OlyCAR-019

Recently, cell therapies, including chimeric antigen receptor (CAR) modified T cell therapy and mesenchymal stem cell (MSC) therapy, have demonstrated considerable potential for systemic lupus erythematosus (SLE). In this study, a CAR-MSC model was constructed, combining two cell therapies. The structural domains of the CAR were designed by using the anti-CD19 scFv, targeting the CD19 antigen on the surface of B cells and the intracellular region of the interferon-gamma receptor, activating the JAK-STAT1 signaling pathway. Then we screened and identified the most effective structural domain of CAR as CAR1, as it facilitates MSCs to maintain significantly higher levels of JAK2 phosphorylation and IDO expression, as shown by western blot analysis. We also demonstrated CAR1 could be consistently and stably expressed at high levels in MSCs, and CAR1 transduction did not significantly affect the surface antigenic phenotypic criteria of MSCs via flow analysis. Furthermore, immunofluorescence results showed CAR1-MSCs could stably bind CD19 antigen, and they were activated by human CD19 antigen resulting in significantly high JAK2 phosphorylation and IDO expression via western blot analysis following co-culture. Besides, when activated peripheral blood mononuclear cells (PBMCs) were co-cultured with untransduced MSCs (UTD-MSCs) and CAR1-MSCs in vitro, respectively, the results showed that the percentage of activated CD3⁺ T cells and CD19⁺ B cells was both significantly lower after co-culturing. The percentage of activated CD19⁺ B cells was lower in the CAR1-MSCs co-culture group than in the UTD-MSCs co-culture group, whereas the percentage of activated CD3⁺ T cells was similar in the two co-culture groups. This suggests that CAR1 increased the inhibitory ability of MSCs on activated CD19⁺ B cells and had no significant effect on the ability of MSCs to inhibit activated CD3⁺ T cells. In conclusion, CAR1-MSCs were successfully constructed and demonstrated the ability to enhance the inhibitory effect of MSCs on activated human CD19⁺ B cells, facilitating SLE therapy.

In their paper, the authors describe clinical outcomes for a small cohort of mantle cell lymphoma (MCL) patients and central nervous system (CNS) involvement treated with anti-CD19 autologous chimeric antigen receptor (CAR)-T-cell therapy. The overall response rate (ORR) was 86% (CNS) and 90% (systemic), albeit with significant neurotoxicity that warrants further investigation. This report adds to existing literature, with only 17 cases of CAR-T-cell therapy for this indication previously reported. Patients with CNS MCL typically experience poor outcomes with an overall survival (OS) <5 months1 and there is no standard therapeutic approach. There is biological rationale for covalent Bruton's tyrosine kinase inhibitors (cBTKi), since ibrutinib penetrates the blood–brain barrier and has activity in MCL. Rusconi et al. performed an observational study in cBTKi naïve patients and found ibrutinib more effective than CNS penetrant chemoimmunotherapy for CNS MCL.2 However, the wide availability of ibrutinib, zanubrutinib and acalabrutinib at first MCL relapse means most patients are now cBTKi exposed at the time of CNS involvement. Data to inform therapeutic strategies in this setting are scarce. Anti-CD19-directed autologous CAR-T-cell therapies have favourable efficacy and manageable toxicity in diffuse large B-cell lymphoma (DLBCL) with CNS involvement. Although ZUMA-1 (axicabtagene autoleucel; axi-cel) and JULIET (tisagenlecleucel) excluded patients with CNS involvement due to concerns regarding increased risk of neurotoxicity, TRANSCEND (lisocabtagene maraleucel) permitted their enrolment, with 3/6 attaining a complete response (CR), none experiencing severe cytokine release syndrome (CRS), and 2/6 experiencing grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS), suggesting a comparable safety profile to patients without CNS involvement. Several case series have since reported similar findings.3-6 The durability of response remain poorly characterised, and one series reports shorter duration of response than when CAR-T is administered for systemic disease.4 The median follow-up in available datasets is <18 months3-6 and longer follow-up is required to understand the durability of CAR-T for CNS indications. The phase II ZUMA-2 study of brexucabtagene autoleucel (brexu-cel) in MCL also excluded patients with CNS involvement.7 The available data for CAR-T in CNS