CAR-T Cell Therapy for Desensitization in Kidney Transplantation

Inclusion Criteria:

1. Male or female patients aged 18-65 years with kidney failure requiring hemodialysis.

2. United Network for Organ Sharing (UNOS) listed for kidney transplant for at least 1year.

3. Patients must meet one of the following two criteria:

4. Protocol-specific cPRA ≥99.5% AND no suitable living donor, ineligible forkidney paired donation programs, have blood group Type O or B, and predictiveof a positive virtual crossmatch to an available deceased donor

5. Protocol-specific cPRA ≥99.9% Protocol-specific cPRA must be rounded from threesignificant figures measured ≤90 days from the time of enrollment (i.e., cPRAof 0.994500 or 0.998500 would be eligible) using the web-based OPTN cPRAcalculator (https://optn.transplant.hrsa.gov/resources/allocation-calculators/cpra-calculator/); accounting for HLA-A, -B, -C, -DRB1, -DRB3/4/5, and -DQB1 Luminex SingleAntigen Beads (SAB) with MFI ≥3000; 1 archived sample within 6 months ofscreening required.

6. Based on center-specific listing policies, a cPRA in UNet Waitlist that is ≥99.5% (the candidate must be eligible for additional priority of kidneys equivalent toindividuals with a 100% cPRA)

7. Able to understand and give written informed consent to participate in all aspectsof the study.

8. Willing to stay within 2 hours of the home study site for at least 28 days after thelast T cell infusion

9. Subjects of reproductive potential must agree to use contraception for at least oneyear after CAR T Cell infusion

10. In the absence of contraindication, vaccinations must be up to date per the DAITGuidance for Patients in Transplant Trials and include TdAP

11. Positive for EBV capsid IgG

12. Negative testing for latent TB infection within 3 months prior to enrollment.Testing should be conducted using either a PPD or interferon-gamma release assay (i.e. QuantiFERON-TB, T-SPOT.TB). Patients with a positive test for latent TBinfection must complete appropriate therapy for Latent Tuberculosis Infection (LTBI). A subject is considered eligible only if they have a negative test for LTBIwithin 3 months prior to enrollment OR they have appropriately completed LTBItherapy prior to transplant. Latent TB infection treatment regimens should be amongthose endorsed by the CDC

13. Hemoglobin ≥9g/dL

14. ANC ≥ 1,800/μL, > 1,200/ μL for patients with Duffy-null associated neutrophil count (DANC)

15. Absolute Lymphocyte Counts ≥1000/μL or CD3 T cell Count ≥900 /μL

16. Platelet count ≥150,000/μL

Exclusion Criteria:

1. Subjects with indwelling catheters as primary access for hemodialysis

2. Previous solid organ (except kidney) or bone marrow transplant

3. BMI ≥30 kg/m2

4. Subjects who have preserved or oliguric urine output > 100 cc/day with history ofrecurrent UTI (2 in 6 months or 3 in 1 year, see study definitions)

5. Subjects described in exclusion #4 with structural disease such as polycystic kidneydisease, obstructive uropathy with nephrolithiasis or those otherwise at higher riskof urinary tract infections. Anuric subjects with structural kidney disease are notexcluded

6. Known active current or history of invasive fungal infection, or non-tuberculousmycobacterial infection. Any infection requiring hospitalization and IV antibioticswithin 4 weeks of screening or PO antibiotics within 2 weeks

7. History of HIV, chronic HBV, or chronic HCV, regardless of treatment

8. Negative CMV serology

9. Detectible viral load HBV, HCV, CMV, EBV, BK or SARS-CoV2 by PCR

10. Any B cell depleting or monoclonal antibody therapy within 6 months prior toenrollment

11. Receiving ongoing immunosuppression including corticosteroids, intravenousimmunoglobulin, cyclophosphamide, tacrolimus, mycophenolic acid, or azathioprinefrom 90 days prior to study entry

12. Active auto-immune disease, including connective tissue disease, uveitis,sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or have a history ofsevere (as judged by the investigator) autoimmune disease requiring prolongedimmunosuppressive therapy, except for renal-limited autoimmune conditions withoutrisk for systemic manifestations (e.g. IgA nephropathy)

13. Any chronic illness requiring uninterrupted anti-coagulation or anti-platelettherapy

14. History of cirrhosis or severe liver disease, including abnormal liver profile (aspartate aminotransferase [AST], alanine aminotransferases [ALT] or totalbilirubin > 3 times upper limit of normal at screening (except for patients in whomhyperbilirubinemia is attributed to Gilbert's syndrome)

15. History of sickle cell disease, or systemic amyloidosis

16. Cardiac clearance for transplant > 6 months old and/or any of the following: NYHAClass III or IV heart failure, unstable angina, left ventricular ejection fraction < 40%, a history of recent (within 6 months) myocardial infarction or implantablecardioverter/ defibrillators and/or biventricular pacing.

