Comparison of Point-of-care Produced CAR T-cell with Commercial CAR T-cells in Patients with R/R LBCL

A phase II, multi-center study to compare the feasibility, and clinical efficacy of local manufacturing of CD19-directed CAR T-cells (ARI-0001 CAR T-cells) with commercial produced CAR T-cells (for example axicabtagene ciloleucel, a CD19 targeting commercially available CAR T-cell) in patients with relapsed or refractory (R/R) DLBCL.

Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of adoptive cell therapy that has proven its efficacy in the treatment of various hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). CD19 has been the most studied target antigen for CAR T-cell immunotherapy. Anti-CD19 CAR T-cell therapy has shown durable responses in patients with different B-NHLs, including Diffuse Large B-cell Lymphoma (DLBCL).

Unfortunately, up to 50-60% of the patients do not respond to CD19-directed CAR T-cell therapy or relapse. There are several shortcomings of current CD19-directed CAR T-cell therapy, that are likely responsible for therapy failure, namely: i) Due to centralized production at commercial sites, the production is time consuming (about 4 weeks), meaning that patients with rapidly progressive lymphoma may not reach the moment of the infusion of the anti-CD19 CAR T-cells. ii) Furthermore, for the current production processes, the autologous T-cells need to be cryopreserved for shipment from the hospital to the production sites and vice versa. This (double) cryopreservation process can decrease the quality of the CAR T-cells. This trial aims to address these shortcomings and will study the feasibility, and clinical efficacy of local manufacturing of CD19-directed CAR T-cells (ARI-0001 CAR T-cells), in a completely closed system using the CliniMACS Prodigy device. This study will compare the clinical efficacy of locally produced CAR T-cells to commercial produced CAR T-cells (for example axicabtagene ciloleucel, a CD19 targeting commercially available CAR T-cell) in patients with relapsed or refractory (R/R) DLBCL.

This in-house (point-of-care) production process of ARI-0001 will take approximately 7-12 days and thus will generate CAR T-cells \&#34;faster\&#34; which will be infused in the patient without cryopreservation (\&#34;fresh\&#34;, of note, a back-up cryopreserved product will also be manufactured). Furthermore, the point-of-care production process can be replicated in academic institutions with the appropriate cellular manufacturing facilities. If successful, this study will show feasibility of local production of CAR T-cell therapy, improving their rapid accessibility and quality.

Eligibility Criteria:
Inclusion Criteria:

* Histologically confirmed DLBCL and associated subtypes, defined by WHO 2016 classification: DLBCL not otherwise specified (NOS), High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B, T-cell/histocyte rich B-cell lymphoma, Primary mediastinal B-cell lymphoma, transformed lymphoma (transformed follicular) and R/R after at least 2 lines of systemic therapy
* Age ≥ 18
* Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0-2
* Secondary central nervous system (CNS) involvement is allowed however, then he/she must have

  \* No signs or symptoms of CNS involvement that would hamper adequate ICANS assessment
* Estimated life expectancy of \&gt;3 months other than primary disease
* Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen
* Signed and dated informed consent before conduct of any trial-specific procedure
* Patient is capable of giving informed consent

Exclusion Criteria:

* Absolute neutrophil count (ANC) \&lt;1.0x10\^9/L
* Platelet count \&lt;50x10\^9/L
* Absolute lymphocyte count \&lt;0.1x10\^9/L
* Primary CNS lymphoma
* Known history of infection with hepatitis C or B virus unless treated and confirmed to be polymerase chain reaction (PCR) negative
* Active HIV infection with detectable viral load or CD4 T-cell count below 0.20x10\^9/L
* Known history or presence of seizure activities or on active anti- seizure medications within the previous 12 months
* Known history of CVA within prior 12 months
* Unstable neurological deficits
* Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease
* Active systemic autoimmune disease for which immunosupressive therapy is required
* Presence of CNS disease that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity, baseline dementia that would interfere with therapy or monitoring, determined using mini-mental status exam at baseline
* Active systemic fungal, viral or bacterial infection
* Clinical heart failure with New York Heart Association class ≥2 (appendix F) or Left Ventricular Ejection Fraction (LVEF) \&lt;40%
* Resting oxygen saturation \&lt;92% on room air
* Liver dysfunction as indicated by total bilirubin, AST and/or ALT \&gt;5 x institutional ULN, unless directly attributable to the lymphoma or Gilbert disease
* GFR \&lt;40 mL/min calculated according to the modified formula of Cockcroft and Gault or by direct urine collection
* Pregnant or breast-feeding woman
* Active other malignancy requiring treatment
* Medical condition requiring prolonged use of systemic immunosuppressives with exception of prednisolone \&lt;10 mg/day
* History of severe immediate hypersensitivity reaction against any drug or its Ingredients/impurities that is scheduled to be given during trial participation e.g. as part of the mandatory lymphodepletion protocol, premedication for infusion, or rescue medication/salvage therapies for treatment related toxicities
* Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule