Adoptive Immunotherapy and Cellular Therapy

Number: 0641


Aetna considers adoptive immunotherapy, using either tumor-infiltrating lymphocytes (TILs) or lymphokine-activated killer (LAK) cells that are activated in-vitro by interleukin-2 (IL-2), experimental and investigational for the treatment of the following indications (not an all-inclusive list) due to lack of adequate evidence that it is more beneficial than IL-2 alone:

  • Alzheimer disease and other amyloid disorders
  • Breast cancer
  • Esophageal cancer
  • Glioblastoma multiforme
  • Head and neck cancer
  • Hepato-cellular carcinoma
  • Intractable viral diseases and other infectious diseases
  • Lung cancer (inclduing non-small cell lung cancer)
  • Malignant glioma
  • Melanoma
  • Myeloma
  • Ovarian cancer
  • Pancreatic cancer
  • Renal cell carcinoma
  • Sporadic inclusion-body myositis
  • Other malignancies

Aetna consider cellular therapy (also known as cell therapy, embryonic cell therapy, fresh cell therapy, live cell therapy, glandular therapy, organotherapy, and xenotransplant therapy) experimental and investigational for the treatment of the following indications (not an all-inclusive list) due to lack of adequate evidence:

  • Acquired immune deficiency syndrome
  • Acute lymphocytic leukemia
  • Arthritis
  • Asthma
  • Cancer
  • Chronic fatigue
  • Colonic diverticulum
  • Diabetes
  • Huntington’s disease
  • Hypertension
  • Ischemic cardiomyopathy
  • Ischemic stroke
  • Myocardial infarction
  • Non-ischemic cardiomyopathy
  • Peripheral arterial diseases (e.g., critical limb ischemia)
  • Tendinopathy

See also CPB 0377 - Dendritic Cell Immunotherapy, and CPB 0638 - Donor Lymphocyte Infusion.


Adoptive Immunotherapy:

Adoptive immunotherapy involves removing lymphocytes from the patient, boosting their anti-cancer activity, growing them in large numbers, and then returning them to the patient:

Lymphokine-activated killer (LAK) cells: Initial experiments in adoptive immunotherapy involved removing lymphocytes from the blood of a patient and growing them in the presence of the lymphokine interleukin-2 (IL-2), an immune stimulator.  The cells were then returned to the patient.  These lymphocytes were called LAK cells.

Tumor-infiltrating lymphocytes (TILs): A stronger response against tumor cells is obtained using lymphocytes isolated from the tumor itself.  These tumor-infiltrating lymphocytes are grown in the presence of IL-2 and returned to the body to attack the tumor.  Researchers are also using radiolabeled monoclonal antibodies for tumor antigens to even more closely identify lymphocytes specific for tumor cells.

Adoptive immunotherapy and dendritic cell immunotherapy are forms of cellular therapy, where ex-vivo processed cells are introduced into the body.  Adoptive immunotherapy uses immune effector cells (e.g., T cells), whereas dendritic cell immunotherapy uses antigen-presenting cells.

Pre-clinical studies suggested anti-tumor activity could be enhanced by using IL-2 together with ex-vivo activated and expanded autologous lymphocytes.  Also, the first objective responses with high-dose bolus IL-2 therapy were noted in patients receiving IL-2 together with LAK cells prepared through in-vitro activation of autologous peripheral blood lymphocytes that were harvested by lymphopheresis, and initially, it appeared that the combination of IL-2/LAK was more active than IL-2 alone.

Clinical studies have failed to demonstrate that the addition of activated LAK cells with IL-2 is any more effective than IL-2 alone.  Major IL-2/LAK clinical trials in patients with renal cell carcinoma have been conducted by several groups, including the National Cancer Institute (NCI) Surgery Branch, the Interleukin-2/LAK Working Group, and the NCI-sponsored Modified Group C centers.  A subset of the NCI Surgery Branch's patients with renal cell carcinoma and with all patients entered into the Modified Group C trials were randomized to receive IL-2 alone or together with LAK cells.  Response rates to IL-2 used alone and together with LAK cells as well as durability of responses did not differ substantially.  In a review of the literature, Grimm (2000) concluded that “the data do not support a major contribution of ex vivo activated and adoptively transferred LAK cells to the efficacy of high-dose bolus IL-2 in patients with renal cell carcinoma.”

Similar conclusions were reached regarding the adoptive transfer of LAK cells in patients with melanoma treated with high-dose bolus IL-2.  Response rates with IL-2/LAK are not different from those observed with high-dose IL-2 alone, and IL-2/LAK therapy in other solid tumors has been disappointing.  While attempts to generate LAK at the tumor site remain attractive, Grimm (2000) concluded that the intravenous infusion of LAK is not likely to prove effective in cases beyond the blood-borne metastatic deposits, which appear just as sensitive to interleukin alone.

Grimm (2000) noted that clinical trials conducted with IL-2 and TIL has also been disappointing.  Clinical trials of IL-2/TIL have been performed on the basis of the theory that TIL would include those with tumor specific activity, which was somehow suppressed in the vicinity of the tumor.  These lymphocytes are produced by placing digested, fresh tumor biopsies into an in-vitro culture with IL-2.  Although some early studies have noted response rates using TIL cells together with IL-2 in the 30 to 40 % range, there are no studies comparing responses with TIL cells compared with IL-2 alone.

A Cochrane meta-analysis examined the published evidence for adoptive immunotherapy in renal cell cancer (Coppin et al, 2004).  The investigators identified 1 study that compared high dose IL-2 plus LAK cells with high dose IL-2 alone (Rosenberg et al, 1993).  Three other studies examined IL-2 given in modified schedules to reduce toxicity but with additions intended to maintain or improve efficacy compared to the high dose IL-2 regimen.  The modifiers included TILs (Figlin et al, 1999), or LAK cells (McCabe et al, 1991; Law et al, 1995).  The investigators found that examination of individual and pooled response rates showed no clear evidence of enhancement for remission (Peto OR 0.93, 95 % confidence interval [CI]: 0.50 to 1.74) (Coppin et al, 2004).  Likewise for the 3 studies reporting survival, 1-year mortality was not reduced (Peto OR 0.78, 95 % CI: 0.50 to 1.21).

