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
• Arthritis
• Asthma
• Cancer
• Chronic fatigue
• Colonic diverticulum
• Diabetes
• Hypertension
• Ischemic cardiomyopathy
• Myocardial infarction
• 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.

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.