Refine
Document Type
- Article (13)
Language
- English (13)
Has Fulltext
- yes (13)
Is part of the Bibliography
- no (13)
Keywords
- Immunotherapy (13) (remove)
Institute
During the past 15 years there have been dramatic changes in the medical landscape, particularly in oncology and regenerative medicine. Cell therapies have played a substantial part in this progress. Cellular immunotherapies can use immune cells, such as T cells or natural killer cells that, after functional modification ex vivo, exert powerful anti-cancer effects when given to the patient. Innovative technologies, such as re-programming terminally differentiated cells into pluripotent stem cells or into other cell types and applying specific enzymes to more precisely edit the human genome, are paving the way towards more potent cell and gene therapies.
Mesenchymal stromal cells are promising cellular immunotherapeutics, which also have potential for use in tissue engineering strategies and other regenerative medicine applications. However, substantial gaps in our knowledge of their biology and therapeutic efficacy present major challenges to their sustainable implementation in the clinical routine.
In this article, progress in the field of cell therapeutics during the past 15 years will be briefly discussed, with a focus on mesenchymal stromal cells, highlighting the impact of this field on patient care.
Chimeric antigen receptor (CAR)-T cell therapies are on the verge of becoming powerful immunotherapeutic tools for combating hematological diseases confronted with pressing medical needs. Lately, CAR-NK cell therapies have also come into focus as novel therapeutic options to address hurdles related to CAR-T cell therapies, such as therapy-induced side effects. Currently, more than 500 CAR-T and 17 CAR-NK cell trials are being conducted worldwide including the four CAR-T cell products Kymriah, Yescarta, Tecartus and Breyanzi, which are already available on the market. Most CAR-T cell-based gene therapy products that are under clinical evaluation consist of autologous enriched T cells, whereas CAR-NK cell-based approaches can be generated from allogeneic donors. Besides modification based on a second-generation CAR, more advanced CAR-immune cell therapeutics are being tested, which utilize precise insertion of genes to circumvent graft-versus-host disease (GvHD) or employ a dual targeting approach and adapter CARs in order to avoid therapy resistance caused by antigen loss. In this review, we are going to take a closer look at the commercial CAR-T cell therapies, as well as on CAR-T and CAR-NK cell products, which are currently under evaluation in clinical trials, that are being conducted in Germany.
Resistance to CD19-directed immunotherapies in lymphoblastic leukemia has been attributed, among other factors, to several aberrant CD19 pre-mRNA splicing events, including recently reported excision of a cryptic intron embedded within CD19 exon 2. While “exitrons” are known to exist in hundreds of human transcripts, we discovered, using reporter assays and direct long-read RNA sequencing (dRNA-seq), that the CD19 exitron is an artifact of reverse transcription. Extending our analysis to publicly available datasets, we identified dozens of questionable exitrons, dubbed “falsitrons,” that appear only in cDNA-seq, but never in dRNA-seq. Our results highlight the importance of dRNA-seq for transcript isoform validation.
Aim: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy.
Methods: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3–14 days before (pre-ICIT) and 21–28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu).
Results: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value.
Conclusion: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value.
Trial registry: ClinicalTrials.gov identifier: NCT03426657.
Immunotherapy involving checkpoint blockades of inhibitory co-receptors is effective in combating cancer. Despite this, the full range of mediators that inhibit T-cell activation and influence anti-tumor immunity is unclear. Here, we identify the GTPase-activating protein (GAP) Rasal1 as a novel TCR-ZAP-70 binding protein that negatively regulates T-cell activation and tumor immunity. Rasal1 inhibits via two pathways, the binding and inhibition of the kinase domain of ZAP-70, and GAP inhibition of the p21ras-ERK pathway. It is expressed in activated CD4 + and CD8 + T-cells, and inhibits CD4 + T-cell responses to antigenic peptides presented by dendritic cells as well as CD4 + T-cell responses to peptide antigens in vivo. Furthermore, siRNA reduction of Rasal1 expression in T-cells shrinks B16 melanoma and EL-4 lymphoma tumors, concurrent with an increase in CD8 + tumor-infiltrating T-cells expressing granzyme B and interferon γ-1. Our findings identify ZAP-70-associated Rasal1 as a new negative regulator of T-cell activation and tumor immunity.
Background: An experienced life-threating anaphylactic reaction to hymenoptera venom can sustainably impair patients’ quality of life (QoL). Besides carrying emergency medication, venom-specific immunotherapy (VIT) exists as a causal treatment of allergy.
Objective: This study aimed to examine QoL, anxiety, depression, and physical and mental health in patients allergic to hymenoptera venom before and during VIT and the impact of a tolerated sting challenge (SC).
Methods: Between July 2017 and August 2017, 142 patients with venom allergy were analyzed using validated questionnaires as the: Vespid Allergy Quality for Life Questionnaire" (VQLQ-d), the "Hospital Anxiety and Depression Scale" (HADS-D) and the "Short Form 36" (SF-36). To evaluate the impact of VIT and SC on the QoL, patients were divided into 3 groups: (A) VIT and tolerated SC (n = 45), (B) VIT before carrying out SC (n = 73), and (C) therapy-naïve before VIT (n = 20). Further parameters like gender, age, insect species, and severity of the anaphylactic reaction were assessed.
