival was 23 months the HLA-A2 molecule of the immunodominant peptide
as compared with 7.5 months in 1521 historical controls from the gp 100 melanoma-associated antigen. Of patients
treated with various other therapies (p = 0.0001). In a more vaccinated with this synthetic peptide, 91% were successfully
powerful analysis, the outcome in 88 patients with Stage IV immunized and, furthermore, it was shown that immuniza-
melanoma, surgically resected, then treated with CancerVax tion of patients with this peptide in IFA resulted in the gen-
was compared with the outcome in 88 matched control eration of antitumor lymphocytes that survived for 138–403
patients who underwent surgery followed by other therapies days in the patients’ circulation [31]. Modification of the
[24]. The patients were matched for important prognostic var- MART-1 immunodominant peptide also resulted in a syn-
iables including site of metastasis and number of tumor- thetic peptides that had increased HLA-A2 binding and high
involved organs, as well as for sex. The 5-year survival rate resistance to biodegradation. Finally, a peptide derived from
was 40% for vaccine patients and only 13% for nonvaccine tyrosinase was shown to be modified post-translationally to a
patients. In these patients and also in the patients with Stage sequence recognized by human CTLs. On the basis of these
III disease, there was an improved survival in patients who observations, a new Phase III prospective randomized inter-
developed an immune response (delayed-type hypersensitiv- group clinical trial has been initiated (E1697). The trial will
ity to the vaccine or IgM antibody to a 90 kDa tumor anti- include 600 patients with known HLA-A2 status. Eligible
gen) as compared with the survival in patients who did not patients are those with locoregional recurrence after prior
develop an immune response [12,25]. On the basis of these adjuvant interferon therapy, local recurrence after adequate
results, a multi-institutional Phase III trial of CancerVax as surgical excision of the primary, mucosal melanoma, Stage IV
surgical adjuvant therapy for patients with Stage IV melanoma, medically unfit for HDI, satellite or intransit dis-
melanoma has been initiated. Patients are randomized to ease, Stage III disease with gross extracapsular extension,
receive CancerVax plus BCG or placebo plus BCG. As in the recurrence in a previously resected nodal basin, four or more
study in patients with Stage III disease, patient accrual has been involved lymph nodes, matted lymph nodes, or an ulcerated
halted and no information regarding any interim analysis has primary melanoma and any involved lymph nodes. Patients
been made public. must not have received prior treatment with GM-CSF and
In summary, the prospects for the success of CancerVax are must be rendered surgically free of disease. Eligible patients
promising. The historical control data are compelling, despite who are HLA-A2-positive will be randomized to control
the fact that they are not as rigorous as data from randomized (placebo), multiepitope peptide vaccine, GM-CSF, or GM-
controlled trials. Also, these are appealing studies to patients CSF + multiepitope peptide vaccine. The multiepitope pep-
and physicians and have been accruing patients at a high rate. tide vaccine consists of peptides, all immunogenic, with sub-
stituted amino acids to improve Class I binding. The pep-
Multiepitope peptide vaccine tides are gp 100 209–217 210M, MART-1 26–35 27L and
Analysis of tumor infiltrating lymphocytes obtained from tyrosinase 368–376 370D. Lee and coworkers reported that
patients with melanoma led to the cloning of the genes that immunization of melanoma patients with the same modified
encode proteins recognized by T-cells with antitumor activ- epitopes derived from gp 100 and tyrosinase emulsified in
ity and subsequent identification and synthesis of the rele- IFA resulted in induction of an antigen-specific immune
vant peptides. Thus, genes encoding shared human response against the peptide vaccine in a significant propor-
melanoma antigens and the relevant peptides have been tion of patients [32]. In the randomized intergroup trial,
identified for MART-1, gp 100 and tyrosinase (and others). patients who are HLA-A2-negative will be randomized to
In clinical trials, immunization of groups of melanoma GM-CSF or placebo.
