Prior Authorization Review Panel MCO Policy Submission A ... · Dendritic cells (DCs) are the most potent type of antigen presenting cells and are vital in inducing activation and

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(https://www.aetna.com/)

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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http://www.aetna.com/cpb/medical/data/300_399/0377.html

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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

The above policy is based on the following references:

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AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0377 Dendritic Cell

Immunotherapy

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www.aetnabetterhealth.com/pennsylvania updated 07/16/2019

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Documents

Prior Authorization Review Panel MCO Policy Submission A ... · Dendritic cells (DCs) are the most potent type of antigen presenting cells and are vital in inducing activation and