3. Optimal dosage
The optimal dose of MSC depends on the different disease and severity and the route of entry.
In the clinical research and application of MSC, cell dose may belong to the most clueless and most scientific aspect. Even if there are some clinical studies involving dose climbing experiments, they are not based on animal experiments.
MSC is different from traditional medicines, because: first, after MSC enters the body, it does not conform to the typical distribution and metabolism model of traditional medicines; traditional medicines are passive distribution, and MSCs have the function of actively chemotactic to the injury site, and the distribution of MSCs in healthy and diseased organisms is different. Second, animal experiments of traditional medicines require multiple administrations to maintain a stable blood concentration, and animal experiments of MSCs are often single injections, so that clinical studies of MSCs often adopt a single injection scheme. In fact, a single injection of MSC cannot achieve a good stable long-term treatment effect, even if there is a significant improvement in the short term.
For a certain disease, in the preclinical studies, animal experiments have not fully demonstrated the minimum and maximum saturation doses at which MSCs work, and the cell doses in different laboratories differ. Factors such as the culture system of different laboratories and the source properties of MSC often lead to differences in the quality of MSC, which directly affects the results of animal experiments and clinical studies of MSC. Therefore, data from preclinical studies of MSCs do not provide a good guide for determining clinical research protocols.
In current clinical studies, the dosage range of MSC used is very large, and the number of MSC cells used per patient ranges from more than 4,000 MSCs to hundreds of millions of MSCs.
For local intervention, the lowest dose appears in the clinical case of MSCs for femoral head necrosis. Each clinical study in Korea and France used more than 4,500 MSCs. The highest dose of interventional therapy appeared in a clinical study in China, which used 860 million cells for MSCs to treat diabetic limb bullae; the second highest dose was 200 million MSC myocardial injections. Clinical studies of more than 100 million MSCs injected locally include: 120 million MSCs for Crohn's disease intestinal fistula, 100 million MSCs for intraarticular injection of knee osteoarthritis, and 100 million MSCs for ischemic cardiomyopathy.
Intravenous doses of cells are relatively stable, and millions of MSCs per kilogram of body weight are often used, ie (1-10) x 10 * 6 / kg. The highest intravenous dose is 10x10 * 6 / kg co-transplanted with hematopoietic stem cells. According to a weight of 60 kg, that also requires 600 million MSCs; and 8x10 * 6 / kg for GVHD. The lowest dose of intravenous injection appeared in clinical trials of MSC and hematopoietic stem cell co-transplantation, which was 0.3x10 * 5 / kg.
The failure of the Phase 3 clinical trial of Prochymal (bone marrow MSC) in the treatment of refractory GVHD in 2009 was a catastrophic event in the clinical application of MSC, which almost denied the clinical efficacy of MSC. Prochymal is derived from the bone marrow of healthy people, and MSC itself has a strong immunosuppressive ability. However, why can't Prochymal be significantly better than the control group in the phase 3 clinical trial?
At that time, Prochymal's indication was hormone-resistant and refractory GVHD. This indication itself was very difficult. If Prochymal did not optimize the treatment plan, especially the breakthrough in conventional thinking in terms of dosage, then failure would be inevitable.
Later increasing the dose of MSC cells to 5x10 * 6 / kg and 8x10 * 6 / kg, the effect of treating hormone-resistant refractory GVHD was better than that before 2009, making the UK and EU treatment guidelines recommend MSC as a treatment for grade 2-4 Third-line treatment for acute GVHD. But Prochymal is still not approved by the US FDA. Interestingly, a meta-analysis article in 2016 suggested that the "dose" factor did not affect the survival rate of MSC in patients with acute GvHD.
Although some experts believe that 5x10 * 6 / kg and 8x10 * 6 / kg are high doses, there is no discussion and proof of what kind of dose is defined as "high dose". If MSC is regarded as a "medicine", then there must be a range. In this range, the higher the dose, the better the effect; then after reaching a saturated dose, continuing to increase the cell dose does not bring more efficacy, but may bring some adverse reactions.
To be continued in Part Four…