patients with each of these peptides individually, adminis-
tered with an adjuvant (incomplete Freund’s adjuvant [IFA] Other vaccines
or QS-21 led to the generation of immune responses and Two other vaccines are not currently in Phase III trials but
evidence of clinical benefit [26–28]. Immunization of patients are noteworthy because they have completed advanced Phase
with six synthetic melanoma-associated peptides derived II trials. One of these is a polyvalent, shed-antigen vaccine
from MART-1, tyrosinase and gp 100 without adjuvant prepared from material shed into the culture medium by
demonstrated that peptide alone injected intradermally three allogeneic and one xenogeneic melanoma cell lines
could generate antigen-specific delayed-type hypersensitivity adapted to long-term growth in serum-free medium. This
(DTH) reactions and increase antigen-specific cytotoxic T- vaccine was previously shown to induce antimelanoma anti-
lymphocyte (CTL) reactivity [29]. These authors further body, CD8+ T-cell responses to melanoma-associated anti-
reported that systemic administration of granulocyte-macro- gens and cellular immune responses that infiltrate melanoma
phage-colony-stimulating factor (GM-CSF) enhanced the nodules. On the basis of these observations, a double-blind,
immune responses to these peptides and, moreover, objec- prospectively randomized, placebo-controlled trial of this
tive tumor responses were observed in all of the study vaccine was initiated [33]. Thirty-eight patients with resected
patients so treated [30]. melanoma to regional nodes (Stage III) were randomized in
www.future-drugs.com 95Spitler a 2:1 ratio to vaccine or placebo. With a median follow-up Cytokines of 2.5 years, there was a statically significant prolongation of GM-CSF (Leukine, sargramostim) time-to-disease-progression but not of OS. The sample size Activated macrophages distinguish tumor cells from normal is so small in this study that a statistically significant time- cells and will kill only the tumor cells [38]. Granulocyte macro- to-progression is striking. The fact that a survival advantage phage colony stimulating factor, which is approved for market- was not seen is expected with such a small sample size. ing for hematopoietic reconstitution and reversal of iatrogenic Unfortunately, the study was stopped because of poor neutropenia, also has activity as a macrophage activator. Granu- patient accrual [34]. locyte macrophage colony stimulates peripheral blood mono- In another approach, patients were immunized with hap- cytes in vitro to become cytotoxic for human melanoma cells. tenized autologous tumor cells. This approach was based on Furthermore, in vivo administration of low doses of GM-CSF animal models showing that presentation of tumor antigens also results in monocyte activation as shown by enhanced cyto- in the context of a strongly immunogenic hapten augments toxicity. Granulocyte macrophage colony also serves as the the development of immunity to those antigens (the ‘hapten- principal mediator of proliferation, maturation and migration carrier effect’). Autologous tumor cells were conjugated to of dendritic cells, antigen-presenting cells that play a major role the hapten, dinitrophenyl (DNP) and administered with in the induction of primary and secondary T-cell immune BCG to patients who had been sensitized to DNP alone. The responses. Finally, GM-CSF causes increased production of vaccine induced an inflammatory response in superficial angiostatin by the macrophages. metastases in 14 of 24 patients. In a follow-on study, 77 We conducted a trial of sargramostim (Leukine™) surgi- patients who had regional nodal metastases >3 cm diameter cal adjuvant treatment of patients at very high risk for recur- were treated with the hapten-modified autologous vaccine rence of melanoma [39]. The patient population included 48 with BCG as postsurgical adjuvant therapy. Survival rates patients with Stage III disease at very high risk for recur- appeared higher than those in patients treated with surgery rence or with Stage IV disease rendered clinically disease- alone. Further studies in 84 patients with measurable metas- free by surgery prior to enrolment. The OS and the DFS tases of