In a phase II clinical study, Kimura and associates (2008) evaluated the effectiveness and toxicity of adjuvant chemo-immunotherapy using dendritic cells and activated killer cells are in post-surgical primary lung cancer patients (n = 31).  The activated killer cells and dendritic cells (AKT-DC) obtained from tissue cultures of tumor-draining lymph nodes (TDLN) or from TDLN co-cultured with peripheral blood lymphocytes (TDLN-Pb) were used for the adoptive transfer of immunotherapy.  Patients received 4 courses of chemotherapy along with immunotherapy every 2 months for 2 years.  Three cases were excluded because of refusal by the patients after 1 to 2 courses of immunotherapy.  For the 28 cases treated, a total of 313 courses of immunotherapy were administered.  The main toxicities were fever (78.0 %), chill (83.4 %), fatigue (23.0 %) and nausea (17.0 %) on the day of cell transfer.  The 2- and 5-year survival rates were 88.9 % (95 % CI: 95.9 to 81.9) and 52.9 % (95 % CI: 76.4 to 29.4).  The authors concluded that adoptive transfer of activated killer cells and dendritic cells from the tumor-draining lymph nodes of primary lung cancer patients is feasible and safe, and a large-scale multi-institutional study is needed for assessing the effectiveness of this treatment.

Bernhard and colleagues (2008) stated that the human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated antigen by immuno-therapeutical approaches based on HER2-directed monoclonal antibodies and cancer vaccines.  These investigators described the adoptive transfer of autologous HER2-specific T-lymphocyte clones to a patient with metastatic HER2 over-expressing breast cancer.  The HLA/multimer-based monitoring of the transferred T lymphocytes revealed that the T cells rapidly disappeared from the peripheral blood.  The imaging studies indicated that the T cells accumulated in the bone marrow (BM) and migrated to the liver, but were unable to penetrate into the solid metastases.  The disseminated tumor cells in the BM disappeared after the completion of adoptive T-cell therapy.  The findings of this study suggest the therapeutic potential for HER2-specific T cells for eliminating disseminated HER2-positive tumor cells and propose the combination of T cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors.

Rolle and colleagues (2010) noted that glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor.  The traditional treatments for GBM, including surgery, radiation, and chemotherapy, only modestly improve patient survival.  Therefore, immunotherapy has emerged as a novel therapeutic modality.  Current immunotherapeutic approaches for glioma can be divided into 3 categories: (i) immune priming (active immunotherapy), (ii) immunomodulation (passive immunotherapy), and (iii) adoptive immunotherapy.

Chekmasova and Brentjens (2010) stated that adoptive transfer of genetically modified autologous tumor-reactive T cells is a promising novel anti-tumor therapy for many cancers.  Ovarian carcinomas in particular appear to be suited to this therapeutic approach based on the fact that these tumors are relatively immunogenic, inducing an endogenous T cell response.  Furthermore, the degree to which this endogenous T cell- mediated immune response is evident correlates to long-term patient prognosis following surgery and chemotherapy.  To this end, adoptive T cell immunotherapy strategies for the treatment of ovarian carcinomas appear to be particularly promising and are currently being investigated at several centers in both pre-clinical and clinical settings.

Adoptive immunotherapy is also being studied as a means for treating non-malignant conditions such as amyloid disorders (e.g., Alzheimer disease, sporadic inclusion-body myositis) and infectious diseases/intractable viral diseases.  However, there is currently insufficient evidence to support the clinical value of these potential applications of adoptive immunotherapy.

Yamasaki et al (2011) noted that Vα24 natural killer T (NKT) cells have potent anti-tumor activity.  These researchers performed a phase II clinical study in patients with head and neck squamous cell carcinoma (HNSCC) using ex-vivo expanded Vα24 NKT cells and α-galactosylceramide (αGalCer; KRN7000)-pulsed antigen-presenting cells (APCs) to investigate the efficacy and induction of NKT cell-specific immune responses.  The subjects were 10 patients with locally recurrent and operable HNSCC.  One course of nasal submucosal administration of αGalCer-pulsed APCs and intra-arterial infusion of activated NKT cells via tumor-feeding arteries was given before salvage surgery.  Anti-tumor effects, NKT cell-specific immune responses in extirpated cancer tissue and peripheral blood, safety, and pathological effects were evaluated.  Five cases achieved objective tumor regression.  The number of NKT cells increased in cancer tissues in 7 cases and was associated with tumor regression.  The combination therapy induced NKT cell-specific immune responses in cancer tissues that were associated with beneficial clinical effects.

Kurusaki et al (2011) stated that APCs play a crucial role in the induction of immune responses.  However, the optimal administration route of tumor-specific APCs for inducing effective immunological responses via cancer immunotherapy remains to be elucidated.  Human NKT cells are known to have strong anti-tumor activities and are activated by the specific ligand, namely, αGalCer. A total of 17 patients with HNSCC were enrolled in this study.  Patients received an injection of αGalCer-pulsed APCs into the nasal, or the oral floor submucosa.  Then total body image and single photon emission computed tomography (SPECT) images were examined.  The immunological responses including the number of peripheral blood NKT cells, anti-tumor activities and the CD4(+) CD25(high) Foxp3(+) T cells (Tregs) induced following APCs were also compared.  APCs injected into the nasal submucosa quickly migrated to the lateral lymph nodes and those injected into the oral floor submucosa dominantly migrated to the submandibular nodes rather than the lateral lymph nodes.  An increase in the absolute number of NKT cells and the IFN-γ producing cells was observed in peripheral blood after injection of the APCs into the nasal submucosa, however, these anti-tumor activities were not detected and the increased frequency of Treg cells were observed after administration into oral floor.  The authors concluded that these findings indicated that a different administration route of APCs has the potential to bring a different immunological reaction.  The submucosal administration of αGalCer into the oral submucosa tends to induce immunological suppression.

