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Dendritic Cell Immunotherapy
Clinical Policy Bulletins Medical Clinical Policy Bulletins
Policy History Last Revi
ew
07/16/2019
Effective: 02/01/200
Next
Review: 04/10/2020
Review
Histor
y
Definitions
Additional Information
Number: 0377
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
Aetna considers dendritic cell immunotherapy experimental and investigational
because the peer-reviewed medical literature does not support its clinical use at
this time.
See
CPB 0641 - Adoptive Immunotherapy and Cellular Therapy
also (../600_699/0641.html)
, and CPB 0802 - Prostate Cancer Vaccine (../800_899/0802.html).
Background
Dendritic cells (DCs) are the most potent type of antigen presenting cells and are
vital in inducing activation and proliferation of T-lymphocytes. Their unique property
has prompted their recent application to therapeutic cancer vaccines. Isolated DCs
containing tumor antigen ex-vivo and administered as a cellular vaccine, have been
found to induce protective and therapeutic anti-tumor immunity in experimental
animals.
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The clinical evaluation of DC immunotherapy in humans is in its earliest phases for
the treatment of malignancies such as leukemia, lymphoma, melanoma, and certain
solid tumors. Specifically, melanoma-associated antigens have been characterized
at the molecular level and melanoma vaccine is currently being investigated in
clinical trials. Dendritic cells immunotherapy involves isolating dendritic cells from
either circulating blood or bone marrow cells from the patient (or HLA-matched
donor) and then exposing them to proteins from the patient's cancer cells in order
to activate T-lymphocytes. These lymphocytes are grown in bioreactors to be
infused into the patient when sufficient numbers have been obtained.
Currently, no conclusions regarding the efficacy of DC immunotherapy can be
made from the anecdotal reports reported in the published, peer-reviewed medical
literature. Although DC immunotherapy appears to be a promising modality for the
treatment of cancer, completion of randomized trials is necessary. Specifically, the
appropriate antigen(s), adjuvant(s), dose, route and schedule need to be
established. In a review of the evidence, Figdor et al (2004) concluded that “[a]
lthough early clinical trials indicate that [dendritic cell] vaccines can induce immune
responses in some cancer patients, careful study design and use of standardized
clinical and immunological criteria are needed”.
Ardon et al (2012) noted that DC-based tumor vaccination has rendered promising
results in relapsed high-grade glioma patients. In the HGG-2006 trial (EudraCT
2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of
DC-based tumor vaccination into standard post-operative radiochemotherapy were
studied in 77 patients with newly diagnosed glioblastoma. Autologous DC was
generated after leukapheresis, which was performed before the start of
radiochemotherapy. Four weekly induction vaccines were administered after the
6-week course of concomitant radiochemotherapy. During maintenance
chemotherapy, 4 boost vaccines are given. Feasibility and progression-free
survival (PFS) at 6 months (6 mo-PFS) were the primary end-points. Overall
survival (OS) and immune profiling, rather than monitoring, as assessed in patients'
blood samples, were the secondary end-points. Analysis has been done on intent- to-
treat basis. The treatment was feasible without major toxicity. The 6 mo-PFS was
70.1 % from inclusion. Median OS was 18.3 months. Outcome improved significantly
with lower EORTC RPA classification. Median OS was 39.7, 18.3, and
10.7 months for RPA classes III, IV, and V, respectively. Patients with a methylated
MGMT promoter had significantly better PFS (p = 0.0027) and OS (p = 0.0082) as
compared to patients with an un-methylated status. Exploratory "immunological
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profiles" were built to compare to clinical outcome, but no statistical significant
evidence was found for these profiles to predict clinical outcome. The authors
concluded that full integration of autologous DC-based tumor vaccination into
standard post-operative radiochemotherapy for newly diagnosed glioblastoma
seems safe and possibly beneficial. They stated that these results were used to
power the currently running phase IIb randomized clinical trial.