melanoma revealed 11 antitumor responses: two were significantly prolonged in patients who received GM- complete responses, four partial responses and five mixed CSF compared to matched historical controls. At 2 years, the responses. In 214 patients with Stage III disease rendered survival in the control group was 15% and 64% in the treat- tumor-free by surgery, with a median follow-up time of ment group. The median survival was 37.5 months in the 4.4 years, the overall 5-year survival was 47% in patients study patients versus 12.2 months in the matched controls treated with the vaccine with BCG, felt comparable to the (p < 0.001). results obtained with HDI.36,37 The vaccine was acquired We have initiated a second trial to further evaluate this by AVAX Technologies, Inc. (MO, USA) and renamed M- therapy in an expanded patient population. Eligible patients Vax™. A multicenter Phase III randomized trial of this vac- are those with Stage II, III, or IV melanoma, surgically cine versus HDI as adjuvant therapy for Stage III melanoma excised. GM-CSF was administered daily subcutaneously at patients with palpable lymph nodes (> 3 cm) was launched 125 µg/m2 for 14 days followed by 14 days off therapy and by AVAX. Unfortunately, in 2001, the FDA put all clinical was continued until recurrence requiring systemic therapy or trials of autologous DNP-modified melanoma vaccine, until the patient had been tumor-free for 3 years. An interim including Phase II and III studies, on temporary hold analysis of this study was presented at the 4th International because of manufacturing issues. Accordingly, there are no Conference on Adjuvant Therapy of Melanoma held at the clinical trials of this vaccine currently under way [102]. Royal College of Physicians in London, March 2002 [40]. In Other vaccines are in earlier stages of development for adju- the analysis, 50 patients were included and results suggested a vant therapy of melanoma. A Phase I trial of a melanoma vac- survival benefit for the patients treated with GM-CSF as cine was conducted in 22 patients with high-risk melanoma, compared with 1000 matched patients from the AJCC data- surgically excised [37]. The vaccine consisted of the gp 100 base, who had been treated with surgery alone (FIGURE 2). A peptide and tetanus helper peptide administered with either follow-on study, combining GM-CSF with thalidomide, will of two adjuvants, Montanide ISA-51 or QS-21. Cytotoxic T be initiated soon. lymphocyte responses were detected in only 14% of the Granulocyte macrophage colony is an appealing approach for patients. The OS of patients was 75% at 4.7 years of follow- adjuvant therapy of melanoma since its use is not limited by up; the authors felt this compared favorably with expected HLA type, as are some vaccines. Therefore, it has applicability survival. In another study, 48 patients with high-risk resected to a wide range of patients. Moreover, low doses can be used Stage III or IV melanoma were immunized with two tumor and are associated with a low toxicity profile, which is appeal- antigen epitope peptides derived from gp 100 and tyrosinase ing both to patients and their physicians. emulsified with incomplete Freund’s adjuvant [32]. A signifi- A prospective randomized trial to definitively evaluate effi- cant proportion of patients mounted an antigen-specific cacy of this approach has been initiated by a consortium of co- immune response and it was felt that IL-12 may increase the operative groups. This trial includes vaccine arms and is immune response. described above. 96 Expert Rev. Anticancer Ther. 2(5), (2002)
Adjuvant therapy for melanoma
Granulocyte macrophage colony has also been used as a Anti-idiotype monoclonal antibodies
melanoma vaccine adjuvant as follows: administered with Anti-idiotype (Anti-Id) monoclonal antibodies are designed to
irradiated autologous or allogeneic melanoma cells [43] trans- mimic tumor-associated antigens. With this approach, a mono-
duced into autologous or allogeneic melanoma cells [44] clonal antibody (Ab2) is generated that reacts with the antigen-
administered in combination with peptides to enhance combining site (idiotype) of an antibody to a tumor-associated
