| Modulation of the immune system
as an approach to attack cancer has been explored
for the past 50 years. Efficacy of this treatment
has been achieved in a limited number of
patients. However, a major obstacle of immune
therapy is the toxicity related to the
nonspecific nature of immune activation. Efforts
to improve the specificity of the immune response
have been investigated through the use of gene
therapy. Clinical trials involving gene therapy
for melanoma, lung cancer, and head and neck
cancer have been conducted by US Oncology at the
Mary Crowley Medical Research Center–Baylor
University Medical Center. These studies
represent one of the most active gene therapy
programs in the USA. Preliminary results have
helped define the mechanism of action, safety,
and potential efficacy of immune stimulatory
treatment approaches in oncology. |
 odulation
of the immune system to treat cancer has been tested
extensively in oncology. Cancers thought to be most
sensitive to immunotherapy include melanoma, renal cell
carcinoma, colorectal cancer, and non–small cell
lung cancer. Common immunotherapy approaches have
involved the use of interleukin (IL)-2 (1), interferon
(IFN)-alpha-2b (2), antibody therapy with muromonab-CD3
(3), lymphokine-activated killer cell infusions (4),
tumor-infiltrating lymphocyte infusions (5), dendritic
cell infusions (6), peptide-stimulated vaccine infusions
(7), and various combinations of these. A limited number
of successes have been observed (approximately 20% in
patients with metastatic melanoma). However, toxicity
related to nonspecific immune activation limits dosing
and the effectiveness of these approaches. Thus, more
recently, a strategy of tumor-specific immune activation
has been explored involving gene therapy.
Key components of the immune system critical to
understanding the therapeutic approaches described in
this review may require definition. Antigens are
targets for immune response that are located on the
surface of malignant cells. Antigen-presenting cells
(i.e., dendritic cells) are cells that roam the body in
search of foreign antigens. Antigenic peptides are
fragments of antigens that can be processed inside
antigen-presenting cells and redisplayed on the cell
surface through linkage to major histocompatibility
complex (MHC) molecules that bind to antigen peptides for
the purpose of cell surface display (Figure
1). T lymphocytes contain receptors
that recognize MHC/antigenic peptides. These cells become
activated upon recognition and binding. Lymphokines
such as IL-1, IL-2, IFN, and GM-CSF
(granulocyte-macrophage colony-stimulating factor) are
released by lymphocytes when stimulated and induce
proliferation and activation of other lymphocytes (B
cells) and monocytes. B lymphocytes recognize
circulating antigens without MHC binding and produce
antigen-specific antibodies, which mediate antitumor
effects through binding to tumor antigens.
Some therapeutic approaches involve the following:
- Improving expression (surface display) of
antigens
- Improving the number and sensitivity of
antigen-presenting cells
- Creating antigenic peptides in order to stimulate
antigen-presenting cells (in vitro)
- Altering MHC so that antigenic peptides can be
exposed, thereby uncloaking malignant cell
identity to immune effector cells attempting to
attack the cancer
Education of the immune system to recognize malignant
cells intensifies the cellular interaction and provides a
focus for the immune attack. Other immunotherapy options
available today focus on the induction of cytokines or
the addition of appropriate cytokines to maximize
anticancer effects. Malignant cells evade the immune
system, in some cases, by decreasing MHC levels and/or
producing factors that inhibit antigen-presenting cell
function or T-cell or B-cell function.
One method of providing tumor antigen stimulation is
to surgically harvest a tumor growing in a patient and to
modify the tumor ex vivo (in the laboratory) so that it
will no longer grow but still displays its surface
antigens to stimulate the immune system when replaced in
the body. This is known as vaccine therapy. Tumor
vaccines have been shown to be efficacious in some
clinical trials, primarily those involving melanoma,
renal cell carcinoma, or colorectal cancer (8–11).
The vaccine effect can be enhanced by several methods.
