CAR-T Cell Therapy for Kidney Transplant Desensitization
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Must not be taking: Immunosuppressants, Corticosteroids
Disqualifiers: BMI ≥30, HIV, Hepatitis, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This research study is for people who have been waiting for a kidney transplant for at least one year, and who have a cPRA of 99.5% or higher. Having a cPRA of 99.5% or higher means that your immune system would reject 99.5% of kidneys available for transplant. The study will test whether new products called Chimeric Antigen Receptor T Cells (CAR T Cells), when given with chemotherapy, is safe and will reduce cPRA.
The main study will last up to 2 years: Participants will have up to 30 clinic or hospital visits over a one-year period. If a transplant takes place, there will be 9 more visits after transplant. Long term follow up is required by the Food and Drug Administration (FDA) for 15 years after receiving CAR T cell.
The primary objective is to evaluate the safety and feasibility of administering CART BCMA + huCART-19 following lymphodepletion, including determination of optimal tolerated regimen (OTR) and/or recommended phase 2 regimen, according to the incidence of dose limiting toxicity (DLT) in highly sensitized patients awaiting kidney transplant.
Will I have to stop taking my current medications?
The trial requires that participants do not receive ongoing immunosuppression, including corticosteroids and other specific medications, from 90 days before joining the study. This suggests you may need to stop certain medications before participating.
What data supports the effectiveness of CAR-T Cell Therapy for Kidney Transplant Desensitization?
The research does not provide direct evidence for the effectiveness of CAR-T Cell Therapy in kidney transplant desensitization, but it highlights the potential of immunomodulating therapies, like costimulation blockade and antibody removal, in improving transplant outcomes. These approaches have shown varying degrees of success in overcoming immune barriers in kidney transplantation.
12345Is CAR-T cell therapy generally safe for humans?
CAR-T cell therapy has been tested in patients with multiple myeloma, showing that most side effects are manageable, though some patients experienced severe reactions like cytokine release syndrome (a condition where the immune system releases too many inflammatory molecules). The FDA is also investigating potential risks of secondary cancers, but many experts believe the benefits outweigh these risks.
678910What makes CAR-T Cell Therapy for Kidney Transplant Desensitization unique?
CAR-T Cell Therapy is unique because it uses specially engineered T cells to target specific proteins on cells, which is different from traditional treatments that may not be as targeted. This therapy has shown promise in treating certain blood cancers by targeting proteins like BCMA and CD19, and it is now being explored for kidney transplant desensitization, which is a novel application.
711121314Eligibility Criteria
This trial is for adults aged 18-65 with kidney failure who have been on the transplant waitlist for over a year and are highly likely to reject a transplanted kidney. They must be able to consent, live near the study site, use contraception post-treatment, and meet specific health criteria like certain blood counts.Inclusion Criteria
I am between 18 and 65 years old and need hemodialysis for kidney failure.
Subjects of reproductive potential must agree to use contraception for at least one year after CAR T Cell infusion
Your platelet count is equal to or greater than 150,000 per microliter.
+10 more
Exclusion Criteria
I have a condition like polycystic kidney disease or issues that increase my risk of urinary infections.
I haven't had B cell or antibody therapy in the last 6 months.
I am on continuous medication for blood thinning.
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Leukapheresis
Subjects undergo leukapheresis to collect T cells for CAR T cell manufacturing
1 week
1 visit (in-person)
Lymphodepletion and CAR T Cell Infusion
Participants receive lymphodepleting chemotherapy followed by CART-BCMA and huCART-19 cell infusions
12 months
Up to 30 visits (in-person)
Post-Transplant Monitoring
If a transplant takes place, participants will have additional monitoring visits
9 visits
Long-term Follow-up
Long term follow up is required by the FDA for 15 years after receiving CAR T cell
15 years
Participant Groups
The study tests if CAR T Cells (CART-BCMA + huCART19) combined with chemotherapy can safely lower immune rejection rates in patients awaiting kidney transplants. It involves multiple clinic visits over two years, plus long-term follow-up as required by the FDA.
1Treatment groups
Experimental Treatment
Group I: Participant CohortsExperimental Treatment4 Interventions
* Safety Run-in phase (2 subjects at UPenn)
* Cohort 1 (3-6 subjects)
* Cohort 2 (3-6 subjects)
* Cohort 3 (3-6 subjects)
CART-BCMA is already approved in United States for the following indications:
🇺🇸 Approved in United States as CART-BCMA for:
- Experimental use for desensitization in kidney transplantation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Massachusetts General Hospital: Transplantation (Site #: 71107)Boston, MA
New York University - Langone (Site #: 71177)New York, NY
University of Pennsylvania Medical Center (Site #: 71111)Philadelphia, PA
NYU Langone Health (Site #: 71177)New York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
National Institute of Allergy and Infectious Diseases (NIAID)Lead Sponsor
University of Pennsylvania Clinical Cell and Vaccine Production Facility (CVPF)Collaborator
References
Costimulation Blockade in Kidney Transplant Recipients. [2020]Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.