MCL are restricted to small observational cohorts; n = 18 and n = 16.9 Wang et al. describe outcomes for 16 patients with CNS MCL treated with brexu-cel, in which efficacy was comparable to those without CNS involvement (n = 152) (ORR 81% vs. 91%, CR 75% vs. 83%, respectively; median progression-free survival [PFS] 9 months vs. 17 months).9 The present study10 describes the detailed clinical course for 10 patients treated with anti-CD19-directed autologous CAR-T-cell therapy at three US academic centres; 9 with brexu-cel and 1 with axi-cel. They were heavily pretreated and 8/10 had received prior CNS-directed therapies and prior cBTKi exposure was common.10 The ORR in patients with CNS disease at time of infusion (n = 7) was 86% (CR 28.6%), with median PFS of 11.7 months and median OS not reached after median follow-up of 15.4 months. One patient experienced grade (G)3 CRS, and there were no G4–G5 events. Seven patients developed ICANS, with 5/10 (50%) G3 and no G4–G5 events. Leptomeningeal involvement and advanced age correlated with ICANS occurrence. The frequency of high-grade (≥3) CRS and ICANS is comparable to previously reported series (Table 1).3-6, 9 86 (CNS) 90 (systemic) 28.6 (CNS) 90 (systemic) The efficacy and toxicity profile in the seven patients with active CNS disease at time of CAR-T-cell infusion more informative than the three with prior CNS disease up to 18 months prior to CAR-T-cell infusion. While the CNS ORR was high (86%), CR appeared inferior (28.6%) compared with systemic responses (CR 90%). Although a partial response (PR) in heavily pretreated patients is encouraging, the durability of CNS PR is unknown, and extrapolating from DLBCL patients with CNS involvement treated with CAR-T, and systemic MCL patients in the ZUMA-2 study, suboptimal outcomes may be anticipated compared with attainment of CR (DLBCL CNS: 1/12 PR [0 ongoing] and 6/12 CR [3 ongoing], ZUMA-2: median PFS 47.6 vs. 2.2 months CR vs. PR).3, 11 Criteria by which systemic and CNS responses were assessed in the current cohort is not reported, and if standard CNS response criteria12 were employed, where CR defining criteria are very precise, many patients with PR by response criteria may not truly have residual disease. This hypothesis is supported by the observation that 2/10 patients had a systemic CR with CNS PR and remain free from progression at 6 and 24 months following infusion. Twelve-month PFS and OS for the whole cohort was 47% and 79%, and in those with confirmed active CNS disease 36% and 71% respectively. Notably, the OS and PFS data provided are from the time of CAR-T-cell infusion. This is appropriate since the study was performed to add to available literature regarding efficacy and toxicity profile of CAR-T. However, there were also noted to be six other patients in whom CAR-T was planned but not delivered: five were not apheresed (three due to death of unreported cause, one due to disease progression and one due to subdural haematoma) and one underwent apheresis but developed sepsis and was unable to proceed with infusion. The intention-to-treat ORR/CR rates would include these six patients as non-responders and accordingly be substantially lower. To date, emerging agents effective in cBTKi exposed MCL such as non-covalent BTKi, bispecific T-cell engaging antibodies are yet to be systematically evaluated in CNS MCL.13 We should encourage ongoing early phase studies of novel agents in lymphoma to include cohorts allowing active CNS disease so that patients unfortunate enough to face this dire complication have access to agents sooner than in the post-approval setting. CAR-T-cell therapy may represent a therapeutic advance in CNS MCL; however, the rarity of this disease makes prospective studies challenging. Larger datasets are required to address both toxicity and efficacy of brexu-cel in this disease. Open access publishing facilitated by The University of Western Australia, as part of the Wiley ? The University of Western Australia agreement via the Council of Australian University Librarians. KLL has served on advisory boards for IQVIA, MSD, AstraZeneca, on trial sterring committee for Lilly, has received honoraria from AstraZeneca, Roche, Janssen and has received expenses for conference attendance from Lilly. CYC has served on advisory boards for Roche, Janssen, Gilead, Astrazenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Dizal, Abbvie, Genmab. BMS and received research funding from BMS, Roche, Abbvie; MSD, Lilly.