Coincubation of the defective antigenetic autologous
tumor cells with bacillus Calmette-Gu?rin (a
nonpathogenic bacterial species) can enhance the
inflammatory response to the vaccine, thereby improving
the antitumor systemic effect. Vaccine approaches can
also use cancer cell lines that are expected to have
antigens similar to the patient's tumor. These cell lines
are lysed following incubation with oncolytic viruses and
are then injected into the patient to stimulate an
antitumor response. Tumor vaccines have been shown to be
effective in animal tumor models.
The mechanism for the antitumor effect includes
induction of antigen-specific antitumor immunity mediated
by CD4 and CD8 T cells. A comparison of vaccine
approaches is shown in Figure 2. Most
recently, gene therapy has been used to increase antigen
surface expression in tumor cells via intratumoral
injection rather than resection of the malignant tissue
for ex vivo processing.
Insertion of immune-modulating cytokine genes (such as
IL-2, IL-4, gamma-IFN, tumor necrosis factor [TNF]-alpha,
M-CSF [macrophage colony-stimulating factor], or GM-CSF)
into tumor cells is another form of gene therapy designed
to enhance an immune response against implanted human
tumors (12–26). Subcutaneous injection of
cytokine-transduced tumor cells in animal tumor models
has been shown to induce prolonged tumor-specific immune
responses and improve survival from lethal tumor
challenges. One of the earliest studies showing such an
effect involved injection of the TNF gene into murine
sarcoma tumors, which were then implanted subcutaneously
into nude mice (27). Implantation of tumor cells
transduced with genes (neomycin) that do not affect
immune responsiveness did not change tumor growth.
However, implantation of TNF-transduced tumor cells
induced significant regression of tumors compared with
controls (Table 1). Tumor regression related to
the implantation of TNF-transduced sarcoma cells appeared
to be mediated by CD4- and CD8-positive lymphocytes. Data
also revealed that implantation of identical sarcoma
cells not transduced with any genes following
implantation of the TNF-transduced cells was associated
with regression of implanted secondary tumors, suggesting
long-term systemic antitumor activity. Implantation of
tumor cells (i.e., breast cancer cells) not used as the
initial vaccine did not induce an immune response,
thereby suggesting that the induced systemic approach was
specific against the tumor used as the gene-transduced
vaccine. Clinical testing would need to confirm that
enhanced targeting of the immune system against the
cancer with gene therapy will increase immunogenicity and
reduce systemic toxicity. Defects that limit immune
recognition of cancer are listed in Table 2. New
therapeutic approaches, including gene therapy, are
designed to target those defects.
Results of the in vitro and in vivo studies described
above were felt to be encouraging, thus justifying
development of clinical trials within our program
initially using retroviral vector gamma-IFN gene. The
published results are summarized below.
Autologous Vaccination of Immune-Modulating
Genes
Our first trial involving gene therapy to enhance
antitumor immunity was performed in 1994 as part of the
Baylor/PRN/Mary Crowley gene therapy program. Sixty-four
patients with advanced melanoma were entered into the
trial in order to harvest autologous tumor tissue and
create a vaccine by introducing the gene for gamma-IFN
(via a retroviral vector) into the tumor cells (Figure
3) (28). Seventy surgical tumor specimens
were processed from 58 evaluable patients. The median age
of treated patients was 53 years (range, 17–83
years). Of the 58 patients who underwent tumor resection,
12 tumor samples could be transduced with the gamma-IFN
gene. Adequate transgene expression (gamma-IFN protein),
production of functional gamma-IFN protein, and
up-regulation of MHC-I and MHC-II molecules on transduced
tumor cells were confirmed in the 12 tumor cell lines.
