comparison of point-of-care produced car t-cell with commercial car t-cells in patients with r/r lbcl

Conditions: NHL; DLBCL - Diffuse Large B Cell Lymphoma

Summary: 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