CAR-T-cell Treatment for Untreated High Risk MANtle Cell Lymphoma

Inclusion Criteria:

1. Histologically confirmed diagnosis of MCL according to WHO classification, withdocumentation of either overexpression of cyclin D1 or presence of t(11;14)

2. At least one High Risk MCL - feature as defined as I. MIPI-c high intermediate (HI)or high (H) risk (i.e. high risk MIPI irrespective of Ki-67 or intermediate riskMIPI and Ki-67>=30% (Ki-67 based on local pathology) and/or II. TP53-mutation and/orTP53-overexpression by immunohistochemistry (> 50% of lymphoma cells)

3. No prior treatment for MCL

4. Stage II-IV (Ann Arbor)

5. 18-75 years

6. At least 1 measurable lesion according to the Lugano Response Criteria (>1.5 cmnodal lesion or > 1cm extranodal lesion); in case of bone marrow infiltration only,bone marrow aspiration and biopsy is mandatory for all staging evaluations.

7. ECOG performance status ≤ 2

8. The following laboratory values at screening (unless discrepancies are related toMCL): I. Absolute neutrophil count (ANC) ≥ 1000 cells/μL II. Platelets ≥75,000 cells/μLIII. Creatinine <2 mg/dL or calculated creatinine clearance ≥60 mL/min IV.Transaminases (AST and ALT) < 2.5 x ULN V. Total bilirubin <= 2 x ULN unless otherreason known (e.g. Gilbert-Meulengracht-Syndrome, or due to lymphoma involvement)

9. No evidence of CNS-disease

10. Written informed consent form according to ICH/EU GCP and national regulations,ability to follow study instructions and likely to attend and complete all requiredvisits

11. Sexually active men and women of child-bearing potential must agree to use one ofthe highly effective contraceptive methods (combined oral contraceptives using twohormones, contraceptive implants, injectables, intrauterine devices, sterilizedpartner) together with one of the barrier methods (latex condoms, diaphragms,contraceptive caps) while on study; this should be maintained for 6 months after thelast dose of KTE-X19 or for 3 months after last dose of Ibrutinib, whichever islonger

12. Negative serum or urine pregnancy test (Females of childbearing potential only,Females who have undergone surgical sterilization or who have been postmenopausalfor at least 2 years are not considered to be of childbearing potential)

13. Willingness not to drive a motor vehicle for 8 weeks post CAR T cell treatment

14. Possibility to reach the site within 2 hours in case of toxicity / emergency

Exclusion Criteria:

1. Subjects not able to give consent

2. Subjects without legal capacity, unable to understand the nature, scope,significance and consequences of this clinical study

3. Known history of hypersensitivity to the investigational drug, to drugs with asimilar chemical structure or to aminoglycosides

4. Simultaneously active participation in another clinical study involving aninvestigational medicinal product within 30 days prior to enrollment. Patientsincluded in follow up periods of other clinical trials without ongoing trialmedication are allowed

5. Subjects with a physical or psychiatric condition which at the investigator'sdiscretion may put the subject at risk, may confound the study results, or mayinterfere with the subject's participation in this clinical study

6. Known or persistent abuse of medication, drugs or alcohol

7. Serious concomitant disease interfering with a regular therapy according to thestudy protocol: I. Clinically significant cardiovascular disease such as symptomatic arrhythmias,congestive heart failure, higher grade AV-block, unstable angina, myocardialinfarction, cardiac angioplasty or stenting within 12 months of Screening, or anyClass 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New YorkHeart Association Functional Classification or LVEF below 50% II. Baseline oxygensaturation ≤ 92% on room air III. Clinical significant pleural effusion (if notlymphoma related) IV. Endocrinological (severe, not sufficiently controlled diabetesmellitus)

8. Current or planned pregnancy or nursing women. History of or active malignancy otherthan MCL, non-melanoma skin cancer, carcinoma in situ (e.g. cervix, bladder, breast)or prostate cancer unless disease-free for at least 3 years (and PSA within normalrange in case of prostate cancer).

9. Presence of fungal, bacterial, viral, or other infection that is uncontrolled orrequiring intravenous (IV) antimicrobials for management.

10. Positive test results for chronic HBV infection (defined as positive HBsAg serology) (mandatory testing) Patients with occult or prior HBV infection (defined as negativeHBsAg and positive total HBcAb) may be included if HBV DNA is undetectable

11. Positive test results for hepatitis C (mandatory hepatitis C virus [HCV] antibodyserology testing). Patients positive for HCV antibody are eligible only if PCR isnegative for HCV RNA

12. Patients with known HIV infection (mandatory test)

13. History or presence of CNS disorder, such as seizure disorder, cerebrovascularischemia/hemorrhage, dementia, cerebellar disease, cerebral edema, posteriorreversible encephalopathy syndrome, or any autoimmune disease with CNS involvement

14. History of or active autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis,systemic lupus) resulting in end organ injury or requiring systemicimmunosuppression / systemic medication within the last 2 years

15. History of deep vein thrombosis or pulmonary embolism requiring therapeuticanticoagulation within 6 months of enrolment

16. Known severe primary immunodeficiency

17. Any medical condition likely to interfere with assessment of safety or efficacy ofstudy treatment

18. Live vaccine ≤ 6 weeks prior to planned start of study treatment

19. Any psychological, familial, sociological, or geographical condition potentiallyhampering compliance with the study protocol and follow up schedule