The majority of patients were, however, unable to
achieve autologous tumor cell line expansion, generally
because of overgrowth of fibroblasts, which were mixed in
with the malignant tissue at the biopsy. Additional
difficulties with processing involved the time to achieve
the targeted minimum of 1 X 107
cells prior to transduction. The duration from harvest of
tumor tissue to release for clinical treatment ranged
from 61 to 168 days. During this time, several patients
had disease progression despite standard care management
and were unable to participate in the treatment phase of
the trial. However, 5 patients achieved sufficient cell
numbers and gamma-IFN expression to undergo treatment
(subcutaneous injection every 2 weeks) with the
retroviral vector gamma-IFN gene vaccine. One patient
received 13 injections, 1 patient received 10 injections,
and 3 patients received <=5 vaccine injections. The
patients receiving the fewest injections had a poor
survival (35–72 days). However, of the 2 patients
who received 10 or 13 injections, 1 survived 885 days,
and the other remains alive without evidence of disease
after >5 years. This patient had metastatic disease to
his liver, brain, and adrenal gland. All lesions were
surgically resected creating a minimum disease state, and
the vaccine was administered every other week for 13
injections. Clinical toxicity to the gene-transduced
vaccine was not observed in any of the 5 treated
patients. Furthermore, no evidence of retroviral vector
contamination was detected in the released cell product
or in patients following treatment.
Given the advanced stage of disease, it was difficult
to evaluate efficacy. However, it is highly unlikely that
patients with brain and solid organ metastases survive
more than 1 year, although a patient in our study has
survived 5 years without disease recurrence.
Nevertheless, spontaneous complete remission occurs at a
0.1% frequency in melanoma (29), so additional trials
were needed.
Researchers at Duke University have looked at
retroviral gamma-IFN gene-transduced autologous melanoma
cell injection for treatment of metastatic melanoma,
using an approach identical to ours, by processing
autologous harvested melanoma tissue and transducing it
with retroviral gamma-IFN gene (30). In our trial, all
treated patients received low-dose IL-2 (1.1 X 106 U) following vaccine
injection, whereas in the Duke trial IL-2 was not
administered to patients. At Duke, 175 tumor samples were
harvested. In 20 patients sufficient gamma-IFN vaccine
was produced for treatment. Gene expression and MHC
up-regulation were also confirmed. No toxicity was
observed in the treated patients, and 4 patients achieved
a minor response to vaccine. Thus, in both trials
injection of retroviral gamma-IFN gene-transduced
autologous melanoma cells was well tolerated and
antitumor activity was observed. However, processing of
the ex vivo vaccine severely limited the number of
patients able to be treated.
Immunotherapy with IL-2 gene-transfected melanoma
cells has also been explored in one phase I trial
involving stage IV melanoma patients (31). Cell
suspensions from surgically harvested melanoma tumors
were transfected with IL-2 gene and irradiated prior to
injection. Fifteen patients received injections of the
vaccine. Observed toxicity was limited to local erythema
at the injection site and flulike symptoms in a few
patients. Delayed-type hypersensitivity reactions
developed in 8 patients following injection; however, a
50% tumor regression was not observed in any patients,
although 3 patients with progressive disease maintained
stable disease for >=3 months.
The combination of systemic gamma-IFN and IL-2 in
murine models has shown enhanced antitumor activity
compared with activity of either agent alone (32, 33).
gamma-IFN functions to enhance immunogenicity of the
targets by activating nonspecific cytotoxic effector
cells (34). Specifically, gamma-IFN increases the
expression of cell surface molecules including MHC
molecules and tumor-associated antigens (35). IL-2
enhances the cytotoxic effect of gamma-IFN by providing a
costimulatory signal that is necessary to activate and
expand cytotoxic T cells (34). However, toxicity related
to the combination of IL-2 and gamma-IFN administered
systemically severely limits therapeutic effects observed
in animal models.
When the therapeutic effectiveness of the
gamma-IFN–transduced tumor cell vaccine was compared
with an IL-2–transduced tumor cell vaccine in mice
with established pulmonary metastasis following infusion
with B16 melanoma cells, both approaches were shown to
inhibit primary tumor establishment when vaccines were
injected subcutaneously before inoculation with
unmodified tumor cells (14). However, mice treated with
gamma-IFN–secreting melanoma cells showed greater
responsiveness and improved survival when compared with
mice treated with melanoma/IL-2–secreting cells.
Combination of IL-2–secreting cells and
gamma-IFN–secreting tumor cells also showed no
additional efficacy compared with vaccination with either
gene-transduced population alone.