immune responses (mutant ras, tyrosinase, gp 100) [30,43,44] antigen (Ab1). The patients are immunized with the Ab2 anti-
administered as a DNA vaccine coexpressing antigen and body to generate an anti-anti-Id antibody (Ab3) that reacts
cytokine [45,46] and used to culture antigen-presenting cells for with the original tumor-associated antigen. Thus, the way in
peptide pulse [44]. which this method presents antigen is substantially different
from other peptide or whole-cell vaccines. One of these called
Monoclonal antibodies TriGem™ mimics the disialoganglioside GD2. In clinical trials
Ch14.18, R24 & hu14-18-IL-2 immunocytokine in patients with advanced melanoma, vaccination with this
Ch14.18 is a monoclonal antibody to the ganglioside GD2 rep- antibody was shown to be safe and to induce robust IgG
resented on melanoma cells. Preclinical studies suggested that immune responses to GD2. On the basis of this, 69 patients
the combination of IL-2 and ch14.18 might be most effective if with Stage III melanoma were treated with this vaccine; 25 also
used in the setting of microscopic residual disease. R24 is a received HDI [54]. It was found that HDI did not suppress the
murine IgG3 monoclonal antibody with specificity for the immune responses to the vaccine and the data suggested a clin-
disialoganglioside GD3 that is represented on most human ical benefit of TriGem in these patients at a median follow-up
melanomas and also on T-lymphocytes. Phase I studies with of 2 years, particularly for patients treated with HDI plus
this antibody defined toxicity [49] and suggested efficacy in TriGem. The product is now owned by Titan Pharmaceuticals
some patients [48]. Preclinical studies have further suggested (CA, USA) and a randomized trial for patients with Stage III
potential efficacy of an immunocytokine consisting of a fusion melanoma is planned in which patients will be randomized to
protein of the antiGD-2 antibody with IL-2 (ch14.18-IL-2) HDI alone versus HDI plus TriGem.
[49,50]. These observations have been translated into several Another of these is the BEC2 Anti-Id monoclonal antibody
Phase I immunotherapy trials at the University of Wisconsin. that mimics the GD3 disialoganglioside. In clinical trials, this
Patients with resected distant metastatic disease or with resected antibody alone was poorly immunogenic but when adminis-
recurrent regional nodal disease are eligible to participate in tered with the adjuvants BCG or QS21, it induced high-titer
these trials. IgG antibodies against BEC-2 [55]. Conjugation of the antibody
to keyhole limpet hemocyanin did not increase the immuno-
AntiCTLA4 monoclonal antibody genicity of BEC2. The antibody is now owned by Imclone
The cytotoxic T-lymphocyte antigen 4 (CTLA4) can potently (NY, USA). They are conducting a Phase III trial of this vaccine
inhibit T-cell activation and this inhibition is reversed by a in patients with limited-stage small-cell lung cancer but have
monoclonal antibody against CTLA4 [51]. This observation has not announced any plans to pursue trials in melanoma.
been applied in a Phase I trial of the antiCTLA4 antibody
measuring toxicity and immunologic parameters. Considerable Gene transfer
development will be necessary before this antibody can be For therapy of melanoma, gene transfer is used most commonly
tested for efficacy in the adjuvant setting. to transduce autologous melanoma cells or allogeneic
1.0
melanoma cell lines with a gene to promote the immunogenic-
GM-CSF (n = 50) ity of the melanoma cells and create a more effective vaccine.
0.9
Phase I clinical trials have been performed with melanoma cells
0.8
transduced with genes for GM-CSF [42,45,54], IL-2 [55,56] and
Proportion surviving
0.7 IL-4 [57]. Other approaches have been to transduce the genes
0.6 into nonmelanoma cell types and administer the product in or
0.5 around the tumor. This has been done with the IL-12 gene in
AJCC melanoma database
0.4 (n = 1000) autologous fibroblasts [58] and with the IL-2 gene in a monkey
0.3 fibroblast cell line (Vero) [59]. Although these early trials have
0.2 been encouraging in terms of safety and potential clinical bene-
0.1 fit, this field is still early in its development and we are not
0.0 aware of any Phase II trials in this area.