In a phase I/II 2-arm trial (Rapoport et al, 2011), a total of 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 co-stimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multi-peptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the anti-apoptotic protein survivin.  Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only.  Patients exhibited robust T-cell recoveries by day 14 with supra-physiologic T-cell counts accompanied by a sustained reduction in regulatory T cells.  The median event-free survival (EFS) for all patients is 20 months (95 % CI: 14.6 to 24.7 months); the projected 3-year overall survival is 83 %.  A subset of patients in arm A (36 %) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS.  Higher post-transplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS.  Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers.  Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including anti-tumor immunity, after autologous stem cell transplantation for myeloma.

In a phase II clinical trial, Geller et al (2010) evaluated the tumor response and in-vivo expansion of allogeneic natural killer (NK) cells in recurrent ovarian and breast cancer.  Patients underwent a lympho-depleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in 7 patients, 200 cGy total body irradiation (TBI) to increase host immune suppression.  An NK cell product, from a haplo-identical related donor, was incubated over-night in 1,000 U/ml IL-2 prior to infusion.  Subcutaneous IL-2 (10 MU) was given 3 times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of greater than or equal to 100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry.  A total of 20 patients (14 ovarian cancer, 6 breast cancer) were enrolled.  The median age was 52 (range of 30 to 65) years.  Mean NK cell dose was 2.16 × 10(7)cells/kg.  Donor DNA was detected 7 days after NK cell infusion in 9/13 (69 %) patients without TBI and 6/7 (85 %) with TBI.  T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (p = 0.03).  Serum IL-15 levels increased after the preparative regimen (p < 0.001).  Patients receiving TBI had delayed hematologic recovery (p = 0.014).  One patient who was not evaluable had successful in-vivo NK cell expansion.  The authors concluded that adoptive transfer of haplo-identical NK cells after lympho-depleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells.  They stated that strategies to augment in-vivo NK cell persistence and expansion are needed.

Weber et al (2011) noted that adoptive T-cell therapy (ACT) using expanded autologous tumor-infiltrating lymphocytes (TIL) and tumor antigen-specific T cell expanded from peripheral blood are complex but powerful immunotherapies directed against metastatic melanoma.  A number of non-randomized clinical trials using TIL combined with high-dose IL-2 have consistently found clinical response rates of 50 % or more in metastatic melanoma patients accompanied by long progression-free survival.  Recent studies have also established practical methods for the expansion of TIL from melanoma tumors with high success rates.  These results have set the stage for randomized phase II/III clinical trials to determine whether ACT provides benefit in stage IV melanoma.  These investigators provided an overview of the current state-of-the art in T-cell-based therapies for melanoma focusing on ACT using expanded TIL and address some of the key unanswered biological and clinical questions in the field.  Different phase II/III randomized clinical trial scenarios comparing the efficacy of TIL therapy to high-dose IL-2 alone were described.  Finally, the authors provided a roadmap describing the critical steps required to test TIL therapy in a randomized multi-center setting.  They suggested an approach using centralized cell expansion facilities that will receive specimens and ship expanded TIL infusion products to participating centers to ensure maximal yield and product consistency.  If successful, this approach will definitively answer the question of whether ACT can enter mainstream treatment for cancer.

Bielamowicz et al (2013) stated that glioblastoma multiforme (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable.  With the current standard of care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients.  Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response.  While this tolerance is subtended by the tumor being utterly "self," it is to a great extent due to local and systemic immune compromise mediated by the tumor.  Different cell modalities including lymphokine-activated killer cells, NK cells, cytotoxic T lymphocytes, and transgenic chimeric antigen receptor or αβ T cell receptor grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system toward the tumor complex.  These researchers noted that promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile.  Efficacy will need to be formally tested in phase II/III clinical trials.  The authors concluded that given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care.

Bregy et al (2013) stated that active immunotherapy is a new area of research that may be a successful treatment option for GBM.  The focus is on vaccines that consist of APCs loaded with tumor antigen.  These researchers conducted a systematic review of prospective studies, case reports and clinical trials to examine the safety and effectiveness of active immunotherapy using dendritic cells in terms of complications, median overall survival (OS), progression free survival (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 dendritic cells.  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, 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.  They stated that larger clinical trials are needed to show the potential benefits of active immunotherapy.

Svane and Verdegaal (2014) stated that ACT based on autologous T cell derived either from tumor as tumor-infiltrating lymphocytes (TILs) or from peripheral blood is developing as a key area of future personalized cancer therapy. TIL-based ACT is defined as the infusion of T cells harvested from autologous fresh tumor tissues after ex vivo activation and extensive expansion. TIL-based ACT has so far only been tested in smaller phase I/II studies, but these studies consistently confirm an impressive clinical response rate of up to 50 % in metastatic melanoma including a significant proportion of patients with durable complete tumor eradication. These remarkable results justify the need for a definitive phase III trial documenting the efficacy of this type of T cell-based Advanced Therapy Medicinal Product in order to pave the way for regulatory approval and implementation of TIL therapy as a new treatment standard in oncology practice. TIL-based ACT can, however, only be offered to a limited group of patients based on the need for accessible tumor tissue, the complexity of TIL production procedures, and the very intensive nature of this three-step treatment including both high-dose chemotherapy and interleukin-2 in addition to T cell infusion. To this end, adoptive T cell therapy using peripheral blood mononuclear cell-derived T cells could be a welcome alternative to circumvent these limitations and broaden up the applicability of ACT.