SINGLE-COURSE INTRATUMORAL INJECTION OF
GAMMA-IFN RETROVIRAL VECTOR IN PATIENTS WITH
METASTATICMELANOMA
In our program's second trial, 13 patients with
metastatic melanoma were treated with intratumoral
injection of the retroviral gamma-IFN gene vector rather
than removal of the tumor and transduction of the
gamma-IFN gene ex vivo. Each patient had lesions
accessible to intratumoral injection and distant lesions
evaluable to measure systemic response. Patients were
entered into 1 of 3 treatment arms. The dose of the
gene-transduced vaccine was identical for each arm (1.5 X 108 PFU/dose administered at
a volume of 0.3 mL for 5 consecutive days). Preclinical
data suggested that gene transduction efficiency varied
depending on the cation (hexadimethrine bromide or
protamine sulfate) mixed with the vector during
injection. In this trial, 4 patients received
hexadimethrine bromide, 4 patients received protamine
sulfate, and 5 patients received no cation (36).
Successful insertion of the gamma-IFN gene into the tumor
cell was based on the enzyme-linked immunospot and
polymerase chain reaction assays and was confirmed in
each arm. Toxicity to the vector was not observed, and
there was no evidence of viable retrovirus contamination
(65 samples tested). Coadministration with cations did
not appear to alter transgene expression following
injection into the tumors. Patients with evidence of
transgene expression had a median survival of 528 days
compared with patients who had no evidence of transgene
expression (median survival, 333 days).
From this study we concluded that treatment via a
single intratumoral injection was safe. Efficacy
evaluation was limited by the removal of the
gene-transduced tumor 8 days after injection in order to
assess transgene expression. No responses in injected or
distal lesions were observed; however, prolonged survival
of patients with identifiable transgene expression was
interesting. Further clinical research using multiple
courses of therapy, combination therapy with systemically
administered cytokines (IL-2), and/or treatment of
patients with earlier stages of less extensive disease is
indicated.
GAMMA-IFN RETROVIRAL VECTOR ADMINISTERED
INTRATUMORALLY WITH MULTIPLE COURSES IN PATIENTS WITH
METASTATIC MELANOMA
Multiple courses of direct intratumoral injection of
adenoviral and retroviral vector preparations have been
shown to be effective in the induction of regional tumor
regression in several mouse tumor models (37–44) and
in patients receiving retroviral vectors involving the
p53 gene (45).
In our third trial with gamma-IFN retroviral vector in
patients with metastatic melanoma, we administered
multiple intratumoral injections of gamma-IFN retroviral
vector at escalating doses without removing the
injected lesion for a single 5-day injection course
(group A, n = 9) or for multiple 5-day injection courses
(group B, n = 8). One cycle consisted of doses of 0.3,
0.5, and 1.5 mL per injection of gamma-IFN retroviral
vector (1 X 107 PFU/mL)
for 5 consecutive days. Patients received either 1 cycle
or 6 cycles administered every 2 weeks.
Enzyme-linked immunosorbent assays were performed to
assess induction of tumor-specific antibodies against 4
melanoma tumor cell lines (DM 92, DM 93, DM 252, and DM
400), 2 nonmelanoma cell lines, and nonmalignant tissue
(fibroblast lines). Studies to determine evidence of
replication-efficient retrovirus were also performed from
patient samples prior to administration. No significant
toxicity was observed, and 10 of the 17 patients treated
showed evidence of elevated antitumor antibody response
titers following injection. These were generally specific
for the melanoma cell lines and were highest in patients
who received the higher dose levels (46). Two patients
achieved a complete histologic response, and 2 patients
achieved a partial response of the injected lesion
(>=50% reduction of disease but not complete). Three
of the 8 patients who received multiple doses of
gamma-IFN retroviral vector achieved a response compared
with only 1 of 9 patients who received a single cycle.