In a systematic review, Tanyi et al (2012) stated that after decades of extensive
research, epithelial ovarian cancer still remains a lethal disease. Multiple new
studies have reported that the immune system plays a critical role in the growth and
spread of ovarian carcinoma. These investigators summarized the development of
DC vaccinations specific for ovarian cancer. So far, DC-based vaccines have
induced effective anti-tumor responses in animal models, but only limited results
from human clinical trials are available. Although DC-based immunotherapy has
proven to be clinically safe and efficient at inducing tumor-specific immune
responses, its’ clear role in the therapy of ovarian cancer still needs to be clarified.
The relatively disappointing low-response rates in early clinical trials point to the
need for the development of more effective and personalized DC-based anti-cancer
vaccines.
Bregy et al (2013) stated that glioblastoma multiforme (GBM), the most common
malignant brain tumor, still has a dismal prognosis with conventional treatment.
Therefore, it is necessary to explore new and/or adjuvant treatment options to
improve patient outcomes. Active immunotherapy is a new area of research that
may be a successful treatment option. The focus is on vaccines that consist of
antigen presenting cells (APCs) loaded with tumor antigen. hese researchers
conducted a systematic review of prospective studies, case reports and clinical
trials to examine the safety and effectiveness of active immunotherapy in terms of
complications, median OS, PFS and quality of life. A PubMed search was
performed to include all relevant studies that reported the characteristics, outcomes
and complications of patients with GBM treated with active immunotherapy using
DCs. Reported parameters were immune response, radiological findings, median
PFS and median OS. Complications were categorized based on association with
the craniotomy or with the vaccine itself. A total of 21 studies with 403 patients
were included in this review. Vaccination with DCs loaded with autologous tumor
cells resulted in increased median OS in patients with recurrent GBM (71.6 to 138.0
weeks) as well as those newly diagnosed (65.0 to 230.4 weeks) compared to
average survival of 58.4 weeks. The authors concluded that active immunotherapy,
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specifically with autologous DCs loaded with autologous tumor cells, seems to have
the potential of increasing median OS and prolonged tumor PFS with minimal
complications. Moreover, they stated that larger clinical trials are needed to show
the potential benefits of active immunotherapy.
Wang et al (2014) noted that glioblastoma multiforme (GBM) has a poor prognosis.
In a systematic review and meta-analysis, these investigators analyzed the
outcomes of clinical trials that compared immunotherapy with conventional therapy
for the treatment of malignant gliomas. PubMed, Cochrane and Google Scholar
databases were searched for relevant studies. The 2-year survival rate was used
to evaluate effectiveness of immunotherapy. Of 171 studies identified, 6
comparative trials were included in the systematic review. Immunotherapy was
associated with a significantly longer OS and 2-year survival compared to
conventional therapy. The authors concluded that immunotherapy may improve the
survival of patients with GBM.
Chen et al (2014) stated that a new strategy of adoptive and passive
immunotherapy involves combining dendritic cells (DCs) with a subset of natural
killer T lymphocytes termed cytokine-induced killer (CIK) cells. In a systematic
review and meta-analysis, these researchers evaluated the safety and
effectiveness of DC-CIK therapy versus placebo, no intervention, conventional
treatments, or other complementary and alternative medicines for malignant
tumors. These investigators searched PubMed, Medline, Embase, Cochrane,
Wangfang, Weipu, CNKI databases and reference lists of articles. They selected
randomized controlled trials (RCTs) of DC-CIK therapy versus placebo, no
intervention, conventional treatments, or other complementary and alternative
medicines in patients with all types and stages of malignant tumor. Primary
outcome measures were OS and treatment response. Secondary outcome
measures were health-related quality of life (HRQoL) assessment, PFS, and
adverse events. A total of 6 trials met the inclusion criteria. There was evidence
that chemotherapy + DC-CIK increased the 2-year (risk ratio [RR] 2.88, 95 %
confidence interval [CI]: 1.38 to 5.99, p = 0.005) and 3-year (RR 11.67, 95 % CI:
2.28 to 59.69, p = 0.003) survival rates and PFS (RR 0.64, 95 % CI: 0.34 to 0.94, p
< 0.0001) in patients with non-small cell lung cancer compared to those treated with
chemotherapy alone. DC-CIK therapy appears to be well-tolerated by cancer
patients and to improve post-treatment patient health related quality of life. The
authors concluded that DC-CIK immunotherapy is a safe and effective treatment for
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patients with malignant tumors. They stated that further clinical trials to provide
supportive evidence for the routine use of DC-CIK therapy in clinical practice are
needed.
