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[Cancer Biology & Therapy 8:10, 981-983; 15 May 2009]; 2009 Landes Bioscience

Commentary

Immune approaches to treating osteosarcoma


Neyssa Marina1,* and Richard Gorlick2
1Division

of Hematology-Oncology; Stanford University & Lucile Packard Childrens Hospital; Palo Alto, CA USA; 2Department of Pediatrics; The Childrens Hospital of
Montefiore; Bronx, NY USA

Key words: osteosarcoma, immunomodulation, immune approaches, therapy, biologic approaches

There is a critical need for new effective therapies in the clinical


management of patients with osteosarcoma. Immune modulation
has been a strategy investigated in these patients. Immunotherapy
approaches in cancer take a variety of forms including antibody
administration, cytokine/immune adjuvants and a variety of in
vivo and ex vivo vaccination strategies. In the context of osteosarcoma, this has manifested itself as investigation of multiple
strategies including activation of macrophages with immunomodulatory drugs [muramyl tripeptidephosphatidyl ethanolamine
(MTP-PE), Junovan] or cytokine administration [systemic interferon or inhaled granulocyte macrophage colony stimulating
factor (GMCSF)] all of which have been tested in Phase 2 and/or
Phase 3 osteosarcoma clinical trials and will be discussed further
subsequently.1-7 In the manuscript by Yu, et al. in this issue of
Cancer Biology & Therapy, a preclinical study of vaccination using
dendritic cells exposed to osteosarcoma total RNA is reported.8
They successfully demonstrate the ability to electroporate total
RNA prepared from an osteosarcoma cell line into dendritic cells.
These cells are capable of inducing cytotoxic T lymphocytes and
immunity against a tumor challenge. These results need to be
experimentally extended through an investigation of the ability of
human osteosarcoma cell lines and primary tumor tissues to elicit
a similar response in the context of human effector cells.8 The
experiments reported thus far represent an important initial proof
of principle and overcome several hurdles that have existed in the
clinical development of vaccination strategies for osteosarcoma.
Many therapeutic antibodies have been developed thus far
based predominantly on the relative the abundance of expression in
tumor versus host cells. These antibodies potentially have multiple
*Correspondence to: Neyssa Marina; Professor of Pediatrics; Associate Chief
of Clinical Affairs; Division of Hematology-Oncology; Stanford University and
Lucile Packard Childrens Hospital; 1000 Welch Rd, Suite 300; Palo Alto, CA
94304-1812 USA; Tel.: 650.723.5535; Fax: 650.723.5231; Email: nmarina@
stanford.edu
Submitted: 03/19/09; Accepted: 03/31/09
Previously published online as a Cancer Biology & Therapy E-publication:
http://www.landesbioscience.com/journals/cbt/article/8602
Commentary to: Yu Z, Sun H, Zhang T, Yang T, Long H, Ma B. Specific antitumor
effects of tumor vaccine produced by autologous dendritic cells transfected with
allogeneic osteosarcoma total RNA through electroporation in rats. Cancer Biol
Ther 2009; This issue.

www.landesbioscience.com

mechanisms of action with some dependent on deprivation of the


factor specifically targeted by the antibody, some specifically delivering a toxin or radionuclide and some active through activating
antibody dependent cell mediated cytotoxicity (ADCC). For many
of these antibodies (including some of the agents more routinely
used in the treatment of hematopoietic malignancies) the relative
contribution of the different mechanisms of action is unclear. As
an example, rituximab, which recognizes CD20 and is routinely
utilized for B-cell malignancies, directly induces apoptosis as
well as activates ADCC with binding.9 In contrast, gemtuzumab
ozogamicin, which binds CD33 and is used for the treatment
of myeloid malignancies, delivers a toxin.10 As most antibodies
are developed for more common adult malignancies, many of
the antigens targeted are not relevant to the majority of pediatric
solid tumors. Within the context of pediatric solid tumors the
antibody approach that has been studied most extensively includes
the antibodies directed to a ganglioside (GD2), for the treatment
of neuroblastoma. These antibodies have been studied extensively
in clinical trials for neuroblastoma with promising results.11 The
ability of cytokines such as GMCSF to augment the response to a
GD2-directed antibody suggests the mechanism of action, at least
in part, is immune mediated.12
Thus far, fewer therapeutic antibodies have been tested for the
treatment of osteosarcoma. Osteosarcoma has been exceedingly
difficult to define as it has complex genetics and expresses many
surface receptors but few, if any, are unique to the tumor relative to
normal host tissues.13 Unlike other pediatric malignancies such as
neuroblastoma mentioned previously, which abundantly expresses
relatively unique ganglioside markers amenable to targeting for
diagnostic and therapeutic purposes, few antibodies have been
identified as even having relative specificity for osteosarcoma.
TP3 is among the few antibodies which has relative specificity
for osteosarcoma. However, it does not have a defined antigen
and thus far has somewhat limited clinical applications.14,15 One
approach that has been utilized is testing osteosarcoma tumor
tissue for expression of surface receptors that have been developed
for other therapeutic approaches. As an example trastuzumab,
developed for human epidermal growth factor receptor2
(HER2) overexpressing breast cancer, has been tested in clinical
trials of osteosarcoma by the Childrens Oncology Group based
on HER2 expression being prognostic in a retrospective study