Furthermore, survival in patients entered into the
multicycle treatment regimen suggested improvement
compared with survival of patients who received only a
single cycle (Figure 4 , P
= 0.027 log rank). Consistent with prior data, gamma-IFN
retroviral vector intratumoral injection was well
tolerated, and there was no evidence of
replication-competent retrovirus in the product or
patient samples. These continue to be analyzed in
surviving patients >4 years after initiation of
investigation with gamma-IFN retroviral vector.
This trial is the first to attempt multiple courses of
direct intratumoral injections of gamma-IFN retroviral
vector. Animal studies suggest that the antitumor effect
related to gamma-IFN retroviral vector injection is
correlated with the number of injections and the titer of
the retroviral vector preparation (44, 46). Further
research involving multiple injections is indicated.
Systemic effects have been infrequent in phase I
studies with immune-modulating gene vectors, although
results of animal studies have demonstrated systemic
antitumor effects following injections with
immune-modulating genes, such as gamma-IFN, HLA-B7, or
IL-2, in association with improved survival (12, 14, 21,
24, 26, 44, 48). Data suggest that transfer of gamma-IFN
gene into tumor cells may alter tumor antigen expression
and induce a localized immune response. However, clinical
effects of a systemic response may be difficult to
evaluate in patients with bulky advanced disease who have
an expected survival of <6 months. It takes several
months to build up the immune response against the tumor.
Before the immune system sufficiently responds to the
vaccine, the malignant progress is still occurring and
may override the patient's immune response if the disease
is too far advanced when immunotherapy is initiated.
Thus, given the potential systemic activity to local
injection, many trial designs consider initial treatment
with chemotherapy or treatment of patients with early
stage disease since toxicity is minimal.
OTHER IMMUNE-MODULATING VACCINE APPROACHES
PERFORMED IN THE MARY CROWLEY MEDICAL RESEARCH FACILITY
Studies exploring vaccines transduced with the GM-CSF
gene (GVAX) using autologous tumor cells and allogeneic
cell lines are being explored in patients with prostate
cancer and non–small cell lung cancer. Also, plasmid
DNA for HLA-B7 (Allovectin-7) complexed with a cationic
lipid is being examined in melanoma patients. Phase I
investigation reveals a low toxicity profile.
The GVAX vaccine has been studied (phase I) in
patients with melanoma, renal cell cancer, and prostate
cancer. GVAX vaccine is an allogeneic vaccine, which does
not require surgical harvest of autologous tumor tissue.
Currently, we are performing trials in patients with
hormonal naive prostate cancer and hormonal refractory
prostate cancer in which the GM-CSF gene is placed into
allogeneic prostate cell lines containing antigens most
likely to be expressed in autologous tumors. Patients
receive multiple intradermal injections of the prostate
GVAX vaccine for as long as stable disease is maintained
or induced response is observed. Gene delivery uses an
adenoviral vector for GM-CSF as opposed to a retroviral
vector, which was used for the gamma-IFN trials
described.
Trials investigating the HLA-B7 gene use a plasmid DNA
complex with a cationic lipid mixture. Lipid-complexed
DNA plasmids have a higher transduction-efficiency rate
than retroviral vectors, but intracellular release
of the transgene product from the lipid complex may have
some limitations. Trials investigating intratumoral
injection of Allovectin-7 include phase II studies in
patients with refractory progressive melanoma and a phase
III investigation comparing patients receiving
Allovectin-7 combined with chemotherapy (dacarbazine)
with patients receiving chemotherapy alone. Response
rates of 35% in injected lesions and 15% in systemic (not
injected) lesions were observed in phase I/II trials.
CONCLUSION
Gene therapy offers a unique opportunity to modulate
the immune system and potentially enhance antitumor
effects. Regardless of the delivery vehicle used, safety
has been confirmed with these approaches. Phase III
trials are ongoing nationally and are being performed at
the Mary Crowley Medical Research Center to determine
whether or not gene therapy offers an advantage over
standard treatment. Additionally, combining these
approaches with standard approaches may also benefit
patients with advanced cancer. Investigation of immune
enhancement is one of several clinical research areas we
are pursuing.
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