Lombardi et al (2015) stated that plasmacytoid dendritic cells (pDCs) are multi-
functional bone marrow-derived immune cells that play a key role in bridging the
innate and adaptive immune systems. Activation of pDCs through toll-like receptor
agonists has proven to be an effective treatment for some neoplastic disorders.
These researchers explored the contribution of pDCs to neoplastic pathology and
discussed their potential utilization in cancer immunotherapy. Current research
suggests that pDCs have cytotoxic potential and can effectively induce apoptosis of
tumor-derived cells lines. They are also reported to display tolerogenic function
with the ability to suppress T-cell proliferation, analogous to regulatory T cells. In
this capacity, they are critical in the suppression of autoimmunity, but can be
exploited by tumor cells to circumvent the expansion of tumor-specific T cells,
thereby allowing tumors to persist. The authors concluded that several forms of
skin cancer are successfully treated with the topical drug imiquimod, which
activates pDCs through toll-like receptor 7. Furthermore, pDC-based anti-cancer
vaccines have shown encouraging results for the treatment of melanoma in early
trials. They stated that future studies regarding the contributions of pDCs to
malignancy will likely afford many opportunities for immunotherapy strategies.
Drakes and Stiff (2016) noted that approximately 80 % of patients with ovarian
cancer are diagnosed with advanced disease. Even with cutting edge surgical
techniques and the best regimens of standard therapies most patients relapse and
die of drug resistant disease within 5 years of diagnosis. Dendritic cell
immunotherapy can induce anti-tumor T cell immunity in patients and holds great
potential in the era of modern anti-cancer treatment. The authors summarized the
important findings in ovarian cancer DC clinical trials, and discussed new directions
which may improve the effectiveness of DC immunotherapy. Expert commentary:
of this study was “Administration of DC vaccines with other forms of immunotherapy
may enhance the efficacy of these treatments, ultimately increasing cures for this
disease”.
Artene and colleagues (2016) stated that the bevacizumab and irinotecan protocol
is considered a standard treatment regimen for recurrent malignant glioma. Recent
advances in immunotherapy have hinted that vaccination with DCs could become
an alternative salvage therapy for the treatment of recurrent malignant glioma.
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These investigators performed a search on PubMed, Cochrane Library, Web of
Science, ScienceDirect, and Embase in order to identify studies with patients
receiving bevacizumab plus irinotecan or dendritic cell therapy (DCT) for recurrent
malignant gliomas. The data obtained from these studies were used to perform a
systematic review and survival gain analysis. A total of14 clinical studies with
patients receiving either bevacizumab plus irinotecan or DC vaccination were
identified; 7 studies followed patients that received bevacizumab plus irinotecan
(302 patients) and 7 studies included patients that received DCT (80 patients). For
the patients who received bevacizumab plus irinotecan, the mean reported median
OS was 7.5 (95 % CI: 4.84 to 10.16) months. For the patients who received DCT,
the mean reported median OS was 17.9 (95 % CI: 11.34 to 24.46) months. For
irinotecan + bevacizumab group, the mean survival gain was -0.02 ± 2.00, while
that for the DCT group was -0.01 ± 4.54. The authors concluded that for patients
with recurrent malignant gliomas, DCT did not have a significantly different effect
when compared with bevacizumab and irinotecan in terms of survival gain (p =
0.535) and did not improve weighted survival gain (p = 0.620). Thus, this survival
gain analysis demonstrated that there is no real clinical benefit for patients
undergoing DC vaccination in comparison to those receiving bevacizumab and
irinotecan for the treatment of recurrent malignant gliomas.