0 5 10 15 20 25 30 Another approach to gene transfer is the use of DNA vac-
Survival (months) cines. This approach is being explored for adjuvant therapy of
melanoma at Memorial Sloan Kettering Cancer Center [Houghton
Figure 2. Survival in patients with high-risk melanoma treated with AN, Pers. Comm.]. One study involves the use of the gp75 (TRP-1)
granulocyte-macrophage-colony-stimulating factor or surgery alone
xenogeneic DNA vaccine and a second is a study of a tyrosinase
(AJCC).
human versus xenogeneic DNA vaccine.
www.future-drugs.com 97Spitler
Cellular therapies Chemotherapy
At the present time, cellular therapy approaches are limited to Vindesine
trials in which autologous dendritic cells are harvested, In a nonrandomized trial with a concurrent control group, 169
treated to render them immunogenic and administered as a patients with melanoma metastatic to regional lymph nodes were
vaccine. Although nonmyeloablative blood stem cell trans- evaluated; 87 received adjuvant chemotherapy with vindesine
plantation has been studied as adoptive allogeneic immuno- after resection of palpable metastatic lymph nodes and 82 had no
therapy for renal cell carcinoma [60], this promising technique systemic treatment after surgery. After a median follow-up of
has not been well studied in melanoma and will probably be 8 years, it was found that the disease-free interval (p = 0.0001),
applied at first only to patients with metastatic disease that time-to-dissemination from lymph node metastases (p < 0.0001)
cannot be surgically excised. Another approach, therapy by and survival after lymph node dissection (p = 0.0227) were supe-
direct gene transfer into the tumor [61,62] would not be appro- rior for the patients who received adjuvant vindesine therapy [74].
priate in the adjuvant setting because the patients would be This study was expanded to include an additional 104 patients
clinically tumor-free. treated with vindesine and DTIC and 45 patients treated with
The most frequent approach to dendritic cell vaccine ther- vindesine and LDI, for a total of 318 patients [76]. Patients in the
apy for melanoma is to leukapherese the patient and isolate groups receiving the vindesine-based adjuvant treatments experi-
autologous dendritic cells. These are then rendered immuno- enced statistically significant benefit as compared with the
genic by pulsing them with peptides representing epitopes of untreated concurrent controls or the AJCC Stage III patients
melanoma-associated antigens [63–66]. Other approaches are enrolled in the Aim High trial, which was conducted in the UK
to pulse the dendritic cells with tumor lysates [44] or to trans- [76]. In the Aim High trial, 674 patients with resected high-risk
duce the dendritic cells with autologous tumor RNA [67]. A melanoma were randomized to receive LDI or observation until
trial has been initiated in which autologous tumor cells plus recurrence or for 2 years. There was no difference in the treat-
autologous dendritic cells are administered as a vaccine [68]. ment arms with regard to either OS or event-free survival.
Patients are stratified as to whether they have demonstrable Despite the encouraging results observed with vindesine, this
metastatic disease or not at the time treatment is initiated. approach has not been widely embraced. Vindesine is not availa-
Although these approaches are promising in that they are safe ble in the USA. Vindesine was tested as adjuvant therapy for
and induce antitumor immune responses, they are labor melanoma in a small randomized trial [77]. The results showed a
intensive and have not progressed to Phase II trials. trend toward benefit in progression-free and OS but these did
not reach the level of significance, probably because the trial
Antiangiogenesis included only 122 eligible patients and thus was underpowered.
