Nonoperative treatment for lumbar spinal stenosis with neurogenic claudication.

BACKGROUND: Lumbar spinal stenosis with neurogenic claudication is one of the most commonly diagnosed and treated pathological spinal conditions. It frequently afflicts the elderly population. OBJECTIVES: To systematically review the evidence for the effectiveness of nonoperative treatment of lumbar spinal stenosis with neurogenic claudication. SEARCH METHODS: CENTRAL, MEDLINE, CINAHL, and Index to Chiropractic Literature (ICL) databases were searched up to June 2012. SELECTION CRITERIA: Randomized controlled trials published in English, in which at least one arm provided data on nonoperative treatments DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. Risk of bias in each study was independently assessed by two review authors using the 12 criteria recommended by the Cochrane Back Review Group (Furlan 2009). Dichotomous outcomes were expressed as relative risk, continuous outcomes as mean difference or standardized mean difference; uncertainty was expressed with 95% confidence intervals. If possible a meta-analysis was performed, otherwise results were described qualitatively. GRADE was used to assess the quality of the evidence. MAIN RESULTS: From the 8635 citations screened, 56 full-text articles were assessed and 21 trials (1851 participants) were included. There was very low-quality evidence from six trials that calcitonin is no better than placebo or paracetamol, regardless of mode of administration or outcome assessed. From single small trials, there was low-quality evidence for prostaglandins, and very low-quality evidence for gabapentin or methylcobalamin that they improved walking distance. There was very low-quality evidence from a single trial that epidural steroid injections improved pain, function, and quality of life, up to two weeks, compared with home exercise or inpatient physical therapy. There was low-quality evidence from a single trial that exercise is of short-term benefit for leg pain and function compared with no treatment. There was low and very low-quality evidence from six trials that multimodal nonoperative treatment is less effective than indirect or direct surgical decompression with or without fusion. A meta-analysis of two trials comparing direct decompression with or without fusion to multimodal nonoperative care found no significant difference in function at six months (mean difference (MD) -3.66, 95% CI -10.12 to 2.80) and one year (MD -6.18, 95% CI -15.03 to 2.66), but at 24 months a significant difference was found favouring decompression (MD -4.43, 95% CI -7.91 to -0.96). AUTHORS' CONCLUSIONS: Moderate and high-quality evidence for nonoperative treatment is lacking and thus prohibits recommendations for guiding clinical practice. Given the expected exponential rise in the prevalence of lumbar spinal stenosis with neurogenic claudication, large high-quality trials are urgently needed.

Timed adoptive T cell transfer during chemotherapy in patients with recurrent platinum-sensitive epithelial ovarian cancer.

BACKGROUND: The presence of T cells and suppressive myeloid cells in epithelial ovarian cancer (EOC) correlate with good and bad clinical outcome, respectively. This suggests that EOC may be sensitive to adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL), provided that immunosuppression by myeloid-derived suppressor cells and M2 macrophages is reduced. Platinum-based chemotherapy can alleviate such immunosuppression, potentially creating a window of opportunity for T cell-based immunotherapy. METHODS: We initiated a phase I/II trial (NCT04072263) in patients with recurrent platinum-sensitive EOC receiving TIL during platinum-based chemotherapy. TILs were administered 2 weeks after the second, third and fourth chemotherapy course. Patients were treated in two cohorts with or without interferon-α (IFNa), as conditioning and TIL support regimen. The primary endpoint was to evaluate the feasibility and safety according to CTCAE V.4.03 criteria and the clinical response and immune modulatory effects of this treatment were evaluated as secondary endpoints. RESULTS: Sixteen patients were enrolled. TIL could be successfully expanded for all patients. TIL treatment during chemotherapy without IFNa (n=13) was safe but the combination with IFNa added to the chemotherapy-induced toxicity with 2 out of 3 patients developing thrombocytopenia as dose-limiting toxicity. Fourteen patients completed treatment with a full TIL cycle and were further evaluated for clinical and immunological response. Platinum-based chemotherapy resulted in reduction of circulating myeloid cell numbers and IL-6 plasma levels, confirming its immunosuppression-alleviating effect. Three complete (CR), nine partial responses and two stable diseases were recorded, resulting in an objective response rate of 86% (Response Evaluation Criteria In Solid Tumors V.1.1). Interestingly, progression free survival that exceeded the previous platinum-free interval was detected in two patients, including an exceptionally long and ongoing CR in one patient that coincided with sustained alleviation of immune suppression. CONCLUSION: TIL therapy can be safely combined with platinum-based chemotherapy but not in combination with IFNa. The chemotherapy-mediated reduction in immunosuppression and the increase in platinum-free interval for two patients warrants further exploration of properly-timed TIL infusions during platinum-based chemotherapy, possibly further benefiting from IL-2 support, as a novel treatment option for EOC patients.