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Immunotherapy in osteosarcoma

of osteosarcoma specimens.16 Although the levels of expression


of HER2 in osteosarcoma and their prognostic significance have
been debated, another concern is the effectiveness of targeted
approaches as it has been recognized to be based upon the tumor
having a unique dependency or addiction to a specific target.17
This dependency thus far has been generally manifested by
genetic amplification, mutation or constitutive expression of the
target receptor or its ligand.18 Whether or not this dependency is
equally necessary for antibodies whose activity is based on ADCC
remains unclear. Despite this caveat, antibodies continue to be of
interest in the treatment of osteosarcoma with considerable effort
at present being placed into the clinical development of insulin
like growth factor receptor 1 (IGF1R) antibodies in part based
on promising preclinical data.19,20 It should be mentioned that a
dependency of osteosarcoma for this particular signaling pathway
is yet to be defined.
Given the inability to identify antigens specifically expressed on
osteosarcoma tumors, much of the effort has been directed towards
approaches to augment immune responses. Despite the lack of
specific antigens, clinical trials of immunomodulatory approaches
have consistently yielded suggestions of clinical activity.2,3,5-7 Some
of these approaches are supported by extensive preclinical data.
Among the more extensively tested in osteosarcoma is the use of
MTP-PE.21 As immunomodulatory agents are difficult to evaluate
in the context of human osteosarcoma Phase 2 clinical trials, a
clinical trial of MTP-PE was performed in canines with spontaneously arising osteosarcoma.21 Canines with osteosarcoma closely
recapitulate the human condition, genetically and in clinical manifestations, with an accelerated time course.22 This canine study
demonstrated a survival advantage with MTP-PE and served as the
basis of a North American randomized Phase 3 trial.21 An initial
report of that study suggesting an interaction between MTP-PE
and ifosfamide, also being studied, led to a search for the mechanistic basis of this occurrence.5 Several reports have been published
suggesting changes in the expression of Fas as the basis of the
interaction.23,24 A subsequent analysis of an overall survival rather
than event free survival endpoint of the same clinical trial indicated
that an interaction was not evident and that combining MTP-PE
with chemotherapy resulted in a significant survival advantage for
patients presenting with localized osteosarcoma.6 The results of
this trial have raised significant controversy,25,26 but based on these
results, MTP-PE has recently been recommended for licensure by
the European Medical Advisory group. Although less extensively
tested, inhaled GMCSF has also been clinically evaluated at the
Mayo clinic and in the context of a Childrens Oncology Group
Phase 2 clinical trial for patients with recurrent osteosarcoma
metastatic to the lung.4,7 Systemic interferon is currently being
evaluated for the subset of osteosarcoma patients with a favorable
histologic response to induction chemotherapy in the context of
an international Phase 3 trial the EURAMOS study.20 This was
largely based on promising results obtained in prior Scandinavian
studies.1-3 Whether these approaches have sufficient activity to
warrant their use in the routine clinical management of osteosarcoma remains both widely debated and a subject of continued
clinical studies.25,26
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In the manuscript by Yu, et al. an approach to immunizing


dendritic cells is explored.8 Vaccine approaches have been extensively investigated for the treatment of cancer, most notably
melanoma, in which it has demonstrated efficacy.27,28 In the
context of pediatric malignancies ex vivo approaches have been
utilized to immunize against the translocation peptide/protein in
the context of Ewing sarcoma.29 Issues with developing vaccines
for osteosarcoma are similar to developing antibody approaches
in that specific appropriate antigens have not been clearly identified. A manuscript has been published reporting T-cell responses
directed towards CD55 as a potential osteosarcoma therapy but
few other studies exist.30 This study by Yu, et al. is interesting
because it utilizes total RNA obtained from the osteosarcoma
cell line for dendritic cell immunization rather than a specific
protein or peptide.8 This approach bypasses the need to identify
a specific protein as an antigenic stimulus, which although more
complicated, may be appropriate for osteosarcoma specifically.
This perhaps can serve as a model for approaching other complex
malignancies that lack specific surface antigens.
Taken together this suggests that continued development of
potentially more potent immune approaches such as the one
described in this manuscript by Yu, et al. is warranted.8 Even
beyond the previously suggested experiments it is likely that much
preclinical work would be necessary to clinically develop this as an
approach that could be used in osteosarcoma trials. Clinical trials
of immunomodulation strategies are likely to continue and it is
anticipated that these approaches will ultimately enter into the
routine clinical treatment of patients with osteosarcoma and will
ultimately result in improved outcome.
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