There are five distinct functional categories of angiogenesis
inhibitors recognized by the FDA [69]: Biochemotherapy
• Agents with unknown mechanism of action There have been reports of efficacy of biochemotherapy, espe-
cially CVD biochemotherapy [78], for patients with metastatic
• Drugs that block extracellular matrix breakdown, such as the melanoma, although the results of a recent intergroup Phase III
matrix metalloprotease inhibitors (MMPIs) randomized trial questioned whether CVD biochemotherapy
• Drugs that specifically block endothelial cells, such as was superior to CVD chemotherapy alone. Nonetheless, on the
endostatin postulate that biochemotherapy might prolong the time-to-dis-
• Modalities that inhibit endothelial cell-specific integrin/sur- ease-progression and improve survival when given in the adju-
vival signaling vant setting, a Phase III randomized trial of biochemotherapy
with CVD, IL-2 and interferon versus HDI for adjuvant therapy
• Drugs that block activation of angiogenesis, such as mono- of melanoma patients with lymph node metastases that have ben
clonal antibodies to VEGF and VEGF receptor blocking surgically resected (MDA-DM-95196, MDA-ID-95196, NCI-
agents G96-1089). It is important to note that this approach carries
The side effect profile of some of these agents may not be as substantial toxicity and stands out as a notable exception to the
favorable as the vaccines. list of relatively nontoxic therapies discussed above.
A large number of antiangiogenic agents are now under
clinical investigation. Of these, SU5416 and several MMPIs Neoadjuvant biochemotherapy
have already failed in various randomized Phase III trials [70]. A pilot Phase II study was done in 48 patients with Stage III
These agents have not been extensively studied in melanoma. melanoma. They were given two cycles of biochemotherapy
Thalidomide, in combination with temozolomide [71–73] or consisting of cisplatin, vinblastine, DTIC (CVD), IL-2 and
its analog Revemid™, used as a single agent, has shown clin- interferon prior to and after lymph node dissection [79]. At a
ical responses in patients with metastatic melanoma. On the median follow-up of 31 months, 38 or the 48 patients (79%)
basis of this a Phase I/II trial of thalidomide plus GM-CSF is were alive and 31 patients (65%) remained free of disease-pro-
planned as adjuvant therapy for patients with Stage II, III gression. On the basis of these results, a larger multicenter
and IV melanoma. study has been initiated to explore this approach further.
98 Expert Rev. Anticancer Ther. 2(5), (2002)Adjuvant therapy for melanoma
Table 5. Noninterferon agents investigated as adjuvant therapy for malignant melanoma: agents that are in
Phase II trials.
Agent Patient selection Comments
GM-CSF 96 patients with Stage II (T4), III or IV melanoma rendered clinically Patient accrual nearly complete as
disease-free by surgery of August 2002. Results are
compared with matched
historical controls
GM-CSF plus thalidomide Patients with Stage II (T4), III or IV melanoma rendered clinically Study has not yet been initiated
disease-free by surgery
Multiepitope peptide vaccine with Patients with resected Stage IIB, IIC, III or IV melanoma are given Study open to accrual [104]
Montanide ISA-51 and either alum the vaccine emulsified with montanide ISA-51
of GM-CSF
Peptide vaccine with montanide Patients with lesions at least 1.5 mm in thickness or at least 1 Study open to accrual but accrual
ISA-51 positive lymph node or ulcerated lesion or local recurrence or for types HLA-A24 and HLA-A31
metastatic lesions completely resected. Patients must be HLA-A1, is closed [94]
A3, A24, A31, or 0201 positive. Patients are assigned vaccine
according to HLA type
Autologous tumor cells plus Patients are stratified as to whether they have demonstrable Study ongoing at Hoag Cancer
autologous dendritic cells metastatic disease or not at the time treatment is initiated Center [Dillman RO Pers. Comm.