Cellular Therapy:

Barrett (2008) stated that cellular therapy (also known as embryonic cell therapy, fresh cell therapy, glandular therapy, live cell therapy, and organotherapy) refers to various procedures in which processed tissue from animal embryos, fetuses or organs, is injected or taken orally.  Products are obtained from specific organs or tissues said to correspond with the unhealthy organs or tissues of the recipient.  Proponents of cellular therapy claim that the recipient's body automatically transports the injected cells to the target organs, where they supposedly strengthen them and regenerate their structure.  The organs and glands used in cell treatment include adrenals, brain, heart, kidney, liver, ovary, pancreas, parotid, pituitary, spleen, testis, thymus, and thyroid.  Several different types of cell or cell extract can be given simultaneously -- some practitioners routinely give up to 20 or more at once.  The author noted that the theory behind cellular therapy is senseless; and the American Cancer Society (ACS) has strongly advised people not to seek it.

According to the American Cancer Society (ACS, 2008), cell therapy (also known as cellular therapy, fresh cell therapy, live cell therapy, glandular therapy, and xenotransplant therapy) entails the injection of processed tissue from the organs, embryos, or fetuses of animals (e.g., cows or sheep).  This approach is supposed to repair cellular damage and heal sick or failing organs.  Cell therapy is promoted as an alternative therapy for cancer, arthritis, heart disease, Down syndrome, and Parkinson disease.   It is also marketed to counter the effects of aging, reverse degenerative diseases, improve general health, increase vitality and stamina, and enhance sexual function.  Some practitioners have proposed using cell therapy to treat AIDS patients.  However, available scientific evidence does not support claims that cell therapy is effective in treating cancer or any other disease.  Moreover, serious adverse reactions can result from cell therapy.

Furthermore, the Centers for Medicare and Medicaid Services states that cellular therapy involves the practice of injecting humans with foreign proteins like the placenta or lungs of unborn lambs.  Cellular therapy is without scientific or statistical evidence to document its therapeutic efficacy and, in fact, is considered a potentially dangerous practice.  Accordingly, cellular therapy is not considered reasonable and necessary.

Alvarez et al (2013) stated that cell therapy (CTh) is a promising novel therapy for myocardial infarction (MI) and ischemic cardiomyopathy (iCMP).  Recognizing adverse events (AEs) is important for safety evaluation, harm-prevention; and this may aid in the design of future trials.  These researchers defined the prevalence of peri-procedural AEs in CTh trials in MI and iCMP.  They performed a literature search using the MEDLINE database from January 1990 to October 2010.  Controlled clinical trials that compared CTh with standard treatment in the setting of MI and/or iCMP were selected; AEs related to CTh were analyzed.  A total of 2,472 patients from 35 trials were included in this study.  There were 26 trials including 1,796 patients who used CTh in MI and 9 trials including 676 patients who used CTh in iCMP.  Peri-procedural arrhythmia monitoring protocols were heterogeneous and follow-up was short in most of the trials.  In MI trials, the incidence of peri-procedural AEs related to intra-coronary cell transplantation was 7.5 % (95 % CI: 6.04 to 8.96 %).  Adverse events related to granulocyte colony-stimulating factor (GCS-F) used for cell mobilization for peripheral apheresis was 16 % (95 % CI: 9.44 to 22.56 %).  During intra-coronary transplantation in iCMP, the incidence of peri-procedural AEs incidence was 2.6 % (95 % CI: 0.53 to 4.67 %).  There were no AEs reported during trans-epicardial transplantation and AEs were rare during trans-endocardial transplantation.  The authors concluded that the majority of peri-procedural AEs in CTh trials in MI occurred during intra-coronary transplantation and GCS-F administration.  In iCMP, peri-procedural AE were uncommon.  They stated that avoiding intra-coronary route for CTh implantation may decrease the burden of peri-procedural AEs; standardization of AEs definition in CTh trials is needed.

Smadja and colleagues (2013) noted that late evolution of peripheral arterial disease results in the apparition of critical limb ischemia (CLI).  Surgery is a therapeutic option for patients with chronic disease; however, in most patients, especially those with diabetes mellitus, there are very few options and the clinical evolution is rapidly dramatic.  For these reasons, CLI is one of the first diseases treated by genetic or cellular therapies aiming to improve blood flow perfusion in the lower limbs.  These investigators described clinical trials on genetic therapy; most of them have been abandoned because of serious side effects, modest effects and major risks.  Different types of stem cells are now used for cellular therapy: endothelial progenitor cells, early or late, activated or not, mesenchymal stem cells, embryonic stem cells and human induced pluripotent stem cells.

Teraa and associates (2013) performed a meta-analysis of all randomized controlled trials (RCTs) available that studied BM-derived cell therapy compared to standard care with or without placebo in CLI patients and provided summary efficacy data on this approach.  A systematic search in the electronic databases of Medline, Embase, and the Cochrane Controlled Trials Register was performed.  All studies were critically appraised and data were extracted and meta-analyzed using a random-effects model.  Major amputation and amputation-free survival were considered as the primary end-points.  A total of 12 RCTs including 510 CLI patients were identified and analyzed.  The meta-analysis showed beneficial effects of BM-derived cell therapy on both subjective and surrogate objective end-points, that is, pain score, pain-free walking distance, ankle-brachial index, and transcutaneous oxygen measurements (all p < 0.00001).  Overall, the RCTs showed reduced amputation rates in the therapeutic arms of the included trials with a relative risk (RR) on major amputation of 0.58 [95 % CI: 0.40 to 0.84; p = 0.004].  However, when only the placebo-controlled RCTs were considered, the beneficial effect on major amputation rates was considerably reduced and non-significant (RR = 0.78; 95 % CI: 0.40 to 1.51; p = 0.46).  Amputation-free survival did not significantly differ between the BM-treated and the control group (RR = 1.16; 95 % CI: 0.92 to 1.48; p = 0.22).  The authors concluded that the findings of this meta-analysis underlined the promising potential of BM-derived cell therapy in CLI patients.  More importantly, the results of placebo-controlled and non-placebo-controlled RCTs seemed to diverge, which stresses the necessity to use placebo in the control arms of these trials.  These researchers stated that future well-designed larger placebo-controlled RCTs are needed and should include long-term follow-up data to assess durability of treatment effects.

