Patients treated with the highest dose of MIC-Lx had lymphocyte reactivity against third-party cells but not stimulatory donor blood cells.
MIC-Lx cell therapy (TolerogenixX) induced long-term donor-specific immunosuppression and yielded a significant increase in regulatory B lymphocytes in kidney transplant recipients, according to 3-year follow-up data from a phase 1 study (NCT02560220).1
Patients treated with the modified immune cell (MIC) therapy had no donor-specific human leukocyte antigen (HLA) antibodies or acute rejections. The 4 patients who received the highest dose of MIC-LX (1.5 × 108) 7 days before surgery were on reduced immunosuppressive therapy and did not have in vitro lymphocyte reactivity against stimulatory donor blood cells while reactivity against third-party cells was preserved. These patients also had 75-fold and 7-fold higher numbers of transitional B lymphocytes than in 12 long-term survivors on minimal immunosuppression and 4 operationally tolerant patients, respectively (P <.001).
"MIC treatment is leading to an operationally tolerant phenotype of patients with profound suppression of anti-donor T cell responses," first author Prof. Dr. Christian Morath, chief scientific officer, TolerogenixX, said in a statement.2 "The 1-year follow-up data published in 2020 already showed excellent safety and tolerability of our treatment, and we are very happy that these favorable results hold up in the three-year follow-up."
The study treated 10 patients with 1.5 × 106 MIC per kg body weight on day -2 (n = 3, group A) or 1.5 × 108 MIC per kg body weight on day -2 (n = 3, group B) or day -7 (n = 4, group C) prior to living donor kidney transplantation, in addition to post-transplant immunosuppression with CyA, EC-MPS, and methylprednisolone.
Over 3 years of follow up, there were no cases of de novo donor-specific antibodies or acute rejection episodes. Investigators found that kidney graft function was stable with a median serum creatinine of 1.40 mg/dL (range, 1.04-2.10), a median estimated glomerular filtration rate (according to the Chronic Kidney Disease Epidemiology Collaboration score) of 61 mL/min/1.73 m2 (range 41–93), and a median urinary protein excretion of 14 g/moL creatinine (range 5–90).
There were no cases of opportunistic infections and no cytomegalovirus or BKV replications during posttransplant screening. Six patients had 12 non-opportunistic infections, 2 of which occurred during the second and third years of follow-up. There were no cases of malignancy or posttransplant lymphoproliferative disorders.
"The results once again demonstrate that we generate an immunoregulatory cell population which carries the promise of exerting a beneficial effect on kidney transplants," author Prof. Dr. Matthias Schaier, chief executive officer, TolerogenixX, added to the statement.2
Investigators found that percentage of regulatory B lymphocytes increased from a median of 6% (range, 0-11) of the total lymphocyte pool to 20% (range, 5-40) on day 180 before dropping to a median of 8% (range, 5-13) by day 720 and remaining stable until day 1080. These levels were not only higher than baseline but also levels in literature for stable immunosuppressed (range, 0-5%) and operationally tolerant patients (range, 3-8%).
Gene expression analysis revealedthat 3 of 4 patients in Group C had the COMBINED-g7 consensus gene-expression signature of operational tolerance.They also determined that interleukin-10-producing transitional B lymphocytes were functionally relevant for donor-specific unresponsiveness.
"These new results show that the effect is long-lasting and associated with a striking increase in regulatory B lymphocytes. They underline the importance of MIC-Lx in paving the way for a novel cell therapy in organ transplantation,” PD Dr. Anita Schmitt, chief technical officer, TolerogenixX, added to the statement.2
Investigators are now conducting a phase 2 study (NCT05365672) to expand the findings seen in the 4 patients in Group C, compared to patients treated with standard of care. Patients in the phase 2 study will hopefully develop an operationally tolerant-like phenotype.