Preliminary evidence of CAR T‐cell therapy activity in vitreoretinal lymphomas: An LOC network study

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Vitreoretinal lymphoma (VRL) is a rare subtype of large B-cell lymphoma (LBCL) that may present as an isolated condition or with central nervous system (CNS) or systemic involvement. Like the brain, the eye is an immune-privileged site, posing unique therapeutic challenges according to the blood–eye barrier. Despite its typically indolent course, VRL is difficult to eradicate, and the long-term prognosis is poor because of the high risk of CNS involvement.1 The median overall survival (OS) is 36–75 months for primary VRL and approximately 57 months for isolated vitreoretinal relapses of primary CNS lymphomas.2 Therefore, new therapeutic strategies are urgently needed. Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a major advancement in managing systemic LBCL.3, 4 Studies show that CAR T-cells can cross the blood–brain barrier and demonstrate high efficacy in CNS lymphomas,5-8 but their potential in VRL treatment is not fully understood, and their efficiency has never been described from an ophthalmologic point of view with the newest validated exams. Since 2020, CAR T-cell therapy has been considered within the French oculocerebral lymphoma network (LOC network) for relapsed or refractory VRL. This study retrospectively analyzed patients with primary or secondary VRL treated with CAR T-cells. We retrospectively identified all VRL patients treated with commercial anti-CD19 CAR T-cells at Pitié-Salpêtrière Hospital (Paris) via the LOC network database until November 2023. Eligible patients had active vitreoretinal involvement, either isolated or with CNS involvement. VRL could be primary or secondary to systemic or CNS lymphoma. Data were retrospectively collected from medical records between April and October 2024. The LOC database was approved by the Institutional Ethical Committee of the coordinating center and the French “Commission Nationale de l'Informatique et des Libertés” (CNIL). All patients provided written informed consent. Responses were evaluated using International Primary CNS Lymphoma Collaborative Group (IPCG) criteria,9 and all ophthalmologic examinations of the patient performed immediately before and after the CAR T-cells were systematically reviewed by a single ophthalmologist from the Pitié-Salpétrière Hospital, based on the photographs taken at each consultation (Supplementary Methods). Progression-free survival (PFS), ophthalmic-free survival (OFS), and OS were defined as the time from CAR T-cell infusion: “to CNS, ophthalmic or systemic disease progression or relapse/to ophthalmic progression or relapse/and to death respectively.” Survival rates were calculated using the Kaplan–Meier method. Statistical analyses were conducted using GraphPad Prism v10.0. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per 2019 American Society for Transplantation and Cellular Therapy (ASTCT) guidelines.10 Interleukin (IL)-10 and IL-6 assays were performed on the aqueous humor (AH) using a sensitive Cytometric Bead Array kit (BD Biosciences) on a FACSCanto II cytometer. The AH IL-10 level was classified as detectable (≥2.5 pg/mL) or undetectable (<2.5 pg/mL) based on the laboratory's standard threshold. The presence of CAR T-cells in the blood and AH was measured by flow cytometry. Each sample was incubated for 15 min with 1 µL of CD19 CAR Detection Reagent (Miltenyi Biotec), followed by staining with the following antibodies: anti-Biotin-PE (Miltenyi Biotec), CD45-KrO (clone J33), CD3-Alexa Fluor A750 (clone UCHT1), CD4-ECD (clone SFCI12T4D11), and CD8-Alexa Fluor 700 (clone B9.11). The final sample was analyzed on a DxFLEX flow cytometer (Beckman Coulter), and data were processed using CytExpert (Beckman Coulter) software version 2.0.2.18. Between August 2020 and December 2023, seven patients with VRL were treated with CAR T-cells. Their main baseline characteristics and individual outcomes are summarized in Tables 1 and S1. 