A phase 1/2a study of TX200-TR101 in renal transplant recipients
Research type
Research Study
Full title
A Multicentre, Open-Label, Single Ascending Dose, Dose Ranging, Phase I/IIa Study to Evaluate the Safety and Tolerability of an Autologous Antigen-Specific Chimeric Antigen Receptor T Regulatory Cell Therapy (TX200-TR101) in Living Donor Renal Transplant Recipients
IRAS ID
265383
Contact name
Paul Harden
Contact email
Sponsor organisation
Sangamo Therapeutics France SAS
Eudract number
2019-001730-34
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Research Summary:
Chronic kidney disease (CKD) is a long-term condition where the kidneys (two organs that filter blood) no longer work as well as they should. It is possible to replicate some of the kidney function with dialysis (where a machine filters the blood) but as the disease worsens, known as end-stage renal disease (ESRD), a kidney transplant remains the treatment of choice. Following a kidney transplant, recipients receive immunosuppressants (drugs which dampen-down the immune system) to allow the body to accept the transplanted kidney as one of its own. These drugs can cause serious side effects and currently need to be taken life-long.
This clinical study is to investigate the safety and side effects of the investigational product TX200-TR101 in humans. TX200-TR101 has not yet been approved by regulatory agencies or any other health authorities for sale, but it has been approved for use in this clinical study. This is the first time that TX200-TR101 will be given to humans.
TX200-TR101 is an investigational gene-modified cell product that is made from the recipient’s own cells that have been genetically modified. It is hoped that TX200-TR101 will help reduce the risk of organ rejection by helping the body to accept the transplanted kidney and in time reduce the need for immunosuppressants.
Participants will have some of their cells collected (via a procedure called leukapheresis) and subsequently modified to become TX200-TR101. These will then be given back to the participant 3 months after their transplant. Participants will continue to take their immunosuppressive medication even after the TX200-TR101 infusion.
Some participants will not receive TX200-TR101 and will act as a comparison.
Sangamo Therapeutics France SAS (the Sponsor) is responsible for the development and oversight of the study. Around 21 participants will take part at approximately 5 medical centres across Europe, including the UK.Lay summary of study results:
Safety in the first 28 days after treatment:
In the 28 days after TX200 infusion (or after Week 12 post-transplant for participants in the control group), 18 side effects were reported in 5 of 11 participants. One participant experienced a serious medical problem, a bowel blockage (duodenal ileus) 10 days after receiving TX200. The participant was treated in hospital and recovered after 4 days. Both the study doctor and the safety monitoring committee reviewed the event and concluded that it was unrelated to TX200.
Safety over the full study period:
During the study, all 11 participants reported at least one side event, with 113 side events reported in total. Four participants experienced a serious medical event. This included the bowel blockage described above, an episode of transplant rejection, a rise in a blood marker of kidney function (creatinine), and in one control participant a stomach infection and low blood pressure following a different medicine used for immune suppression. None of these serious events were considered to be related to TX200. Seven more side effects were considered severe, 6 in TX200-treated participants and 1 in a control participant. None of these events resulted in loss of the transplanted kidney.
No participants stopped taking part in the study or had their TX200 treatment interrupted. There were no cases of certain viral infections that are of particular concern after transplant including BK virus, Epstein-Barr virus, and cytomegalovirus. There were also no cases of cancer, no loss of the transplanted kidney, and no deaths during the study. Side effects did not become more frequent or more severe at higher TX200 dose levels. Routine blood tests, vital signs, and heart activity tests did not raise safety concerns, and no participant developed a serious immune reaction (cytokine release syndrome) that can sometimes occur with cell therapies.
Effects on kidney rejection:
None of the 8 participants who received TX200 experienced a confirmed episode of kidney rejection that caused symptoms, compared with 1 of the 3 control participants. Changes seen in kidney tissue samples (biopsies) that may sometimes be interpreted as early signs of rejection were observed in a similar proportion of participants in both groups (4 of 8 participants who received TX200 and 1 of 3 control participants). However, it is possible that these findings may also be seen when the immune system is adapting to accept the transplanted kidney and may not necessarily indicate harmful rejection.
No participant in either group developed long-term (chronic) rejection. Kidney function remained generally stable post-transplant, and within the expected range for transplant recipients.
Immune markers (donor-specific antibodies):
Some participants developed new antibodies against their transplanted kidney. Antibodies are proteins made by the immune system that can sometimes contribute to transplant rejection. New antibodies were seen at a similar rate in participants who received TX200 and those in the control group, despite participants receiving TX200 group taking lower amounts of immunosuppression medication.
Evidence that TX200 reached the kidney:
Specialised laboratory tests found small numbers of TX200 cells in kidney biopsy samples from some participants.
Although only a very small fraction of the kidney is examined during a biopsy finding these TX200 cells in these samples suggests that the treatment was able to travel to and reach the transplanted kidney. TX200 cells were also detected in the blood for up to 7.5 months after treatment providing further evidence that the cells remained in the body over time.
The kidney biopsies were also examined for specialised immune cell structures that are speculated to help the body accept a transplanted kidney. These structures were seen frequently in kidney biopsies from TX200-treated participants (7 of 8) and also in the control group (1 of 2 participants with evaluable biopsy samples). Whenever
TX200 cells were found in a kidney biopsy, these immune structures were also present, suggesting that TX200 may help create an environment that supports acceptance of the transplanted kidney.
Effects on immunosuppressive medicine use:
One goal of the study was to see whether participants receiving TX200 could safely reduce the amount of standard anti-rejection medicine they needed after their kidney transplant. By the end of the study, 4 of the 5 participants who received TX200 at the middle and highest dose levels were able to reduce their treatment to a single anti-rejection medicine (tacrolimus alone). In comparison, none of the participants who received the lowest dose of TX200 and none of the control participants were able to do this. Overall, participants who received TX200 also received lower total doses of two other commonly used anti-rejection medicines (mycophenolate and tacrolimus) during the study compared with control participants. These reductions were planned as part of the study design and suggest that
TX200 may help some transplant recipients maintain good transplant health while taking less immunosuppressive medication.REC name
South Central - Oxford A Research Ethics Committee
REC reference
19/SC/0531
Date of REC Opinion
24 Mar 2020
REC opinion
Favourable Opinion