International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges.

Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.

Cell and gene therapy investment: evolution and future outlook on investor perspectives.

BACKGROUND AIMS: To better understand the attitudes and behaviors of investors involved in funding cell and gene therapy (CGT) businesses, the Business Development and Finance) subcommittee of International Society for Cell and Gene Therapy, in collaboration with Truist Securities, conducted a broad survey of the investment community in late 2021. METHODS: This survey follows a similar study that this group executed in 2018, and the longitudinal comparisons between the two time periods provide insights into how investor behavior in the CGT field has evolved. RESULTS: The vast majority of investor respondents are specialist biotech investors who are primarily active in deploying capital in North America and Europe. There was a notable increase in the proportion of investors actively deploying capital in China and Japan between 2018 and 2021. The percentage of respondents' portfolios dedicated to CGT companies has also increased in this period, reflecting a noteworthy trend in the therapeutic landscape. CONCLUSIONS: Clinically significant data remain the dominant force behind investment decisions, whereas competition from other drug modalities has now emerged as the most-cited barrier to making a CGT investment, eclipsing safety concerns as the most significant barrier to investment in 2018. Concerns around manufacturing and scale-up have also increased in prominence amongst the investment community. Gene-editing technologies are attracting investors as the most compelling new CGT technology. This survey also revealed that most investors expect to increase their level of investment in allogeneic technologies relative to autologous products in the coming years.

Patient preference and willingness to pay for knee osteoarthritis treatments.

PURPOSE: To review treatments for osteoarthritis of the knee (OAK) received by patients across five European countries, and to obtain patients' perceptions and willingness to pay for current treatments. PATIENTS AND METHODS: A prospective, internet-based, double-blind survey of adults with OAK was conducted in France, Germany, Italy, Spain, and the United Kingdom. The questionnaire included questions about diagnosis, treatment history, and perceptions of OAK treatments, followed by a discrete choice-based conjoint exercise to identify preferred attributes of OAK treatments, evaluating 14 sets of four unbranded products. RESULTS: Two thousand and seventy-three patients with self-reported OAK completed the survey; 17.4% of patients rated their knee pain as drastically affecting their ability to perform normal daily activities, and 39.3% of employed patients reported that they had lost work time because of OAK. The most common treatments were exercise (69.7%), physical therapy (68.2%), and nonprescription oral pain medication (73.9%). Treatments perceived as most effective were: viscosupplement injections (74.1%), narcotics (67.8%), and steroid injection (67.6%). Patient co-pay, duration of pain relief, and type of therapy exhibited the largest impact on patient preference for OAK treatments. The average patient was willing to pay €35 and €64 more in co-pay for steroid and viscosupplement injections, respectively, over the cost of oral over-the-counter painkillers (per treatment course, per knee) (each P<0.05). CONCLUSION: OAK is a debilitating condition that affects normal daily activities. In general, treatments most commonly offered to patients are not those perceived as being the most effective. Patients are willing to pay a premium for treatments that they perceive as being more effective and result in longer-lasting pain relief, and those that can be administered with fewer visits to a physician.

Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Two-Year Follow-up of a Prospective Randomized Trial.