2002)]
Neoadjuvant biochemotherapy Multicenter study has been initiated to evaluate this approach
Dacarbazine Expert opinion
Dacarbazine (DTIC) is the only chemotherapeutic agent The revised AJCC staging system for melanoma allows precise
approved for therapy of metastatic melanoma and a recent large, determination of the prognosis for individual patients based on
randomized trial which included 240 patients indicated that clinical and histopathological findings. However, what, if any,
combination chemotherapy with DTIC, cisplatin, vinblastine treatment to offer patients at high-risk for recurrence is not clear.
and tamoxifen (the ‘Dartmouth Regimen’) was no better than High-dose interferon may offer some DFS benefit but no clear
therapy with single-agent DTIC in terms of tumor response or OS benefit and toxicity is great. It is an imperfect solution.
survival [80]. Since of its efficacy in more advanced disease, a ran- Vaccines are an appealing alternative for adjuvant therapy of
domized trial of DTIC was conducted as surgical adjuvant ther- melanoma and hold promise as effective adjuvant therapy for
apy for melanoma but treatment with DTIC showed no benefit melanoma with considerably less toxicity than interferon. It is
in this setting [81]. Dacarbazine is the only chemotherapeutic disappointing that trials of four vaccines in this setting have all
agent approved of therapy of melanoma and in randomized trials been negative, but important information was gained from
none of the combinations currently in use have proved superior. these studies. Specifically, the trial of VMCL showed a consid-
erable prolongation of median survival and results appear to be
Bacillus Calmette-Guerin as good as those obtained with HDI if one were to apply the
An early report suggested efficacy of Bacillus Calmette-Guerin same statistical standard (i.e., use a two-sided test to determine
as adjuvant therapy for melanoma [82] but subsequent rand- significance). Similarly, in the trial of Melacine, the data
omized trials showed it was not effective and it is no longer regarding clinical benefit in patients who are HLA-A2- and/or
used as a single agent for this purpose [83–85], although it con- HLA-C3-positive is impressive and it seems likely that the
tinues to be used as a vaccine adjuvant. planned trial in patients with these HLA types may demon-
strate a survival benefit. It is unfortunate that this trial will take
Levamisole 8–10 years to complete. The data accumulated on CancerVax
In a large, prospective, randomized trial, levamisole was been is also compelling, especially that using matched controls. It is
reported to be effective in the adjuvant therapy of high-risk also impressive that so many patients have been treated with
melanoma [86] and on the basis of that study, levamisole was this vaccine and similar results obtained worldwide.
approved for this purpose in Canada but not in the USA. A Nonetheless, despite these encouraging results there are
similar, prospective, randomized, placebo-controlled trial failed potential problems in approaches aimed at enhancing the
to show benefit of levamisole in adjuvant treatment of tumor-specific immune responses in patients. Neoplastic cells
melanoma but the dose used was slightly different [105]. The escape host defenses by a variety of means, including creating
manufacturer has ceased production of levamisole so it is no powerful immunosuppressive effects in the tumor microenvi-
longer available in the USA. ronment. Subjects with melanoma often have lymphocytes in
www.future-drugs.com 99Spitler
cytokine milieu and/or defense mechanisms capable of sup-
Table 6. Noninterferon agents investigated as adjuvant pressing or avoiding an antitumor immune response. Perhaps
therapy for malignant melanoma: agents that are in additional measures will be necessary to overcome these
Phase I/II trials to define sagety and immunologic escape mechanisms.
responses in patients with melanoma. The trials of other biologics for adjuvant therapy of
Agent Comments melanoma are at much earlier stages of development, with
the exception of GM-CSF. The results of the Phase II trials
IL-2 and ch14.18 Study being conducted at the of GM-CSF are as encouraging as results to date with vac-
University of Wisconsin [Albertini MR
Pers. Comm. 2002]
cines, have already been incorporated into a multicenter
Phase III trial and have the added appeal of not requiring the
R24 Study being conducted at the participation of sensitized lymphocytes and of not being
University of Wisconsin [Albertini MR
Pers. Comm. 2002]
restricted by HLA type.
It seems reasonable to encourage patients with high-risk
ch14.18-IL-2 Study being conducted at the melanoma to continue to participate in clinical trials aimed at find-
University of Wisconsin [Albertini MR ing agents that are more effective and less toxic than interferon. It
Pers. Comm. 2002]
is likely that such agents will be found as a result.
