Arthroscopic autologous chondrocyte implantation in the knee with an in situ crosslinking matrix: minimum 4-year clinical results of 15 cases and 1 histological evaluation.

PURPOSE: To clinically evaluate an arthroscopic autologous chondrocyte implantation (ACI) technique with an in situ crosslinking matrix for the treatment of full thickness cartilage defects of the knee and to present histological results of a graft cartilage biopsy obtained after 1.5 years. METHODS: Fifteen cases of arthroscopic autologous chondrocyte implantation in the knee performed between November 2011 and October 2012 were included in the study. Medical charts and operational reports were screened and the patients were contacted after 0.8 ± 0.3 years (0.4-1.3) and 4.3 ± 0.3 years (4.0-4.8) to asses subjective IKDC and re-operation. The Tegner activity scale was collected at the second follow-up time point. Subjective IKDC response rates were assessed at both follow-up time points. RESULTS: The first and second follow-up was completed by all 15 patients (100%). The subjective IKDC scores showed a significant improvement (pre-operative 44.5 ± 15.9, first follow-up 71.1 ± 15.9, p < 0.001, second follow-up 72.6 ± 17.3, p < 0.001). The overall response rate was 66.7% (n = 10) at follow-up one and two. There were no significant differences in pre-injury (4, range 1-9) and follow-up two (4, range 2-7) Tegner activity scales (p = n.s.). Two patients required re-operation in the index knee, not related to the ACI procedure. No complication related to the ACI or the implantation technique occurred. The histological results showed excellent cartilage regeneration. CONCLUSION: Arthroscopic ACI using an in situ crosslinking matrix is a safe and reliable treatment option for full-thickness cartilage defects of the knee.

[Technique of all arthroscopic autologous chondrocyte implantation (ACI) for the treatment of cartilage defects in the knee]. / Technik der vollarthroskopischen autologen Chondrozytentransplantation zur Behandlung von Knorpeldefekten des Kniegelenks.

OBJECTIVE: All arthroscopic treatment of deep cartilage defects in the knee for reconstruction of the articular surface. INDICATIONS: Focal cartilage defects of the knee (ICRS ≥ grade 3) from a size of 2.5 cm2 and more. CONTRAINDICATIONS: Osteoarthritis (Kellgren-Lawrence > grade 2), osseus defect situation, cartilage lesion of the opposing articular surfaces (ICRS > grade 2), instability, malalignment (>3-4°), inflammatory joint diseases. SURGICAL TECHNIQUE: First procedure (cell harvesting): Treatment of additional pathologies, preparation of the cartilage defect, harvesting of osteochondral cylinders for cell culture. Second procedure (cell implantation): Dry arthroscopy, cleaning and drying of the already prepared defect, implantation of the in situ crosslinking cartilage cell suspension. POSTOPERATIVE MANAGEMENT: First procedure (cell harvesting): Early functional treatment with weight bearing as tolerated. Second procedure (cell implantation): No drains, extension brace for 4 days, then free range of motion, partial weight bearing for 4 weeks in patellofemoral implantation and for 8 weeks in tibiofemoral implantation, continuous passive motion beginning in postoperative week 2, cycling from postoperative week 9. RESULTS: In the literature, results for ACI in the knee are reported to be good, especially for larger cartilage defects. Arthroscopic techniques should lead to a decrease of complications and perioperative morbidity. No technique-specific complications occurred in our cohort. From 2012-2015, 98 patients were treated using the above mentioned technique, whereby 62 patients were retrospectively evaluated after 31.0 ± 14.8 (12.5-61.4) months. In 15 patients (28%) additional procedures were performed (7 anterior cruciate ligament reconstructions, 3 correction osteotomies and 5 medial patellofemoral ligament reconstructions). Average cartilage defect size was 4.7 ± 2.8 cm2, in 18 patients (29%) more than one cartilage defect was treated. The subjective IKDC and total KOOS scores resulted in 66 ± 10 and 73 ± 19 points.

Rapid generation of NY-ESO-1-specific CD4+ THELPER1 cells for adoptive T-cell therapy.

Tumor-associated antigens such as NY-ESO-1 are expressed in a variety of solid tumors but absent in mature healthy tissues with the exception of germline cells. The immune system anti-cancer attack is mediated by cell lysis or induction of growth arrest through paralysis of tumor cells, the latter of which can be achieved by tumor-specific CD4+, IFNγ-producing THelper type 1 (TH1) cells. Translation of these immune-mediated mechanisms into clinical application has been limited by availability of immune effectors, as well as the need for complex in vitro protocols and regulatory hurdles. Here, we report a procedure to generate cancer-testis antigen NY-ESO-1-targeting CD4+ TH1 cells in vitro for cancer immunotherapy in the clinic. After in vitro sensitization by stimulating T cells with protein-spanning, overlapping peptide pools of NY-ESO-1 in combination with IL-7 and low dose IL-2, antigen-specific T cells were isolated using IFNγ capture technique and subsequently expanded with IL-2, IL-7 and IL-15. Large numbers of NY-ESO-1-specific CD4+ T cells with a TH1 cytokine profile and lower numbers of cytokine-secreting CD8+ T cells could be generated from healthy donors with a high specificity and expansion potential. Manufactured CD4+ T cells showed strong specific TH1-responses with IFNγ+, TNFα+, IL-2+ and induced cell cycle arrest and apoptosis in tumor cells. The protocol is GMP-grade and approved by the regulatory authorities. The tumor-antigen specific CD4+ TH1 lymphocytes can be adoptively transferred as a T-cell therapy to boost anticancer immunity and this novel cancer treatment approach is applicable to both T cells from healthy allogeneic donors as well as to autologous T cells derived from cancer patients.