Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients

Figures & data

Figure 1. Production scheme of TG-C. The cells used to create the cell banks for human chondrocytes were derived from a human donor. The transduced cell line (hChonJb#7) was isolated according to the limiting-dilution method. The cryopreserved cells were thawed and washed, and the hChonJb#7 cells were irradiated prior to mixing at a 3:1 ratio (hChonJ:hChonJb#7) at the planned dose. Prepared doses are injected into the joint.

Table I. Inclusion and exclusion criteria.

Inclusion criteria

Exclusion criteria

•Aged 18 years or older, providing written informed consent•In good general health, as determined by physical examination, blood and urine laboratory testing results, and a BMI between 18.5 and 45.5.•Diagnosed as OA of the knee refractory to existing therapies• Radiographically confirmed defect size >2 cm^2• Severe OA (grade 4) confirmed by radiographic criteria of Kellgren & Lawrence• Symptomatic pain for more than 4 consecutive months of intensity >4 on a 10-point scale

•Patients with abnormal laboratory blood and/or urine screening results• Patients taking anti-inflammatory medications within 14 days prior to dosing• Patients with a history of drudg abuse or a positive drug/alcohol urine test at time of screening• Women who are pregnant or breastfeeding• Patients who had received injections to the target knee within 2 months prior to treatment• Patients with systemic rheumatic or inflammatory disease of the knee or chondrocalcinosis, hemochromatosis, inflammatory arthritis, necrosis of the femoral condyle, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropathy, infectious arthritis, Charcot's knee joint, villonodular synovitis and synovial chondromatosis• Patients with ongoing infectious disease, including Human Immunodeficiency Virus (HIV) and hepatitis• Patients with clinically significant cardiovascular, renal, hepatic, endocrine disease, cancer or type I diabetes• Patients participating in a study of an experimental drug or medical device within 30 days of study entry

Table II. Summary of adverse events.

		Safety
Group	Patient number (sex, age)	TGF-β1 ELISA/PCR	Laboratory results	Adverse events
Dose level 1, 3 × 10^6 cells	001 (M, 77)	Normal	Normal	2 days post-dosing: 3–4 h after dinner, patient complained of itching and warming sensation in the injection area. Sensation subsequently disappeared spontaneously in a few hours
	002 (F, 62)	Normal	Normal	No adverse events
	003 (F, 59)	Normal	Normal	Patient experienced grade 2 hydrarthrosis(joint fluid collection) of the injected joint from day 14 until day 18 post-dosing, which was probably related to TG-C treatment. Patient was treated with aspiration, Nonsteroidal Anti-inflammatory Drug (NSAID), acetaminophen and resolved
	004 (F, 73)	Normal	Normal	No adverse events
Dose level 2, 1 × 10^7 cells	006 (F, 53)	Normal	Normal	1 day post-dosing: patient complained of pain, swelling and warming sensation of the injected joint. Prescribed NSAID at 8 days post-dosing (medication for 38 days). The symptom had disappeared at 45 days post-dosing
	007 (F, 52)	Normal	Normal	Afternoon of the day of dosing: patient had headache and a warming sensation in the injected joint. Symptoms spontaneously disappeared in a few hours
	008 (M, 69)	Normal	Normal	4–5 h post-dosing: patient had pain in the injected joint, which disappeared spontaneously in a few hours. Pain of the injected joint at 23 days post-dosing. Prescribed NSAID and acetaminophen from day 24 to day 30 post-dosing (for 7 days). Symptom was resolved
	009 (M, 60)	Normal	Normal	At 22 days post-dosing, patient had swelling and effusion (fluid collection) of the injected joint after hiking. Prescribed Etololac 600 mg (once a day) from day 22 to day 28 post-dosing. Symptoms were resolved
Dose level 3, 3 × 10^7 cells	010 (F, 71)	Normal	Normal	For 7 days after injection, patient felt stiffness and discomfort of knee. The symptoms disappeared without any treatment
	011 (M, 65)	Normal	Normal	From 1 day post-dosing, patient had swelling and dull pain. Hydroarthrosis and warmth was observed at the joint. Prescribed Acetaminophen 650 mg (3 times/day, for days 5–35 post-dosing), Celecoxib 200 mg (once a day, for days 11–35 post-dosing). Symptoms disappeared by day 40 post-dosing
	012 (M, 55)	Normal	Normal	For 2 weeks after injection, patient had dull pain and swelling of the injected knee. The symptoms disappeared without any treatment
	013 (F, 62)	Normal	Normal	There was swelling and mild fever on the day of injection. Hydroarthrosis was observed. Treated with Acetaminophen 650 mg (3 times/day, from 1-day post-dosing), Celecoxib 200 mg (once a day, for days 7–30 post-dosing). Symptoms disappeared by day 30 post-dosing

M, male; F, female; age, years.

Figure 2. Proton-density coronal magnetic resonance image for patient 007 at baseline (a, c), 3 months (b) and 6 months (d). The appearance of subtle cartilage regeneration is seen in (b) and (d) at the weight-bearing portion of the lateral femoral condyle, as indicated with the arrow.

Figure 3. Proton-density coronal magnetic resonance image for patient 011 at baseline (a, c), 6 months (b) and 12 months (d). The appearance of cartilage regeneration is seen in (b) and (d), especially around the periphery of the grade 4 lesion site at the medial femoral condyle, as indicated with the arrow.

Figure 4. The average change in score (positive mean improvement) in KSCRS (a) pain score, (b) range of motion score and (c) overall score from baseline until 12 months post-dosing (M12). Improvements in KSCRS pain and range of motion scores for dose levels 2 and 3 could be seen with a corresponding improvement in overall score.

Figure 5. The average change in score (positive mean improvement) in WOMAC (a) stiffness score and (b) overall score from baseline until 12 months (M12). On average, patients receiving dose levels 1 and 2 showed improvement early on (by day 21) but there was no clear trend in WOMAC scores after 12 months.

Figure 6. The average change in score (positive mean improvement) in VAS on pain score from baseline until 12 months (M12). On average, patients showed a decrease in pain with all three dose levels, with a marked improvement with dose level 3 at 3 months with a regression at 6 months.