Results: A significant correlation between the health-related QoL and the parameters of gender and state of treatment was seen. Especially male patients, as well as patients allergic to yellow jacket venom, benefit from a SC in terms of a significant increase in their QoL. In the total study cohort, a clear trend was observed towards a higher QoL in patients under VIT who tolerated a SC. Overall, neither the patients’ age nor the insect species exerted a relevant influence on QoL, depression or anxiety. However, women showed a lower QoL combined with higher anxiety and depression scores than men.
Conclusion: Immunotherapy leads to an improved QoL, which can be further increased by a SC. A tolerated SC conceivably reassures the patients by objectifying the treatment success. Female patients appear to have a stronger impaired QoL per se. Taken together, a SC can be performed during VIT to strengthen the patients’ QoL.
Multidrug-resistant TB (MDR-TB) is a major threat to global health security. In 2017, only 50% of patients with MDR-TB who received WHO-recommended treatment were cured. Most MDR-TB patients who recover continue to suffer from functional disability due to long-term lung damage. Whilst new MDR-TB treatment regimens are becoming available, conventional drug therapies need to be complemented with host-directed therapies (HDTs) to reduce tissue damage and improve functional treatment outcomes. This viewpoint highlights recent data on biomarkers, immune cells, circulating effector molecules and genetics which could be utilised for developing personalised HDTs. Novel technologies currently used for cancer therapy which could facilitate in-depth understanding of host genetics and the microbiome in patients with MDR-TB are discussed. Against this background, personalised cell-based HDTs for adjunct MDR-TB treatment to improve clinical outcomes are proposed as a possibility for complementing standard therapy and other HDT agents. Insights into the molecular biology of the mechanisms of action of cellular HDTs may also aid to devise non-cell-based therapies targeting defined inflammatory pathway(s) in Mtb-driven immunopathology.
Background: Cytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmaceutical intervention post-transplant. Whether immunosuppression with mycophenolate mofetil (MMF) or Ciclosporin A (CsA) influences the cytotoxic effect of CIK cell immunotherapy is still an open issue.
Methods: CIK cells were generated from PBMC as previously described followed by co-incubation with mycophenolic acid (MPA) or CsA. Proliferation, cytotoxicity and receptor expression were investigated following short- (24 h), intermediate- (3 days) and long-term (7 days) MPA incubation with the intention to simulate the in vivo situation when CIK cells were given to a patient with relevant MPA/CsA plasma levels.
Results: Short-term MPA treatment led to unchanged proliferation capacity and barely had any effect on viability and cytotoxic capability in vitro. The composition of CIK cells with respect to T-, NK-like T- and NK cells remained stable. Intermediate MPA treatment lacked effects on NKG2D, FasL and TRAIL receptor expression, while an influence on proliferation and viability was detectable. Furthermore, long-term treatment significantly impaired proliferation, restricted viability and drastically reduced migration-relevant receptors accompanied by an alteration in the CD4/CD8 ratio. CD3+CD56+ cells upregulated receptors relevant for CIK cell killing and migration, whereas T cells showed the most interference through significant reductions in receptor expression. Interestingly, CsA treatment had no significant influence on CIK cell viability and the cytotoxic potential against K562.
Conclusions: Our data indicate that if immunosuppressant therapy is indispensable, efficacy of CIK cells is maintained at least short-term, although more frequent dosing might be necessary.
Introduction: Combination therapy for melanoma brain metastases (MM) using stereotactic radiosurgery (SRS) and immune checkpoint-inhibition (ICI) or targeted therapy (TT) is currently of high interest. In this collective, time evolution and incidence of imaging findings indicative of pseudoprogression is sparsely researched. We therefore investigated time-course of MRI characteristics in these patients.
Methods: Data were obtained retrospectively from 27 patients (12 female, 15 male; mean 61 years, total of 169 MMs). Single lesion volumes, total MM burden and edema volumes were analyzed at baseline and follow-up MRIs in 2 months intervals after SRS up to 24 months. The occurrence of intralesional hemorrhages was recorded.
Results: 17 patients (80 MM) received ICI, 8 (62 MM) TT and 2 (27 MM) ICI + TT concomitantly to SRS. MM-localization was frontal (n = 89), temporal (n = 23), parietal (n = 20), occipital (n = 10), basal ganglia/thalamus/insula (n = 10) and cerebellar (n = 10). A volumetric progression of MM 2–4 months after SRS was observed in combined treatment with ICI (p = 0.028) and ICI + TT (p = 0.043), whereas MMs treated with TT showed an early volumetric regression (p = 0.004). Edema volumes moderately correlated with total MM volumes (r = 0.57; p < 0.0001). Volumetric behavior did not differ significantly over time regarding lesions’ initial sizes or localizations. No significant differences between groups were observed regarding rates of post-SRS intralesional hemorrhages.
Conclusion: Reversible volumetric increases in terms of pseudoprogression are observed 2–4 months after SRS in patients with MM concomitantly treated with ICI and ICI + TT, rarely after TT. Edema volumes mirror total MM volumes. Medical treatment type does not significantly affect rates of intralesional hemorrhage.
Background: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.
Methods: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).
Results: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.
Conclusions: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.
Trial registration: NCT01598129. Registered 19/04/2012