Non-Myeloablative HSCT Regimen Shows Potential for Immune Tolerance in Haploidentical Living Donor Combined Kidney/Hematopoietic Transplant

Kidney Transplant | Image Credit: ©
Kellie Ehrmann/MJH Life Sciences using AI

Non-myeloablative hematopoietic stem cell transplantation (HSCT) with total lymphatic irradiation (TLI)/total body irradiation (TBI)/antithymocyte globulin (ATG) conditioning was well tolerated and led to immune quiescence and tolerance in patients also undergoing haploidentical living donor kidney transplant, according to interim findings from a single-center phase 1 trial presented at the 2025 Transplantation & Cellular Therapy Meetings.¹

Chronic allograft rejection limits the utility of organ transplantation, while chronic immunosuppression can result in high morbidity and mortality. Combined donor organ and HSCT can lead to immune tolerance induction.

“The mechanism of action of the mixed chimerism involves the donor and recipient immune systems interacting together for the reinduction of peripheral regulatory pathways, notably with T regulatory cells, inducing a lot of this function, as well as the potential for central deletion to occur through thymic regeneration of donor populations,” senior study author Everett Meyer, MD, PhD, associate professor of medicine, pediatrics, and surgery at Stanford Medicine in California, stated in a presentation delivered during the meeting.

The study was comprised of three arms. Data from the first arm, which have been previously published, did not show that long-term withdrawal of immunosuppression was possible in a partially-matched human leukocyte antigen (HLA)–matched cohort of patients undergoing kidney transplant; however, the establishment of persistent mixed chimerism in haplotype-matched patients allowed for partial immunosuppressive drug withdrawal without rejection.²

“We’ve subsequently gone on to look at two different approaches. One is to slightly intensify the conditioning with a little bit of TBI at the end of the TLI and with a fixed dose of conventional T cells. In addition, in collaboration with UCSF, we’ve used ex vivo expanded T regulatory cells with the idea that, that might be used to facilitate donor engraftment, which has been seen in preclinical models, and boost initial chimerism, and then [result in] the ability to withdraw immunosuppression,” Meyer explained.

The protocol for conditioning that has been used at Stanford and previously published in the New England Journal of Medicine³ involves “a gentle, non-myeloablative conditioning regimen,” Meyer stated.

As part of the study, living donors underwent hematopoietic stem cell mobilization and leukapheresis 6 weeks prior to kidney donation.¹ For conditioning, patients received 10 doses of 120 centigrays of TLI and 5 doses of 1.5 mg/kg of ATG following kidney transplant, with HCT on day 11 (arm 1; TLI/ATG).

HCT consisted of CD34- and CD3-positive cells. Twenty-seven patients received HHM living donor transplants with an escalating dose of CD3-positive cells from 3 to 150 x 10⁶ CD3+ cells/kg. In patients in the second arm, the last dose of TLI was substituted for a low dose of TBI (arm 2; TLI/TBI/ATG). In the third arm, investigators evaluated the addition of 1 to 10 million recipient T regulatory cells/kg at time of HSCT (arm 3; TLI/TBI/ATG + regulatory T cells).

A total of 27, 6, and 4 patients have been treated in arms 1, 2, and 3, respectively. The median ages were 35.3 (male, n = 16; White/not Latino, n = 10), 41.3 (male, n = 4; White/not Latino, n = 3), and 34.7 (male, n = 2; White/not Latino, n = 3), respectively. Among the second and third cohorts, there was no engraftment loss. The 1- and 5-year overall survival (OS) rates in the second cohort were 100%, and the 1-year OS rate in the third cohort was 100%.

One patient in the second cohort had grade 2 skin graft-vs-host disease (GVHD), which resolved with treatment, and no patients in the third cohort experienced GVHD. “Overall, these approaches have been very safe. We’ve not seen any major safety problems,” Meyer stated.

Mixed hematopoietic chimerism lasting at least 1 year occurred in approximately half of patients receiving TLI/ATG conditioning. However, long-term immunosuppression withdrawal was not improved with CD3 T-cell dose escalation. The addition of a low dose of TBI significantly increased the levels and stability of mixed chimerism during the first year after treatment.

Additionally, complete immunosuppressive drug withdrawal during the 2nd year after treatment occurred in 2 patients. Furthermore, by adding T regulatory cells at the time of transplantation investigators observed a reduction in initial donor T-cell engraftment.

“The TLI/TBI/ATG group had a successful increase in both initial and persistent mixed chimerism. Although the Treg group is treated similarly to the TLI/TBI group, the effect of the Tregs given at the time of the bone marrow graft is to slow donor engraftment. And [we saw] significantly less persistent donor T cell chimerism equal to what we’d seen previously, without the very mild conditioning intensification,” Meyer explained.

With respect to the incidence of graft transition syndrome, Meyer noted that there was a significant percentage burden for patients in arms 1 and 3. However, high-grade transition syndrome wasn’t as common with the slight intensification of the conditioning regimen in the haploidentical setting in arm 2.

“In terms of the tolerance outcomes, there’s immunosuppression with no chimerism, full immunosuppression and chimerism, low immunosuppression and chimerism, and off immunosuppression and chimerism, which would be considered the grand slam. With the TLI/TBI/ATG conditioning, we’re achieving that at least in this small patient cohort a third of the time,” Meyer noted.

“Over the past 20 years, we’ve had success being able to induce stable and transient mixed tolerance with long-term immunosuppression withdrawal, first on a phase 1 basis, and then now very recently, reported as a positive phase 3 trial outcome,” Meyer added.

Findings from the phase 3 trial (NCT03363945), which were recently published in the American Journal of Transplantation, illustrated that kidney transplant recipients who received MDR-101 achieved donor mixed chimerism and functional immune tolerance for more than 2 years with no death, graft loss, donor-specific antibodies, or GVHD, and results demonstrated improved quality of life compared with standard treatment.⁴

“What we’re doing now is re-timing the Treg infusion at day 6 after bone marrow transplant to see if we can have a major effect in modulating any immune interaction between the 2 immune systems. We’re also looking at the incorporation of third-generation donor graph products that are highly selected to try to improve engraftment and reduce graft transition syndrome. There are [also] new immunosuppressive agents that are very exciting to test. We’re also looking at delayed transplant cohorts,” Meyer concluded.

Disclosures: Meyer reported sponsored research support from Orca Biosystems, Incyte, and Kyverna Therapeutics; and consulting/equity for Jura Bio, TRACT Therapeutics, Indee Labs, and GigaMune.

References

1. Busque S, Scandling J, Lenihan C, et al. Phase 1 trial results for patients undergoing haploidentical living donor combined kidney and non-myeloablative hematopoietic cell transplantation for immune tolerance induction.Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract ID 86.
2. Busque S, Scandling JD, Lowsky R, et al. Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal. Sci Transl Med. 2020;12(528):eaax8863. doi:10.1126/scitranslmed.aax8863
3. Scandling JD, Busque S, Shizuru JA, et al. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011;365(14):1359-1360. doi:10.1056/NEJMc1107841
4. Kaufman DB, Akkina SK, Stegall MD, et al. Induction of immune tolerance in living related HLA-matched kidney transplantation: a phase 3 randomized clinical trial. Published online February 6, 2025. doi:10.1016/j.ajt.2025.01.044