Lui and Ng (2013) summarized the current evidence on the safety and effectiveness of cell therapy for the treatment of tendinopathy.  These researchers performed a systematic literature search using various databases with relevant keywords.  Both original animal and human controlled studies, covering any cell type for the treatment of naturally occurring, overuse or collagenase-induced tendinopathy, and with full text available, were included.  The quality of all included studies was assessed.  Relevant data on study design, safety and efficacy outcomes were extracted.  A total of 11 original studies were selected, of which 9 were pre-clinical studies using the collagenase-induced tendon injury model and 2 were clinical studies.  Types of cells, scaffolds, dosages and treatment regimens used varied.  All the studies performed cell injection once.  A critical appraisal of the included studies showed sub-optimal blinding.  Cell therapy was generally reported to be safe, except minor complications, in the short-term.  Cell therapy was reported to improve tendon architecture in histology but equivocal finding was observed in sonographic/MRI examination, functional and biomechanical performance.  The authors concluded that the current evidence was inadequate to make a conclusion whether cell therapy was safe and effective.  They stated that further study with adequate sample size and follow-up time, appropriate controls and optimal blinding is needed.  Confirmation of finding, using different tendinopathy animal models, by systematic investigation of the effects of cell sources, dosages and regimens on the outcomes, and by the inclusion of tendon pain assessment in both animals and human, is recommended.

Cisbani and Cicchetti (2014) remarked that the hope that cell transplantation therapies will provide an ideal treatment option for neurodegenerative diseases has been considerably revived with the remarkable advancements in genetic engineering towards active cell fate determination in-vitro.  However, for disorders such as Huntington's disease (HD), the challenges that researchers face are still enormous.  This autosomal dominant genetic disorder leads, in part, to massive neuronal loss and severe brain atrophy which, despite the cell type used, cannot be easily repaired.  And before large clinical trials are even considered, investigators must take a critical look at the outcomes of the pilot studies already available, not only from a clinical perspective but also by a careful assessment of what they can learn from the autopsies of HD patients who have undergone transplantation.  The authors summarized and discussed the 7 transplantation pilot trials that were initiated worldwide in HD patients more than 10 years ago, with a particular emphasis on the post-mortem analyses of 9 unique cases.  Moreover, they described a series of factors, both technical and related to patient selection, that they deem important to predict the outcome of cell grafts in HD therapy.

Liu and colleagues (2014) stated that cell therapy is emerging as a viable therapy to restore neurological function after stroke.  Many types of stem/progenitor cells from different sources have been explored for their feasibility and efficacy for the treatment of stroke.  Transplanted cells not only have the potential to replace the lost circuitry, but also produce growth and trophic factors, or stimulate the release of such factors from host brain cells, thereby enhancing endogenous brain repair processes.  Although stem/progenitor cells have shown a promising role in ischemic stroke in experimental studies as well as initial clinical pilot studies, cellular therapy is still at an early stage in humans.  Many critical issues need to be addressed including the therapeutic time window, cell type selection, delivery route, and in-vivo monitoring of their migration pattern.  These researchers provided a comprehensive synopsis of pre-clinical evidence and clinical experience of various donor cell types, their restorative mechanisms, delivery routes, imaging strategies, future prospects and challenges for translating cell therapies as a neuro-restorative regimen in clinical applications.

Marquis-Gravel et al (2014) noted that stem cell (SC) therapy improves left ventricular function and dimensions in ischemic heart disease.  Few small-scale trials have studied the effects of SC therapy on non-ischemic CMP, the leading cause of heart transplantation in the adults.  These investigators examined the effects of SC therapy for non-ischemic CMP by conducting a systematic review of the literature and meta-analysis of RCTs.  Medline, EBM Reviews-Cochrane Central Register of Controlled Trials, Embase, and the databases were screened for RCTs involving SC for treatment of non-ischemic CMP.  Weighted mean differences of improvement of left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD) were calculated using a random effect analysis model.  A total of 4 trials were included in this meta-analysis (244 patients).  The weighted mean LVEF improvement was 4.87 % (95 % CI: 1.32 to 8.43 %) in the treatment group compared with the control group (p = 0.01).  The weighted mean decrease of LVEDD in the treatment group was of -2.19 mm (95 % CI: -5.69 to 1.30) compared with the control group (p = 0.22).  On subgroup analysis, results were similar in studies involving peripheral CD34-positive or bone marrow-derived mononuclear cells (p = 0.33 for subgroup differences).  The authors concluded that this was the first meta-analysis to show that for the treatment of non-ischemic CMP, SC therapy might improve LVEF, but not LVEDD.  They stated that further trials should aim to circumscribe the optimal SC regimen in this setting, and to assess long-term clinical outcomes as primary end-points.

In a phase I clinical trial, Lee and colleagues (2015) stated that chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukemia (ALL and CLL) and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported.  In a phase I clinical trial, these researchers defined feasibility, toxicity, maximum tolerated dose (MTD), response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells.  This dose-escalation trial consecutively enrolled children and young adults (aged 1 to 30 years) with relapsed or refractory ALL or non-Hodgkin lymphoma (NHL).  Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signaling domains.  All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells.  Using a standard 3 + 3 design to establish the MTD, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated.  After the dose-escalation phase, an expansion cohort was treated at the MTD.  Between July 2, 2012, and June 20, 2014, a total of 21 patients (including 8 who had previously undergone allogeneic hematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells; 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for 2 patients (90 % feasible).  All patients enrolled were assessed for response.  The MTD was defined as 1 × 10(6) CD19-CAR T cells per kg.  All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in 3 (14 %) of 21 patients (95 % CI: 3.0 to 36.3).  The most common non-hematological grade 3 adverse events were fever (9 [43 %] of 21 patients), hypokalemia (9 [43 %] of 21 patients), fever and neutropenia (8 [38 %] of 21 patients), and cytokine release syndrome (3 [14 %) of 21 patients).  The authors concluded that CD19-CAR T cell therapy was feasible, safe, and mediated potent anti-leukemic activity in children and young adults with chemotherapy-resistant B-precursor ALL.  All toxicities were reversible and prolonged B-cell aplasia did not occur.