17. Moderate-severe pulmonary function abnormality, defined as resting oxygen saturation <92% on room air or FEV1, TLC, or DLCO (after correction for hemoglobin) <50% ofpredicted values

18. Patients who have received any live vaccine within 30 days of planned leukapheresis

19. Treatment with any investigational agent within 4 weeks (or 5 half-lives ofinvestigational drug, whichever is longer) of screening

20. Pregnant, currently breastfeeding, or planning to become pregnant during the primaryor post-transplant follow up of the study.

21. Past or current social or medical problems; or findings from physical examination orlaboratory testing that are not listed above, which in the opinion of investigator,may pose additional risks from participation in the study, may interfere with theparticipant's ability to comply with study requirements or that may impact thequality or interpretation of the data obtained from the study

Lymphodepleting Chemotherapy Eligibility:

Study entry eligibility must be re-assessed prior to starting lymphodepletion. In addition, subjects must undergo respiratory viral testing on nasal or nasopharyngeal swabs (per institutional practice) for SARS-CoV-2 and influenza within 7 days prior to the first planned lymphodepletion chemotherapy.

1. If the subject is positive for influenza, Tamiflu® or equivalent should beadministered per package insert. The subject must complete treatment and symptomsmust be improving and either resolved or nearly resolved in the judgment of thetreating investigator prior to receiving lymphodepleting chemotherapy and CAR Tcells. Repeat influenza testing is not required prior to initiating lymphodepletingchemotherapy and CAR T cell infusion.

2. If the subject tests positive for SARS-CoV-2, the subject will be managed perinstitutional practice. Subject will be eligible to initiate lymphodepletingchemotherapy and CAR T cell infusion once cleared from requirement for isolationaccording to institutional and/or CDC guidance.

3. If testing is positive for another respiratory virus (e.g., as part of a multiplexrespiratory pathogen panel in the course of testing for influenza or SARS-CoV-2),the lymphodepleting chemotherapy and CAR T cell infusion will be delayed for atleast 7 days to be sure clinical symptoms of a viral infection do not develop. Ifclinical symptoms develop, the lymphodepleting chemotherapy and CAR T cell infusionwill be delayed until resolution of these symptoms.

CAR T Cell Infusion Eligibility:

The criteria below will be assessed by the investigator following lymphodepleting chemotherapy and before administration of CAR T cells. Subjects who do not satisfy these criteria may have CAR T cell infusion delayed until such time as criteria are satisfied. Subjects who receive lymphodepleting chemotherapy but in whom CAR T cell infusion is delayed >4 weeks after the first day of lymphodepleting chemotherapy will receive a second cycle of lymphodepleting chemotherapy prior to CAR T cell infusion. For subjects receiving fludarabine, a second cycle of cyclophosphamide can be administered, but fludarabine will not be repeated.

1. Subjects must not have developed deterioration in performance status or overallclinical condition or new laboratory abnormalities that would, in the opinion of thetreating investigator, render it unsafe to proceed with CAR T cell infusion. Thefollowing are specific conditions that warrant delaying CAR T cell infusion:

2. Requirement for supplemental oxygen to maintain peripheral oxygen saturation ≥95%.

3. Presence of clinically significant radiographic abnormalities on chest x-ray.Chest x-ray is not required to evaluate for radiographic abnormalities in theabsence of suggestive symptoms or exam findings.

4. New cardiac arrhythmia not controlled with medical management. EKG is notrequired to evaluate for arrhythmia in the absence of suggestive symptoms orexam findings.

5. Hypotension requiring vasopressor support.

6. Active infection: Diagnostic test results indicating new bacterial, fungal, orviral infection within prior 48 hours.

7. Subjects must have adhered to restrictions on pre-infusion therapy.