Modern approaches to incompatible kidney transplantation. [2020]The presence of human-leukocyte antigen (HLA)-antibodies and blood group incompatibility remain a large barrier to kidney transplantation leading to increased morbidity and mortality on the transplant waiting list. Over the last decade a number of new approaches were developed to overcome these barriers. Intravenous immunoglobulin (IVIG) remains the backbone of HLA desensitization therapy and has been shown in a prospective, randomized, placebo controlled trial to improve transplantation rates. Excellent outcomes with the addition of rituximab (anti-B cell) to IVIG based desensitization have been achieved. There is limited experience with bortezomib (anti-plasma cell) and eculizumab (complement inhibition) for desensitization. However, these agents may be good adjuncts for patients who are broadly sensitized with strong, complement-fixing HLA antibodies. Excellent short and long-term outcomes have been achieved in ABO incompatible transplantation with the combination of antibody removal, B cell depletion, and pre-transplant immunosuppression. Kidney paired donation has emerged as a reasonable alternative for programs who cannot provide desensitization or in conjunction with desensitization. Future therapies directed toward cytokines that alter B cell proliferation are under investigation.
Desensitization in kidney transplantation: review and future perspectives. [2015]More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg.
Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates. [2023]We have previously reported successful induction of renal allograft tolerance via a mixed chimerism approach in nonhuman primates. In those studies, we found that costimulatory blockade with anti-CD154 mAb was an effective adjunctive therapy for induction of renal allograft tolerance. However, since anti-CD154 mAb is not clinically available, we have evaluated CTLA4Ig as an alternative agent for effecting costimulation blockade in this treatment protocol. Two CTLA4Igs, abatacept and belatacept, were substituted for anti-CD154 mAb in the conditioning regimen (low dose total body irradiation, thymic irradiation, anti-thymocyte globulin and a 1-month posttransplant course of cyclosporine [CyA]). Three recipients treated with the abatacept regimen failed to develop comparable lymphoid chimerism to that achieved with anti-CD154 mAb treatment and these recipients rejected their kidney allografts early. With the belatacept regimen, four of five recipients developed chimerism and three of these achieved long-term renal allograft survival (>861, >796 and >378 days) without maintenance immunosuppression. Neither chimerism nor long-term allograft survival were achieved in two recipients treated with the belatacept regimen but with a lower, subtherapeutic dose of CyA. This study indicates that CD28/B7 blockade with belatacept can provide a clinically applicable alternative to anti-CD154 mAb for promoting chimerism and renal allograft tolerance.
Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). [2022]Profound T-cell depletion before allotransplantation with gradual posttransplant T-cell repopulation induces a state of donor-specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52-specific monoclonal antibody that produces profound T-cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T-cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T-cell depletion.
FDA Investigating CAR-Related T-cell Malignancies. [2023]The FDA is investigating reports that BCMA- and CD19-directed autologous chimeric antigen receptor T-cell immunotherapies, which are used to treat a variety of blood cancers, may be causing secondary malignancies. However, the agency and hematologists say the potential benefits of the agents, which have saved thousands of lives, outweigh this risk.
Chimeric antigen receptor T cell therapy for multiple myeloma. [2020]Chimeric antigen receptor (CAR) T cell therapy is a new cancer immunotherapy targeting cancer-specific cell surface antigen. CD19-CAR T cells have been already shown to be very effective to B cell leukemia/lymphoma. Now, many researchers are developing CAR T cells for multiple myeloma. CAR T cells targeting B cell maturation antigen (BCMA) showed promising efficacy in early phase clinical trials. We have recently reported that CAR T cells targeting the activated integrin β7 can selectively eradicate MM cells including CD19+ clonotypic B cells and are preparing a clinical trial.
Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. [2020]Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.
[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma]. [2022]To investigate the toxicity management and efficacy evaluation of BCMA-chimeric antigen receptor T cells(CART) in the treatment of relapsed and refractory multiple myeloma (MM).
A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. [2022]B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR-exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.
B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. [2020]Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM).
A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. [2020]Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
CAR-T Cell Therapy: From the Bench to the Bedside. [2020]CAR (Chimeric Antigen receptor)-T cell therapy is a novel type of therapy that uses engineered T cells with an antibody single-chain variable fragment (ScFv) extracellular domain that binds tumor-associated antigens[...].
Risk factors of acute kidney injury during BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma. [2022]To explore the risk factors of acute kidney injury (AKI) during B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma (MM).