Jansen Of Lorkeers et al (2015) stated that in regenerative therapy for ischemic heart disease, use of both autologous and allogeneic stem cells has been investigated.  Autologous cell can be applied without immunosuppression, but availability is restricted, and cells have been exposed to risk factors and aging.  Allogeneic cell therapy enables pre-operative production of potent cell lines and immediate availability of cell products, allowing off-the-shelf therapy.  It is unknown which cell source is preferred with regard to improving cardiac function.  These researchers performed a meta-analysis of pre-clinical data of cell therapy for ischemic heart disease.  They conducted a systematic literature search to identify publications describing controlled pre-clinical trials of unmodified stem cell therapy in large animal models of myocardial ischemia.  Data from 82 studies involving 1,415 animals showed a significant improvement in mean LVEF in treated compared with control animals (8.3 %, 95 % CI: 7.1 to 9.5; p < 0.001).  Meta-regression revealed a similar difference in LVEF in autologous (8.8 %, 95 % CI: 7.3 to 10.3; n = 981) and allogeneic (7.3 %, 95 % CI: 4.4 to 10.2, n = 331; p = 0.3) cell therapies.  The authors concluded that autologous and allogeneic cell therapy for ischemic heart disease show a similar improvement in LVEF in large animal models of myocardial ischemia, compared with placebo.  They stated that these results are important for the design of future clinical trials.

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 "+":
ICD-10 codes will become effective as of October 1, 2015:
Adoptive Immunotherapy:
Other CPT codes related to the CPB:
36511 Therapeutic apheresis; for white blood cells
86357 Natural killer (NK) cells, total count
88230 Tissue culture for non-neoplastic disorders; lymphocyte
88237 Tissue culture for neoplastic disorders; bone marrow, blood cells
88239     solid tumor
HCPCS code not covered for indications listed in the CPB:
S2107 Adoptive immunotherapy i.e., development of specific anti-tumor reactivity (e.g., tumor-infiltrating lymphocyte therapy) per course of treatment
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A00.0 - B99.9 Certain infectious and parasitic diseases
C00.0 - D09.9 Malignant neoplasms and malignant carcinoid tumors
E85.0 - E85.9 Amyloidosis
G30.0 - G30.9 Alzheimer's disease
G72.41 Inclusion body myositis [IBM]
Cellular Therapy:
HCPCS codes not covered for indications listed in the CPB:
M0075 Cellular therapy
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
B20 Human immunodeficiency virus [HIV] disease
C00.0 - D09.9 Malignant neoplasms and malignant carcinoid tumors
E08.0 - E13.9 Diabetes mellitus
G10 Huntington's disease
I10 Essential (primary) hypertension
I21.01 - I22.9 ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction
I24.8 - I24.9 Other forms of acute and unspecified ischemic heart disease
I25.89 Other forms of chronic ischemic heart disease
I42.8 Other cardiomyopathies [non-ischemic cardiomyopathy]
I63.50 - I63.9 Cerebral infarction due to unspecified occlusion
I70.0 - I70.92 Atherosclerosis
I73.00 - I73.9 Other peripheral vascular disease [e.g., critical limb ischemia]
I74.2 - I74.4 Embolism and thrombosis of arteries of the extremities
I75.011 - I75.029 Atheroembolism of extremities
I80.00 - I80.209 Phlebitis and thrombophlebitis of extremities
I82.401 - I82.5Z9 Venous embolism and thrombosis of vessels of lower extremity
I99.9 Unspecified disorder of circulatory system
J45.20 - J45.99 Asthma
K57.00 - K57.93 Diverticular disease of intestine
M05.00 - M14.89 Inflammatory polyarthropathies
M67.00 - M71.9 Other disorders of synovium, tendon and bursa
M76.00 - M77.9 Enthesopathies
R53.82 Chronic fatigue, unspecified

The above policy is based on the following references:

    Adoptive Immunotherapy:

    1. Ward DE. Immunotherapy and cancer vaccines. In: The Cancer Handbook. A Guide for the Nonspecialist. The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Research Institute. Columbus, OH: Ohio State University Press; 1996. Available at: Accessed July 1, 2002.
    2. Grimm EA. Cytokines: Biology and applications in cancer medicine. In: Cancer Medicine. 5th ed. Ch. 63. RC Bast, DW Kufe, RE Pollock, eds. Hamilton, ON: BC Decker, Inc.; 2000.
    3. Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst. 1993;85(8):622-632.
    4. Rosenberg SA. Karnofsky Memorial Lecture: The immunotherapy and gene therapy of cancer. J Clin Oncol. 1992;10:180-199.
    5. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105-2116.
    6. Benyunes MC, Fefer A. IL-2 in the treatment of hematologic malignancies. In: Therapeutic Applications of Interleukin. MB Atkins, JW Mier, eds. New York, NY: Marcel Dekker; 1993:163-175.
    7. Sznol M, Hawkins MJ. Interleukin-2 in malignancies other than melanoma and renal cell carcinoma. In: Therapeutic Applications of Interleukin. MB Atkins, JW Mier, eds. New York, NY: Marcel Dekker; 1993:177.
    8. Weiss GR, Margolin KA, Aronson FR, et al. A randomized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus lymphokine-activated killer cells for advanced renal cell carcinoma. J Clin Oncol. 1992;10(2):275-281.
    9. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319(25):1676-1680.
    10. Margolin KA, Rayner AA, Hawkins MJ, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: Analysis of toxicity and management guidelines. J Clin Oncol. 1989;7(4):486-498.
    11. McCabe MS, Stablein D, Hawkins MJ. The Modified Group C experience - Phase III randomized trials of IL-2 vs IL-2 + LAK in advanced renal cell carcinoma and advanced melanoma [abstract]. Proceedings of the Annual Meeting of the American Society of Clinical Oncology. 1991;10:A714.
    12. 1991;10:A714.Hoffman DM, Gitlitz BJ, Belldegrun A, et al. Adoptive cellular therapy. Semin Oncol. 2000;27(2):221-233.
    13. Wallack MK, Sivanandham M, Balch CM, et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: The final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg. 1998;187(1):69-79.
    14. Kimura H, Yamaguchi Y. A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer. 1997;80(1):42-49.
    15. Ratto GB, Zino P, Mirabelli S, et al. A randomized trial of adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 versus standard therapy in the postoperative treatment of resected nonsmall cell lung carcinoma. Cancer. 1996;78(2):244-251.
    16. Law TM, Motzer RJ, Mazumdar M, et al. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer. 1995;76(5):824-832.
    17. Kimura H, Yamaguchi Y. Adjuvant immunotherapy with interleukin 2 and lymphokine-activated killer cells after noncurative resection of primary lung cancer. Lung Cancer. 1995;13(1):31-44.
    18. Gold JE, Malamud SC, LaRosa F, et al. Adoptive chemoimmunotherapy for the treatment of relapsed and refractory solid tumors using ex vivo activated memory T cells (autolymphocyte therapy) and cyclophosphamide. J Immunother. 1993;13(3):213-221.
    19. Graham S, Babayan RK, Lamm DL, et al. The use of ex vivo-activated memory T cells (autolymphocyte therapy) in the treatment of metastatic renal cell carcinoma: Final results from a randomized, controlled, multisite study. Semin Urol. 1993;11(1):27-34.
    20. Lavin PT, Maar R, Franklin M, et al. Autolymphocyte therapy for metastatic renal cell carcinoma: Initial clinical results from 335 patients treated in a multisite clinical practice. Transplant Proc. 1992;24(6):3059-3064.
    21. Koretz MJ, Lawson DH, York RM, et al. Randomized study of interleukin 2 (IL-2) alone vs IL-2 plus lymphokine-activated killer cells for treatment of melanoma and renal cell cancer. Arch Surg. 1991;126(7):898-903.
    22. Figlin RA, Thompson JA, Bukowski RM, et al. Multicenter, randomized, phase III trial of CD+ tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999;17:2521-2529..
    23. Morse MA, Clay TM, Lyerly HK. Current status of adoptive immunotherapy of malignancies. Expert Opin Biol Ther. 2002;2(3):237-247.
    24. Mitchell DA, Fecci PE, Sampson JH. Adoptive immunotherapy for malignant glioma. Cancer J. 2003;9(3):157-166.
    25. Yamaguchi Y, Ohshita A, Kawabuchi Y, et al. Adoptive immunotherapy of cancer using activated autologous lymphocytes--current status and new strategies. Hum Cell. 2003;16(4):183-189.
    26. Koehl U, Sorensen J, Esser R, et al. IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation. Blood Cells Mol Dis. 2004;33(3):261-266.
    27. Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2004;(3):CD001425.
    28. Oelke M, Krueger C, Schneck JP. Technological advances in adoptive immunotherapy. Drugs Today (Barc). 2005;41(1):13-21.
    29. Rossig C, Brenner MK. Genetic modification of T lymphocytes for adoptive immunotherapy. Mol Ther. 2004;10(1):5-18.
    30. Oelke M, Krueger C, Schneck JP. Technological advances in adoptive immunotherapy. Drugs Today (Barc). 2005;41(1):13-21.
    31. McGavern DB. Immunotherapeutic relief from persistent infections and amyloid disorders. Neurology. 2006;66(2 Suppl 1):S59-S64.
    32. Yamaguchi Y, Hihara J, Hironaka K, et al. Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: Possible application for compensatory anti-inflammatory response syndrome. Oncol Rep. 2006;15(4):895-901.
    33. McKee MD, Fichera A, Nishimura MI. T cell immunotherapy. Front Biosci. 2007;12:919-932.
    34. Parmiani G, Castelli C, Santinami M, Rivoltini L. Melanoma immunology: Past, present and future. Curr Opin Oncol. 2007;19(2):121-127.
    35. Wysocki PJ, Zolnierek J, Szczylik C, Mackiewicz A. Recent developments in renal cell cancer immunotherapy. Expert Opin Biol Ther. 2007;7(5):727-737.
    36. Thistlethwaite FC, Elkord E, Griffiths RW, et al. Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma. Cancer Immunol Immunother. 2008;57(5):623-634.
    37. Kondo H, Hazama S, Kawaoka T, et al. Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res. 2008;28(1B):379-387.
    38. Kimura H, Iizasa T, Ishikawa A, et al. Prospective phase II study of post-surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes in primary lung cancer patients. Anticancer Res. 2008;28(2B):1229-1238.
    39. Bernhard H, Neudorfer J, Gebhard K, et al. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer. Cancer Immunol Immunother. 2008;57(2):271-280.
    40. Motohashi S, Nakayama T. Clinical applications of natural killer T cell-based immunotherapy for cancer. Cancer Sci. 2008;99(4):638-645.
    41. Till BG, Jensen MC, Wang J, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112(6):2261-2271.
    42. Hersey P, Halliday GM, Farrelly ML, et al. Phase I/II study of treatment with matured dendritic cells with or without low dose IL-2 in patients with disseminated melanoma. Cancer Immunol Immunother. 2008;57(7):1039-1051.
    43. Cannon MJ, O'Brien TJ. Cellular immunotherapy for ovarian cancer. Expert Opin Biol Ther. 2009;9(6):677-688.
    44. Chekmasova AA, Brentjens RJ. Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer. Discov Med. 2010;9(44):62-70.
    45. Rolle CE, Sengupta S, Lesniak MS. et al. Challenges in clinical design of immunotherapy trials for malignant glioma. Neurosurg Clin N Am. 2010;21(1):201-214.
    46. Di Stasi A, Tey SK, Dotti G, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011;365(18):1673-1683.
    47. Sakamoto M, Nakajima J, Murakawa T, et al. Adoptive immunotherapy for advanced non-small cell lung cancer using zoledronate-expanded γδTcells: A phase I clinical study. J Immunother. 2011;34(2):202-211.
    48. Yamasaki K, Horiguchi S, Kurosaki M, et al. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin Immunol. 2011;138(3):255-265.
    49. Kurosaki M, Horiguchi S, Yamasaki K, et al. Migration and immunological reaction after the administration of αGalCer-pulsed antigen-presenting cells into the submucosa of patients with head and neck cancer. Cancer Immunol Immunother. 2011;60(2):207-215.
    50. Doskali M, Tanaka Y, Ohira M, et al. Possibility of adoptive immunotherapy with peripheral blood-derived CD3⁻CD56+ and CD3+CD56+ cells for inducing antihepatocellular carcinoma and antihepatitis C virus activity. J Immunother. 2011;34(2):129-138.
    51. Rapoport AP, Aqui NA, Stadtmauer EA, et al. Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood. 2011;117(3):788-797.
    52. Geller MA, Cooley S, Judson PL, et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy. 2011;13(1):98-107.
    53. Weber J, Atkins M, Hwu P, et al; Immunotherapy Task Force of the NCI Investigational Drug Steering Committee. White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: A report of the CTEP subcommittee on adoptive cell therapy. Clin Cancer Res. 2011;17(7):1664-1673.
    54. Zhong JH, Li H, Li LQ, et al. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: A systematic review of randomized trials. Eur J Surg Oncol. 2012;38(4):286-295.
    55. Tang X, Liu T, Zang X, et al. Adoptive cellular immunotherapy in metastatic renal cell carcinoma: A systematic review and meta-analysis. PLoS One. 2013;8(5):e62847.
    56. Wang J, He XD, Yao N, et al. A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can J Gastroenterol. 2013;27(6):351-363.
    57. Bielamowicz K, Khawja S, Ahmed N. Adoptive cell therapies for glioblastoma. Front Oncol. 2013;3:275.
    58. Bregy A, Wong TM, Shah AH, et al. Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. Cancer Treat Rev. 2013;39(8):891-907.
    59. Shi H, Sun M, Liu L, Wang Z. Chimeric antigen receptor for adoptive immunotherapy of cancer: Latest research and future prospects. Mol Cancer. 2014;13:219.
    60. Svane IM, Verdegaal EM. Achievements and challenges of adoptive T cell therapy with tumor-infiltrating or blood-derived lymphocytes for metastatic melanoma: What is needed to achieve standard of care? Cancer Immunol Immunother. 2014;63(10):1081-1091.

