CD19.CAR T cells versus obinutuzumab—who will win the race for use in deep B cell depletion therapy in systemic autoimmunity?

Over recent months, a number of noteworthy case reports and small case series have reported safety and unprecedented efficacy for CD19-targeting Chimeric Antigen Receptor (CAR) T cell therapy in various severe and refractory autoimmune diseases. A new milestone in innovative, cell-based treatment in systemic autoimmunity is on the horizon. Treatment with CD19-targeting CAR T cells is now an established therapy in haematology, and it is increasingly being suggested for the treatment of various non-malignant diseases [1]. The first use of anti-CD19.CAR T cells in rheumatology was in a patient affected by severe SLE, and significant clinical and serological improvement was observed after the treatment [2]. Most recently, Pecher et al. presented a rituximab (anti-CD20)-refractory case of antisynthetase syndrome that responded to treatment with CAR T cells in combination with MMF [3]. We treated a highly progressive case of Scl70+ dcSSc, observing a remarkable pulmonary response after the addition of third-generation anti-CD19.CAR T cells to MMF and nintedanib therapy [4]. This SSc patient was the first rheumatic patient with long-term persistence of CAR T cells. Circulating immune complexes disappeared after CAR T cell administration [4]. Regarding adverse events associated with the use of CAR T cell therapy in rheumatology, case reports recently being published describe the occurrence of cytokine-release syndrome (CRS) grade I with fever in 5 out of 9 patients [2–4]. Serious adverse events have not been observed. The underlying pharmacological mechanism is based on deep B cell depletion and absent peripheral B cells after administration of CAR T cells [2–4]. The rationale behind targeting CD19 in treatment with CAR T cells was to achieve deeper and broader B cell depletion compared with that achieved with rituximab, by including CD20-negative CD19-positive plasmablasts, plasma cells, and tissue-resident B cells known to be incompletely depleted by rituximab. This strategy was associated with a previously unknown clinical benefit in high-risk autoimmune CTDs [2–4]. In the following paragraphs, we would like to initiate a discussion on the best option for deep B cell depletion in severe autoimmune diseases, as mAbs targeting B cells have been further developed in parallel. Among the latter, the second generation anti-CD20 antibody obinutuzumab is the most advanced in rheumatology, in our opinion. On the basis of similar hypothetical considerations to those described above, we had previously used obinutuzumab successfully in patients with rituximab-refractory systemic autoimmune diseases [5]. Among the patients treated with obinutuzumab was a patient with anti-Jo1-positive antisynthetase syndrome with severe muscular and pulmonary manifestations, as well as two patients with refractory SLE with a SLEDAI of 30 and 32, with multiple organ involvements [5]. After one course of obinutuzumab, all three patients showed significant clinical and serological improvement, and the SLE patients were withdrawn from dialysis. One SLE patient was initially treated in our critical care unit due to severe carditis [5]. Studies have shown that obinutuzumab has greater ability to deplete B cells compared with rituximab, in vitro as well as in vivo [6]. The underlying mechanism discussed relates to the enhanced antibody-dependent cell cytotoxicity (ADCC) and phagocytosis (ADCP), and the improved local efficacy of obinutuzumab in inflamed tissues. In LN, obinutuzumab has been shown to have promising efficacy and safety in a phase II trial [7]. In SS, obinutuzumab has shown efficacy after secondary non-response to rituximab [8]. Furthermore, a case series has shown efficacy and safety of obinutuzumab in the context of ANCA-associated vasculitis [9]. Despite the need for complex pre-treatment procedures, CAR T cells may have some intrinsic advantages. In contrast to obinutuzumab, CAR T cells do not rely on functioning Fc-dependent mechanisms that could hypothetically be compromised in autoimmune disease, negatively influencing ADCC and ADCP [10]. Also, the efficacy of CAR T cells is most probably not affected by Fcγ receptor single-nucleotide polymorphisms, which impact responses to rituximab treatment and could also be an important factor in the case of obinutuzumab therapy [10]. Mackensen et al. reported that all patients with SLE who had obtained remission under treatment with CAR T cells did not need to receive further immunosuppression and had been off-therapy for 5–17 months at the time of publication [2]. This off-treatment remission was attributed to a complete reset of the B cell compartment, which has not been reported for mAbs. Some disadvantages of CAR T cells will probably be alleviated in the future by improving production efficiency (and thus lowering costs) and by developing allogeneic products that can be instantly administered without complex pre-treatment. Treatment with CAR T cells requires leukapheresis, viral transduction of isolated T cells, and potentially risky lymphodepletion chemotherapy [1, 2]. MMF had to be continued in two patients treated with CAR T cells [3, 4]; off-treatment remission may depend on the disease and the individual patient. The long-term persistence of CAR T cells in our Scl70+ SSc case raises questions regarding the controllability of this therapy [4]. Easier application, with the possibility of instant administration via simple infusion favours the use of obinutuzumab, with the additional benefit of less expense in terms of costs and infrastructure. In contrast to CAR T cells, obinutuzumab can be also given in the context of critical care, if the health status of a patient worsens very quickly. The therapeutic experience with obinutuzumab therapy obtained from the phase II trial NOBILITY [7], including 125 randomized patients, is greatly superior to that of the use of CAR T cells in autoimmune diseases, and this has provided valuable information on side effects, which is another factor in favour of its use. The emerging evidence indicates that both CAR T cells and obinutuzumab possess good treatment efficacy and safety, each having specific advantageous characteristics. Easier administration and more trialling favour the use of obinutuzumab therapy, while the impressive clinical effect and the mechanism of action favour the use of CAR T cells. Whether the broader suppression of the adaptive immune system by CD19-targeting CAR T cells, compared with the slightly less broad suppression effect of the anti-CD20 antibody obinutuzumab, is associated with better efficacy or a higher risk of infectious complications, or both, must be evaluated in future studies. Other CD20- or CD19-targeting mAbs, and anti-CD38-targeting mAbs and drugs targeting B cell homeostasis, will be or are in clinical development. In this editorial, we focused on CAR T cells and obinutuzumab because of our own clinical experience and word count restrictions. In conclusion, we propose the simultaneous further development of both cell- and antibody-based B cell–depleting therapies. All of the data for this article were included in the published versions of the articles being discussed. This work was supported by the Deutsche Gesellschaft für Innere Medizin (to W.M.). Disclosure statement: W.M. received unrestricted third-party funds from Roche (manufacturer of obinutuzumab) from 2015 to 2018.