Javelin peptide-hsp70 Study being conducted at the
complex vaccine Memorial Sloan Kettering Cancer Five-year view
Center [Houghton AN Pers. Comm. 2000]
High dose interferon is the only agent approved in the USA as
gp75 (TRP-1) xenogeneic Study being conducted at the adjuvant to surgery in patients with high-risk melanoma. It is
DNA vaccine Memorial Sloan Kettering Cancer unlikely that the approval for HDI will be withdrawn, despite
Center [Houghton AN Pers. Comm. its toxicity and lack of a clear survival advantage because there is
2000]
no group supporting such a measure.
Dendritic cell vaccine Study being conducted at the Trials of agents as surgical adjuvant therapy in patients with
comparing Langerhans vs. Memorial Sloan Kettering Cancer high-risk melanoma take 7–10 years to complete since one is
interstitial-type dendritic cell Center [Houghton N Pers. Comm. 2000]
vaccine using tyrosinase and
not looking for regression of metastatic disease but rather evalu-
gp100 peptides. ating time-to-disease-progression and survival. This means that
the only agents that might be candidates for marketing
Tyrosinase human vs. Study being conducted at the approval for this purpose within 5 years in the USA, in addition
xenogeneic DNA vaccine Memorial Sloan Kettering Cancer
Center [Houghton AN Pers. Comm. 2000] to HDI, are those that are already in Phase III trials. Thus the
candidates include CancerVax, the multiepitope peptide vac-
GD3 conjugate vaccine Study being conducted at the cine, GM-CSF, Melacine + LDI, and biochemotherapy. There
Memorial Sloan Kettering Cancer
Center [Livingston P Pers. Comm. 2002]
are problems with each of these ongoing studies that may pre-
clude completion, analysis, and product approval in the 5-year
GD2 conjugate vaccine Study being conducted at the timeframe. The trial of CancerVax is temporarily closed to
Memorial Sloan Kettering Cancer accrual during the move to new manufacturing facilities and it
Center [Livingston, 2002 Abstract 780}
is uncertain when accrual will be resumed. The trial involving
AntiCTLA4 monoclonal Study being conducted at the the multiepitope peptide vaccine and GM-CSF is accruing
antibody University of Chicago [Gajewski TF slowly because of restrictive entry criteria and may not be com-
Pers. Comm. 2002]
pleted in the 5-year timeframe. Unlike the other agents in
Phase III trials, biochemotherapy carries significant toxicity and
the peripheral blood or lymph nodes and even infiltrating might not be an appealing alternative even if it were shown to
lymphocytes in the melanoma tumors, but these lymphocytes be equivalent to HDI. The GMK vaccine is in a Phase III trial
may be defective in their response to the tumor [91]. Tumor in Europe in patients with Stage II melanoma and could be
growth occurs despite the presence of these cells. The local approved there is the trial is successful; it is uncertain whether
production of immunosuppressive cytokines, including IL- or not it might be approved in the USA on the basis of this
1092, IL-493, IL-694, IL-894, and TGF-β94 by the tumor study, especially given the negative Phase III of this vaccine ver-
cells or infiltrating lymphocytes may explain the ineffective- sus HDI, described above.
ness of these infiltrating cells. Moreover, HLA antigens are The prospects are good for completion of appropriate trials
downregulated on some melanomas and other tumors [95], and approval in the US of vaccines and cytokines with better
leading to the possibility that the tumors will not be recog- efficacy and less toxicity than HDI within 10 years. Other bio-
nized by the sensitized lymphocytes Finally, tumor cells are logics, including gene transfer, antiangiogenesis agents, other
capable of killing the invading lymphocytes by expression of vaccines, cell therapy and monoclonal antibodies are far earlier
Fas ligand [96] or B7-H1 [97] and other mechanisms. These in development and unlikely to be approved even in the 10-
data are supportive of the suggestion that tumor cells create a year timeframe.
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