    Cellular Therapy:

    1. Barrett S. Cellular therapy. 2003. Available at: Accessed June 26, 2013.
    2. American Cancer Society. Cell therapy. Last Revised: November 1, 2008. Available at: Accessed on June 26, 2013.
    3. Centers for Medicare and Medicaid Services. National Coverage Determination for Cellular Therapy. NCD #30.8. Available at: &KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAACAAAAAA&. Accessed on June 26, 2013.
    4. Alvarez PA, Schwarz ER, Ramineni R, et al. Periprocedural adverse events in cell therapy trials in myocardial infarction and cardiomyopathy: A systematic review. Clin Res Cardiol. 2013;102(1):1-10.
    5. Smadja D, Silvestre JS, Levy BI. Genic and cellular therapy for peripheral arterial diseases. Transfus Clin Biol. 2013;20(2):211-220.
    6. Teraa M, Sprengers RW, van der Graaf Y, et al. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: A meta-analysis of randomized controlled clinical trials. Ann Surg. 2013;258(6):922-929.
    7. Lui PP, Ng SW. Cell therapy for the treatment of tendinopathy -- a systematic review on the pre-clinical and clinical evidence. Semin Arthritis Rheum. 2013;42(6):651-666.
    8. Robbers LF, Nijveldt R, Beek AM, et al; HEBE Investigators. Cell therapy in reperfused acute myocardial infarction does not improve the recovery of perfusion in the infarcted myocardium: A cardiac MR imaging study. Radiology. 2014;272(1):113-22.
    9. Sevestre MA, Larghero J, Castier Y, et al. Pilot safety study of perivascular injection of tissue-engineered allogeneic aortic endothelial cells in patients undergoing minimally invasive peripheral revascularization. J Vasc Surg. 2014;59(6):1597-1606.
    10. Cisbani G, Cicchetti F. The fate of cell grafts for the treatment of Huntington's disease: The post-mortem evidence. Neuropathol Appl Neurobiol. 2014;40(1):71-90.
    11. Liu X, Ye R, Yan T, et al. Cell based therapies for ischemic stroke: From basic science to bedside. Prog Neurobiol. 2014;115:92-115.
    12. Marquis-Gravel G, Stevens LM, Mansour S, et al. Stem cell therapy for the treatment of nonischemic cardiomyopathy: A systematic review of the literature and meta-analysis of randomized controlled trials. Can J Cardiol. 2014;30(11):1378-1384.
    13. Jenei-Lanzl Z, Capellino S, Kees F, et al. Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecholaminergic cells in experimental arthritis. Ann Rheum Dis. 2015;74(2):444-451.
    14. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet. 2015;385(9967):517-528.
    15. Jansen Of Lorkeers SJ, Eding JE, Vesterinen HM, et al. Similar effect of autologous and allogeneic cell therapy for ischemic heart disease: Systematic review and meta-analysis of large animal studies. Circ Res. 2015;116(1):80-86.

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