Neoantigen Targetability in Progressive Advanced Melanoma.

PURPOSE: The availability of (neo)antigens and the infiltration of tumors by (neo)antigen-specific T cells are crucial factors in cancer immunotherapy. In this study, we aimed to investigate the targetability of (neo)antigens in advanced progessive melanoma and explore the potential for continued T-cell-based immunotherapy. EXPERIMENTAL DESIGN: We examined a cohort of eight patients with melanoma who had sequential metastases resected at early and later time points. Antigen-presenting capacity was assessed using IHC and flow cytometry. T-cell infiltration was quantified through multiplex immunofluorescence. Whole-exome and RNA sequencing were conducted to identify neoantigens and assess the expression of neoantigens and tumor-associated antigens. Mass spectrometry was used to evaluate antigen presentation. Tumor recognition by autologous T cells was assessed by coculture assays with cell lines derived from the metastatic lesions. RESULTS: We observed similar T-cell infiltration in paired early and later metastatic (LM) lesions. Although elements of the antigen-presenting machinery were affected in some LM lesions, both the early and later metastasis-derived cell lines were recognized by autologous T cells. At the genomic level, the (neo)antigen landscape was dynamic, but the (neo)antigen load was stable between paired lesions. CONCLUSIONS: Our findings indicate that subsequently isolated tumors from patients with late-stage melanoma retain sufficient antigen-presenting capacity, T-cell infiltration, and a stable (neo)antigen load, allowing recognition of tumor cells by T cells. This indicates a continuous availability of T-cell targets in metastases occurring at different time points and supports further exploration of (neo)antigen-specific T-cell-based therapeutic approaches for advanced melanoma.

Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S.

BACKGROUND: Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. Whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function is unknown. METHODS: In this study, we investigated the ability of human colorectal cancer (CRC)-derived CAFs to cross-present neoantigen-derived synthetic long peptides (SLPs), corresponding to tumor-derived mutant peptides, and how this affects tumor-specific T-cell function. Processing of the SLP was studied by targeting components of the cross-presentation machinery through CRISPR/Cas9 and siRNA-mediated genetic ablation to identify the key molecules involved in fibroblast-mediated cross-presentation. Multispectral flow cytometry and killing assays were performed to study the effect of fibroblast cross-presentation on T cell function. RESULTS: Here, we show that human CRC-derived CAFs display an enhanced capacity to cross-present neoantigen-derived SLPs when compared with normal colonic fibroblasts. Cross-presentation of antigens by fibroblasts involved the lysosomal protease cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD137) and increased exhaustion (TIM3, LAG3 and CD39) marker expression. CONCLUSION: These data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.

Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-reactive T cells has shown consistent clinical efficacy. We evaluated the response to ACT in combination with interferon alpha (IFNa) preconditioning in patients with stage IV metastatic melanoma, most of which were progressive on cytotoxic T-lymphocyte-associated protein 4 and/or programmed cell death protein 1 checkpoint blockade therapy. METHODS: Thirty-four patients were treated with ex vivo expanded tumor reactive T cells, derived from mixed lymphocyte autologous tumor cultures, or with autologous tumor-infiltrating lymphocytes and evaluated for clinical response. Clinical and immunological parameters associated with response were also evaluated. RESULTS: Best overall response defined as clinical benefit, comprising either complete response, partial response or stable disease >6 months, was observed in 29% of the patients. Forty-three per cent of the 14 immunotherapy-naïve patients and 20% of the 20 patients progressive on prior immunotherapy benefited from ACT. The overall survival (OS) was 90% versus 28.6% at 1 year and 46.7% versus 0% at 3 years follow-up, of responder and non-responder patients, respectively. Median OS was 36 versus 7 months, respectively. IFNa pretreatment resulted in leukopenia, neutropenia and lymphopenia, which was sustained during the treatment in clinical responders and associated with response. Differences in antigen specificity, but not in phenotype, cytokine profile or CD8+ T cell number of the ACT products correlated with clinical response. Cross-reactivity of the ACT products to one or more allogeneic human leukocyte antigen-matched melanoma cell lines was associated with short OS after treatment while the ACT products of very long-term survivors showed no cross-reactivity but recognized patient-specific neoantigens. CONCLUSION: This study demonstrates that ACT in combination with a mild IFNa preconditioning regimen can induce clinical benefit even in immunotherapy pretreated patients, although with lower success than in immunotherapy-naïve patients. ACT products comprising neoantigen reactivity may be more effective.

Phase I/II study protocol to assess safety and efficacy of adoptive cell therapy with anti-PD-1 plus low-dose pegylated-interferon-alpha in patients with metastatic melanoma refractory to standard of care treatments: the ACTME trial.

INTRODUCTION: Treatment with anti-PD-1 immunotherapy does not lead to long-lasting clinical responses in approximately 60% of patients with metastatic melanoma. These refractory patients, however, can still respond to treatment with tumour infiltrating lymphocytes (TIL) and interferon-alpha (IFNa). A combination of TIL, pegylated-interferon-alpha (PEG-IFNa) and anti-PD-1 is expected to provide a safe, feasible and effective therapy for patients with metastatic melanoma, who are refractory to standard of care treatment options. METHODS AND ANALYSIS: Patients are treated in two phases. In phase I, the safety of the combination TIL and anti-PD-1 is assessed (cohort 1) according to CTCAE 4.03 criteria. Subsequently, the safety of cotreatment with PEG-IFNa is tested in cohort 2. The efficacy will be evaluated in the second phase of the trial. Efficacy is evaluated according to RECIST 1.1 and immune-related response criteria. Clinical and immunological parameters will be evaluated for their relation with clinical responsiveness. ETHICS AND DISSEMINATION: Ethical approval of the trial was obtained from the Central Committee on Research Involving Human Subjects in the Netherlands. The trial results will be shared with the scientific community at (inter)national conferences and by publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03638375; Pre-results.

Nonoperative treatment of lumbar spinal stenosis with neurogenic claudication: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: To systematically review the evidence for the effectiveness of nonoperative treatment of lumbar spinal stenosis with neurogenic claudication. SUMMARY OF BACKGROUND DATA: Neurogenic claudication can significantly impact functional ability, quality of life, and independence in the elderly. METHODS.: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, and ICL databases up to January 2011 for randomized controlled trials published in English, in which at least 1 arm provided data on nonoperative treatments. Risk of bias in each study was independently assessed by 2 reviewers using 12 criteria. Quality of the evidence was evaluated using Grades of Recommendations, Assessment, Development, and Evaluation (GRADE). RESULTS: From the 8635 citations screened, 56 were assessed and 21 trials with 1851 participants were selected. There is very low-quality evidence from 6 trials that calcitonin is no better than placebo or paracetamol, regardless of mode of administration or outcome. From single small trials, there is low-quality evidence that prostaglandins, and very low-quality evidence that gabapentin or methylcobalamin, improve walking distance. There is very low-quality evidence from a single trial that epidural steroid injections improve pain, function, and quality of life up to 2 weeks compared with home exercise or inpatient physical therapy. There is low-quality evidence from a single trial that exercise is of short-term benefit for leg pain and function compared with no treatment. There is low- and very low-quality evidence from 6 trials that multimodal nonoperative treatment is less effective than indirect or direct surgical decompression with or without fusion. CONCLUSION: Moderate- and high-GRADE evidence for nonoperative treatment is lacking and thus prohibiting recommendations to guide clinical practice. Given the expected exponential rise in the prevalence of lumbar spinal stenosis with neurogenic claudication, large high-quality trials are urgently needed.