CAR-T Cell Therapy for Kidney Transplant Desensitization

Recruiting at 6 trial locations

Overseen By Mary Kaminski, PA

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: BMI ≥30, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 31

20 Participants Needed

Trial Summary

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. ^{1 2 3 4 5}

Is 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. ^{6 7 8 9 10}

What 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. ^{7 11 12 13 14}

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.

Research Team

Alfred Garfall, MD

Principal Investigator

University of Pennsylvania Medical Center: Transplantation

Vijay Bhoj, M.D., Ph.D.

Principal Investigator

University of Pennsylvania Medical Center: Transplantation

Ali Naji, MD, Ph.D.

Principal Investigator

University of Pennsylvania Medical Center: Transplantation

Eligibility 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

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.

I have been on the kidney transplant list for at least a year.

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.

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

Treatment Details

Interventions

• CART-BCMA
• Cyclophosphamide
• Fludarabine
• huCART19

Trial Overview 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.

Participant Groups

Group I: Participant Cohorts Experimental Treatment 4 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

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

University of Pennsylvania Clinical Cell and Vaccine Production Facility (CVPF)

Collaborator

Trials

1

Recruited

20+

Findings from Research

Costimulation blockade therapy, like belatacept, offers a targeted approach to managing the immune response in kidney transplant recipients, potentially reducing non-immune side effects associated with traditional immunosuppressive therapies.

While belatacept has shown promise in certain subgroups of kidney transplant patients, its use is limited due to an increased risk of acute rejection, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Costimulation Blockade in Kidney Transplant Recipients. van der Zwan, M., Hesselink, DA., van den Hoogen, MWF., et al.[2020]

Intravenous immunoglobulin (IVIG) is a key treatment for HLA desensitization in kidney transplantation, significantly improving transplantation rates according to a randomized, placebo-controlled trial.

Combining IVIG with rituximab has led to excellent outcomes in desensitization, while other agents like bortezomib and eculizumab show promise for patients with strong HLA antibodies, indicating a multi-faceted approach to overcoming transplantation barriers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modern approaches to incompatible kidney transplantation. Wongsaroj, P., Kahwaji, J., Vo, A., et al.[2020]

Desensitization therapies for kidney transplant candidates, such as plasmapheresis and immunoadsorption, are often insufficient alone to achieve lasting reductions in harmful anti-HLA antibodies, leading to high rates of antibody-mediated rejection (AMR).

Combining low-dose intravenous immunoglobulins (IVIg) with plasmapheresis has shown improved survival rates compared to dialysis, but still results in unacceptable AMR rates, highlighting the need for new strategies like bortezomib, a proteasome inhibitor, as a potential alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Desensitization in kidney transplantation: review and future perspectives. Abu Jawdeh, BG., Cuffy, MC., Alloway, RR., et al.[2015]

In a study evaluating alternatives to anti-CD154 mAb for inducing renal allograft tolerance, belatacept was found to be effective, with three out of five recipients achieving long-term kidney survival without ongoing immunosuppression.

In contrast, the use of abatacept did not result in comparable chimerism or graft survival, highlighting belatacept's potential as a clinically applicable option for promoting tolerance in kidney transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates. Yamada, Y., Ochiai, T., Boskovic, S., et al.[2023]

In a study involving seven patients receiving living-donor kidney transplants, pretransplant T-cell depletion with alemtuzumab did not lead to tolerance in human renal allografts, as all patients experienced reversible rejection episodes shortly after transplantation.

Despite the initial rejection episodes, patients were able to maintain graft function on reduced immunosuppression, primarily using sirolimus, indicating that while T-cell depletion is significant, it does not eliminate the risk of rejection and highlights the role of monocytes in the rejection process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Kirk, AD., Hale, DA., Mannon, RB., et al.[2022]

The FDA is currently investigating potential links between BCMA- and CD19-directed CAR T-cell therapies and the development of secondary cancers in patients, highlighting a safety concern.

Despite these concerns, both the FDA and hematologists emphasize that the life-saving benefits of these immunotherapies for treating blood cancers outweigh the risks associated with secondary malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Investigating CAR-Related T-cell Malignancies. [2023]

CAR T cell therapy, particularly targeting B cell maturation antigen (BCMA), has shown promising efficacy in early clinical trials for treating multiple myeloma, indicating its potential as a new treatment option.