BACKGROUND: Randomized controlled trials studying the efficacy and safety of matrix-applied characterized autologous cultured chondrocytes (MACI) versus microfracture (MFX) for treating cartilage defects are limited. PURPOSE: To compare the clinical efficacy and safety of MACI versus MFX in the treatment of patients with symptomatic cartilage defects of the knee. STUDY DESIGN: Randomized controlled clinical trial; Level of evidence, 1. METHODS: Patients enrolled in the SUMMIT (Demonstrate the Superiority of MACI implant to Microfracture Treatment) trial had ≥1 symptomatic focal cartilage defect (Outerbridge grade III or IV; ≥3 cm(2)) of the femoral condyles or trochlea, with a baseline Knee Injury and Osteoarthritis Outcome Score (KOOS) pain value <55. The co-primary efficacy endpoint was the change in the KOOS pain and function subscores from baseline to 2 years. Histological evaluation and magnetic resonance imaging (MRI) assessments of structural repair tissue, treatment failure, the remaining 3 KOOS subscales, and safety were also assessed. RESULTS: Of the 144 patients treated, 137 (95%) completed the 2-year assessment. Patients had a mean age of 33.8 years and a mean lesion size of 4.8 cm(2). The mean KOOS pain and function subscores from baseline to 2 years were significantly more improved with MACI than with MFX (pain: MACI, 37.0 to 82.5 vs MFX, 35.5 to 70.9; function: MACI, 14.9 to 60.9 vs MFX, 12.6 to 48.7; P = .001). A significant improvement in scores was also observed on the KOOS subscales of activities of daily living (MACI, 43.5 to 87.2 vs MFX, 42.6 to 75.8; P < .001), knee-related quality of life (MACI, 18.8 to 56.2 vs MFX, 17.2 to 47.3; P = .029), and other symptoms (MACI, 48.3 to 83.7 vs MFX, 44.4 to 72.2; P < .001) for patients treated with MACI compared with MFX. Repair tissue quality was good as assessed by histology/MRI, but no difference was shown between treatments. A low number of treatment failures (nonresponders: MACI, 12.5% vs MFX, 31.9%; P = .016) and no unexpected safety findings were reported. CONCLUSION: The treatment of symptomatic cartilage knee defects ≥3 cm(2) in size using MACI was clinically and statistically significantly better than with MFX, with similar structural repair tissue and safety, in this heterogeneous patient population. Moreover, MACI offers a more efficacious alternative than MFX with a similar safety profile for the treatment of symptomatic articular cartilage defects of the knee.

Reduced chondrocyte viability is associated with the use of surgical marker pen ink.

BACKGROUND: Sterile surgical marker pens are commonly used in cartilage repair surgery to aid in the placement of periosteal patches or collagen membranes in autologous chondrocyte implantation. PURPOSE: To investigate the effects that methylene blue and crystal violet marker pen ink have on human chondrocytes when cultured on collagen membranes in vitro. STUDY DESIGN: Controlled laboratory study. METHODS: Human chondrocytes were applied to Chondro-Gide collagen membranes at a volume of 12 million cells. In the first experiment, 2 sterile marker pens, one containing methylene blue and the other crystal violet inks, were used to mark membranes immediately before the addition of cells. In the second experiment, the same marker pens marked the membranes after 7 days of cell culture. In each experiment, 3 groups of membrane were tested for each pen. Group A consisted of no ink mark, group B had only the uppermost "smooth" layer marked, and group C had the lower "porous" layer marked. All membranes were then cultured in standard growth media for 24 hours. Cell viability was assessed at 24 hours on all membranes using a live/dead-cell viability assay. Cell viability was quantified with florescent microscopy with mean percentage of live cells in each marker pen group compared with control membranes using the Student t test (P < .05). RESULTS: Control membranes (group A) with no ink showed cell viability approaching 100%. A statistically significant reduction in cell viability with both methylene blue (23.1%; P < .0001) and crystal violet (18.9%; P < .0001) was found adjacent to the ink mark on the smooth side (group B) and on the porous side remote from the ink (group C) in both experiments (<30%; P < .0001). A reduction in cell viability was noted on the smooth side remote from the ink mark but did not reach statistical significance. Marked cell death was seen with both dyes (<15%; P < .0001) adjacent to the ink on the porous side. CONCLUSION: Chondrocyte viability is significantly reduced when cells are cultured in vitro on collagen membranes marked with methylene blue and crystal violet pen ink. CLINICAL RELEVANCE: Surgeons should be aware of the potential negative effect of marker pens in cell-based therapies.

Change in Harris hip score in patients on the waiting list for total hip replacement.

AIM: To investigate the change in the Harris hip score in patients waiting for a total hip replacement, between the time of listing for operation and immediately pre-operatively. PATIENTS AND METHODS: For 167 consecutive patients listed for total hip replacement, the Harris hip score was taken both at time of listing for surgery and at pre-operative assessment 2 weeks prior to surgery. RESULTS: The median wait for operation in our unit was 330 days. The Harris score immediately preoperatively decreased compared with the initial score, with a mean decrease of 8.9 points. This result was highly statistically significant. Decrease in score also correlated with time on the waiting list. CONCLUSIONS: Patients requiring total hip replacement deteriorate while on the waiting list. Waiting times should be as short as possible to reduce unnecessary suffering.