6 R-MPVA + RT, R-ICE, Ibrutinib + ASCT (TBC), Pembrolizumab, Ibrutinib Rituximab Revlimid, R-MPV, Rituximab MTX TMZ, ITV MTX G1 CRS, G4 ICANS CTX + intensive care 2 R-MBVP + RA, ICE + ASCT (TBC) MTX TMZ G1 CRS, G1 ICANS Tocilizumab + CTX Systemic DLBCL + VRL 2 R-CHOP-MTX + ASCT (Thiotepa Carmustine), Phase I/II protocol ITV MTX R-ICE G1 CRS, no ICANS Tocilizumab Systemic DLBCL + VRL 4 R-CHOP-MTX-Aracytine, R-ICE, ITV MTX, Ibrutinib Rituximab Revlimid Grade 2 CRS, Grade 1 ICANS Tocilizumab 4 R-MPV, R-ICE, Phase I/II protocol, Revlimid Rituximab G2 CRS, G1 ICANS Tocilizumab 5 Rituximab-MTX-Aracytine, R-ICE + ASCT (TBC), TMZ, Ibrutinib, Revlimid G2 CRS, G4 ICANS CTX + intensive care 2 MTX-Aracytine, Revlimid G2 CRS G4 ICANS Tocilizumab + CTX + intensive care At the time of the CAR T-cell therapy decision, four patients had isolated VRL, whereas three also had brain parenchymal involvement. Their median age was 70 years (range, 50–76), and their median Eastern Cooperative Oncology Group performance status was 1 (range, 1–3). The median number of prior therapies before leukapheresis was 4 (range, 2–6), including autologous stem cell transplantation (ASCT) (thiotepa-based induction regimen) in four patients (two patients were ineligible for ASCT at the time of CAR T-cells). All but one patient received bridging therapy using drug regimens directed against ocular/brain disease such as methotrexate, temozolomide, ibrutinib, or cytotoxic chemotherapies (ifosfamide, etoposide, and carboplatin) (Table 1). There were no steroid-containing regimens. At the time of CAR T-cell infusion, with regard to ophthalmic involvement, two patients had a complete response (CR), two had a partial response (PR), two had stable disease, and one had progressive disease. Additionally, three patients had CNS progressive disease. Three patients received tisagenlecleucel and four received axicabtagene ciloleucel (axi-cel). At 1 month, an ophthalmologic response was observed in all five evaluable patients, including PR in two (40%) and CR in three (60%). Data were unavailable for two patients who developed severe neurotoxicity and could not undergo ophthalmologic assessment at this time (Table S1). During follow-up, the best response achieved was CR or CR unconfirmed for all seven patients. The median time from CAR T-cell infusion to first response was 1 month (range, 1–4). After a median follow-up of 23 months (range, 10–47), the 2-year OFS, PFS, and OS rates were 83%, 69% and 83%, respectively (Figure 1A,B). IL-10 dosage in the AH in six tested patients during the first 6 months post-CAR T-cell therapy was undetectable for all but one patient who relapsed a few months later (Figure S1). On the other hand, IL-6 levels exceeding 2.5 pg/mL were detected in the AH of all six patients tested during this period (range, 19–194 pg/mL), with no observed correlation to the occurrence of grade ≥ 3 ICANS. Two of seven patients experienced relapses: one patient had an isolated intraocular relapse 10 months after CAR T-cell infusion, and the other one experienced a relapse in the brain and cerebrospinal fluid 5 months after CAR T-cell infusion. To better characterize the trafficking and persistence of CAR T-cells in the eye, flow cytometry was performed at different time points in three patients (one patient was assessed four times, and two were assessed twice). One patient demonstrated AH positivity for CAR T-cells at 11 days, 1 month, 4 months, and 10 months (last ophthalmologic follow-up) (Figure 1C). The other two patients tested negative for CAR T-cells at all time points. All three patients remained in CR at their last ophthalmologic follow-up (17, 16, and 10 months after CAR T-cell infusion, respectively). Peripheral blood CAR T-cell expansion during the first 30 days post-infusion is illustrated in Figure S2. All patients developed cytokine release syndrome (Grade 1 in three patients, Grade 2 in four patients). ICANS of any grade occurred in six patients (Grade 3 in one, Grade 4 in two). T

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.