Tang and colleagues (2017) noted that DCs play a pivotal role in the tumor
microenvironment (TME). As the primary antigen-presenting cells in the tumor,
DCs modulate anti-tumor responses by regulating the magnitude and duration of
infiltrating cytotoxic T lymphocyte responses. Unfortunately, due to the
immunosuppressive nature of the TME, as well as the inherent plasticity of DCs,
tumor DCs are often dysfunctional, a phenomenon that contributes to immune
evasion. Recent progresses in the understanding of tumor DC biology have
revealed potential molecular targets that allow researchers to improve tumor DC
immunogenicity and cancer immunotherapy. These investigators reviewed the
molecular mechanisms that drive tumor DC dysfunction. They discussed recent
advances in the understanding of tumor DC ontogeny, tumor DC subset
heterogeneity, and factors in the TME that affect DC recruitment, differentiation,
and function. The authors described potential strategies to optimize tumor DC
function in the context of cancer therapy.
Hargadon (2017) stated that melanoma is a highly aggressive form of skin cancer
that frequently metastasizes to vital organs, where it is often difficult to treat with
traditional therapies such as surgery and radiation. In such cases of metastatic
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disease, immunotherapy has emerged in recent years as an exciting therapeutic
option for melanoma patients. Despite unprecedented successes with immune
therapy in the clinic, many patients still experience disease relapse, and others fail
to respond at all, thus highlighting the need to better understand factors that
influence the efficacy of anti-tumor immune responses. At the heart of anti-tumor
immunity are DCs, an innate population of cells that function as critical regulators of
immune tolerance and activation. As such, DCs have the potential to serve as
important targets and delivery agents of cancer immunotherapies. Even
immunotherapies that do not directly target or employ DCs, such as checkpoint
blockade therapy and adoptive cell transfer therapy, are likely to rely on DCs that
shape the quality of therapy-associated antitumor immunity. Thus, understanding
factors that regulate the function of tumor-associated DCs is essential for optimizing
both current and future immunotherapeutic strategies for treating melanoma. To
this end, the author focused on advances in the understanding of DC function in the
context of melanoma, with particular emphasis on the role of immunogenic cell
death in eliciting tumor-associated DC activation, immunosuppression of DC
function by melanoma-associated factors in the tumor microenvironment, metabolic
constraints on the activation of tumor-associated DCs, and (the role of the
microbiome in shaping the immunogenicity of DCs and the overall quality of anti-
melanoma immune responses they mediate. Furthermore, the author highlighted
novel DC-based immunotherapies for melanoma that are emerging from recent
progress in each of these areas of investigation, and discussed current issues and
questions that will need to be addressed in future studies aimed at optimizing the
function of melanoma-associated DCs and the anti-tumor immune responses they
direct against this cancer.
Bryant and associates (2019) noted that the ability of immune therapies to control
cancer has recently generated intense interest. This therapeutic outcome is reliant
on T cell recognition of tumor cells. The natural function of DCs is to generate
adaptive responses, by presenting antigen to T cells, hence they are a logical target
to generate specific anti-tumor immunity. The understanding of DC biology is
expanding, and they are now known to be a family of related subsets with variable
features and function. Most clinical experience to-date with DC vaccination has
been using monocyte-derived DC vaccines. There is now growing experience with
alternative blood-derived DC derived vaccines, as well as with multiple forms of
tumor antigen and its loading, a wide range of adjuvants and different modes of
vaccine delivery. Key insights from pre-clinical studies, as well as lessons learned
from early clinical testing drive progress towards improved vaccines. The authors
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concluded that the potential to fortify responses with other modalities of
immunotherapy makes clinically effective "2nd generation" DC vaccination
strategies a priority for cancer immune therapists.
Hepatocellular Carcinoma
Chen and colleagues (2018) stated that DC-based immunotherapy has recently
been reported frequently in the treatment of hepato-cellular carcinoma (HCC);
however, its efficacy remains controversial. In a systematic review and meta-
analysis, these researchers evaluated the clinical efficacy of DC-based
immunotherapy on HCC. PubMed, Cochrane Library, Embase and Web of Science
were searched to identify clinical trials on DC-based immunotherapy for HCC
published up to January 31, 2018. The articles were selected according to pre-
established inclusion criteria and methodologic quality, and publication bias were
evaluated. A total of 1,276 cases from 19 clinical trials were included. Compared
with traditional treatment, further DC-based therapy enhanced the CD4+ T/CD8+ T
ratio (standardized mean difference [SMD]: 0.68, 95 % CI: 0.46 to 0.89, p < 0.001);
increased the 1-year, 18-month and 5-year PFS rate and the 1-year, 18-month and 2-
year OS rate (RR greater than 1, p < 0.05), prolonged the median PFS time (median
survival ratio [MSR]: 1.98, 95 % CI: 1.60 to 2.46, p < 0.001) and median
OS time (MSR: 1.72, 95 % CI: 1.51 to 1.96, p < 0.001). Adverse reactions were
mild. The authors concluded that DC-based therapy not only enhanced anti-tumor
immunity, improved the survival rate and prolonged the survival time of HCC
patients, but it was also safe. These researchers stated that these findings
provided encouraging information for further development of DC-based
immunotherapy as an adjuvant treatment for HCC. However, these findings must
be interpreted with caution because of the small study numbers, publication bias
and the various of study designs, pre-treatment and therapeutic processes of DCs.
Gastric Cancer
Wang and colleagues (2018) noted that immunotherapy is emerging as a new
treatment strategy for gastric cancer (GC). However, the safety and efficacy of this
technique remain unclear. In a meta-analysis, these investigators examined the
effect of cytokine-induced killer cell (CIK)/DC-cytokine-induced killer cell (DC-CIK)
treatment for GC after surgery. Hazard ratio (HR), OS rates, and disease-free
survival (DFS) rates were calculated using a Mantel-Haenszel (M-H) fixed-effects
model (FEM), and results were displayed using forest plots. Publication bias was
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assessed by Begg test, and data were presented using funnel plots. Date
robustness was assessed by the trim and fill method. Descriptive analysis was
performed on T lymphocytes and adverse effects. A total of 9 trials (1,216 patients)
were eligible for inclusion in this meta-analysis. Compared with the control group,
the HR for OS was 0.712 (95 % CI: 0.594 to 0.854) and 0.66 (95 % CI: 0.546 to
0.797) for overall DFS. The RR of the 3 and 5-year OS rate was 1.29 (95 % CI:
1.15 to 1.46) and 1.73 (95 % CI: 1.36 to 2.19), respectively. The RR for the 3 and
5-year DFS rate 1.40 (95 % CI: 1.19 to 1.65) and 2.10 (95 % CI: 1.53 to 2.87),
respectively. The proportion of patients who were CD3+, CD4+, and CD4+/CD8+
increased in the cellular therapy groups. No fatal adverse reactions were noted.
The authors concluded that chemotherapy combined with CIK/DC-CIK therapy after
surgery resulted in low HR, and significantly increasing OS rates, DFS rates, and
T-lymphocyte responses in patients with GC. These investigators expected more
multi-center randomized trials to be performed to verify the efficacy of this
technique in the near future. This therapy is a potentially effective strategy for the
treatment of GC. Although pre-clinical studies showed that immunotherapy has a
significant effect upon GC, many problems need to be solved urgently, for example,
is use of immunotherapy combined with chemotherapy more effective? What is the
cycle and duration of maintenance of immunotherapy? The authors stated that the
prospect of immunotherapy for GC is promising, but more research and a
standardized treatment regimen are still needed.
These researchers noted that this study had several drawbacks. First, the
difference between the number of patients involved in each study may have led to
partial differences. Second, there were differences in the use of immune cells
across different studies. The immune responses induced by different immune cells
were different and may have had different effects on the development of the
disease. Furthermore, different surgical procedures may have led to different
outcomes, thus creating a study bias; patients in stages I to III underwent radical
surgery, whereas patients in stage IV underwent palliative surgery.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
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Dendritic cell immunotherapy:
ICD-10 codes not covered for indications listed n the CPB:
D03.0 - D03.9
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0377 Dendritic Cell
Immunotherapy
There are no amendments for Medicaid.
www.aetnabetterhealth.com/pennsylvania updated 07/16/2019
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