Recent research has also demonstrated that CAR T cells targeting activated integrin β7 can effectively eliminate multiple myeloma cells, including specific B cell types, and preparations for a clinical trial are underway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy for multiple myeloma. Hasegawa, K., Hosen, N.[2020]

In a clinical trial involving 17 patients with relapsed and refractory multiple myeloma, the biepitope-targeting CAR T therapy (LCAR-B38M) showed a high overall response rate of 88.2%, with 13 patients achieving stringent complete response (sCR).

While the treatment was generally effective, 10 patients experienced mild cytokine release syndrome (CRS) and 6 had severe but manageable CRS, indicating that while adverse effects can occur, they are often clinically manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Xu, J., Chen, LJ., Yang, SS., et al.[2020]

In a study of 21 patients with relapsed and refractory multiple myeloma treated with BCMA-chimeric antigen receptor T cells (CART), 17 patients showed effective responses, including 10 achieving complete remission, indicating a promising efficacy of this treatment.

The treatment was associated with manageable adverse reactions, primarily cytokine release syndrome (CRS), which occurred in 20 patients but was mostly mild (Grade 1 or 2), demonstrating that BCMA-CART can be safely administered with proper monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma]. Zhang, XY., Ding, HY., Gang, DX., et al.[2022]

The fully human BCMA-specific CAR T-cell therapy, CT103A, demonstrated a remarkable overall response rate of 100% in 18 patients with relapsed/refractory multiple myeloma, with 72.2% achieving complete or stringent complete responses.

CT103A showed a favorable safety profile, with the most common adverse events being mild hematologic toxicities, and no cases of severe neurotoxicity were reported, indicating its potential as a promising treatment option for patients, including those who previously relapsed from murine BCMA CAR therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Wang, D., Wang, J., Hu, G., et al.[2022]

In a phase I study involving 25 patients with relapsed/refractory multiple myeloma, CART-BCMA therapy demonstrated clinical activity, with response rates of 44% in the lowest dose cohort and 64% in the highest dose cohort, indicating its potential effectiveness as a treatment.

While CART-BCMA infusions were associated with some serious side effects like cytokine release syndrome and neurotoxicity, these were mostly reversible, suggesting a manageable safety profile for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. Cohen, AD., Garfall, AL., Stadtmauer, EA., et al.[2020]

In a phase 1 study involving 57 patients with relapsed/refractory multiple myeloma, LCAR-B38M CAR T cell therapy showed an impressive overall response rate of 88%, with 68% of patients achieving a complete response.

While the therapy had a manageable safety profile, with common adverse events including leukopenia and cytokine release syndrome, it demonstrated durable responses with a median progression-free survival of 15 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Zhao, WH., Liu, J., Wang, BY., et al.[2020]

CAR-T cell therapy utilizes genetically modified T cells that express an antibody fragment to specifically target and bind to cancer cells, enhancing the immune response against tumors.

This innovative approach represents a promising advancement in cancer treatment, as it harnesses the body's own immune system to identify and destroy cancer cells more effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy: From the Bench to the Bedside. Golubovskaya, V.[2020]

In a study of 99 patients with relapsed/refractory multiple myeloma undergoing BCMA CAR-T cell therapy, acute kidney injury (AKI) occurred in 25.3% of cases, typically within 15 days post-infusion, indicating a significant risk associated with this treatment.

Key independent risk factors for developing AKI included elevated serum creatinine levels after chemotherapy preconditioning and the severity of cytokine release syndrome (CRS), with higher grades of CRS leading to a notably increased incidence of AKI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors of acute kidney injury during BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma. Lyu, Y., Zhang, M., Wei, G., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Costimulation Blockade in Kidney Transplant Recipients. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Modern approaches to incompatible kidney transplantation. [2020]

3. Denmark pubmed.ncbi.nlm.nih.gov

Desensitization in kidney transplantation: review and future perspectives. [2015]

4. United States pubmed.ncbi.nlm.nih.gov

Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). [2022]

6. United States pubmed.ncbi.nlm.nih.gov

FDA Investigating CAR-Related T-cell Malignancies. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy for multiple myeloma. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. [2020]

9. China pubmed.ncbi.nlm.nih.gov

[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma]. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. [2020]

12. England pubmed.ncbi.nlm.nih.gov

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]

13. Switzerland pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy: From the Bench to the Bedside. [2020]

14. China pubmed.ncbi.nlm.nih.gov

Risk factors of acute kidney injury during BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma. [2022]