Driving CAR-Ts SafeSLE Free

In this issue of Blood, Müller et al¹ report on an analysis of the safety profile of CD19-targeted chimeric antigen receptor (CAR) T cells given to adults with relapsed/refractory B-cell lymphomas vs those with severe, refractory systemic lupus erythematous (SLE). Insights from this analysis of 18 patients with SLE support a favorable toxicity profile of CAR T cells in SLE, and larger scale studies will be needed to continue to further define the overall experience.

The widespread applicability of CAR T cells in hematologic malignancies has only been feasible though the careful study of life-threatening toxicities and development of strategies to mitigate these side effects. The toxicity hurdle needed to be overcome to achieve consistent benefit. Ongoing efforts continue to identify unique toxicities and refine the clinical definitions thus far established, with the goal of further safety and efficacy optimization. As the use of CAR T-cell therapy extends to indications beyond cancer, the therapeutic index calculus may shift, incorporating altered risk-benefit considerations. This is reflective of treating diseases that are not immediately life threatening, albeit associated with both substantial short- and long-term disease-related morbidities, including shortened life span. Moreover, disease-specific parameters that influence immune effector cell (IEC)–associated toxicities are variable and may impart a different impact than that found in the malignancy setting. Although the early experience with CAR T cells in SLE has been promising, there is limited information about the toxicity profile, especially in comparison to the vast experience with CAR T cells in B-cell malignancies.

It is encouraging that the results of the analysis performed by Müller et al highlight the relative safety profile of CD19-targeted CAR T cells used as therapy for SLE. For SLE, goals of treatment include induction of a long-term remission state to prevent disease progression and severe organ toxicity. To achieve optimal therapeutic efficacy, it is not currently known how deep and for what duration B-cell depletion is needed. This contrasts with the treatment of B-cell malignancies, for which complete eradication of a malignant clone is necessary for cure. It is promising that data reported using CD19-directed CAR T-cell therapy in small cohorts of patients with SLE show potency against this progressive chronic disease.^2-6 

This study compared a cohort of adults (N = 48) with varied B-cell malignancies, the majority of whom had high-grade B-cell non-Hodgkin lymphomas (B-NHLs) and received different second-generation CD19-targeted CAR T cells (including commercial and investigational CAR constructs inclusive of those with CD28z and 41BB costimulatory domains), to a cohort of patients with SLE (N = 18), all of whom received a uniform investigational 41BB-containing CAR T-cell product. Collectively, the adverse events recorded in patients with SLE evaluated in this study were relatively mild, with no patient experiencing high-grade cytokine release syndrome, IEC neurotoxicity syndrome, or IEC-associated hemophagocytic lymphohistiocytosis–like syndrome. The depth and duration of hematotoxicity was low and well managed with growth factor injections, without requiring thrombopoietic agonists. Although circulating biomarker cytokines were indicative generally of a heightened inflammatory state, these were not grossly informative in explaining the lower postinfusion toxicity in SLE compared to patients with B-NHL, a limitation in the utility of using cytokine panels as a whole.⁷ Importantly, and as further evidence of the milder side-effect profile, patients with SLE in sum received fewer doses of agents used to treat inflammatory toxicities. Although the authors did not comment on a newly recognized mild and self-limited focal inflammatory response seen in patients with autoimmunity treated with B-cell targeted CAR T-cell therapy, local immune effector cell–associated toxicity syndrome (LICATS)⁸ is a key example of how toxicities may differ based on the underlying disease.

Given the need for B-cell reconstitution after immunological “reset” driven by the elimination of pathogenic B-cell clones, it is notable that B-cell recovery occurred earlier in patients with SLE than in those with B-NHL. Despite this, all patients remained in an ongoing SLE remission without any immunomodulatory or immunosuppressive treatment at 6 months after infusion. Although B-cell recovery corresponded with shorter persistence of CAR T cells in the SLE cohort, without controlled comparison across cell products, it is challenging to determine whether this observation is related to the defining characteristics of the CAR T cells themselves or because of the disease microenvironment. Similarly, recovery of T-cell numbers was observed at 1 year in patients with SLE, whereas patients with B-NHL had delayed recovery. Interestingly, although infused at a relatively lower dose, CD19 CAR T cells manufactured from patients with SLE had similar total expansion and in vivo exposure compared to those manufactured from patients with B-NHL, as calculated by the area under the curve between days 0 and 90 after infusion. Differences in CAR T-cell phenotype after infusion were noted. However, patients with B-NHL received a variety of CAR T-cell products, and this analysis was not strictly controlled to account for manufacturing and intrinsic CAR T-cell differences that very well may be responsible for these observations.^9,10 Although secondary analysis was completed controlling for costimulatory domain, the manufacturing environment during T-cell activation and expansion has a profound effect on resultant T-cell phenotype that limits the interpretation of conclusions made without consideration of these critical variables. Large-scale studies will need to be performed to better understand the differences in CAR T-cell biology when used for autoimmunity.

Despite small numbers, the work by Müller et al provides important insights into the potentially favorable toxicity profile of CAR T cells in SLE. Importantly, this underscores the critical need for comprehensive assessment of toxicities as the field advances using established frameworks for IEC toxicity recognition. Given the unique potential of CAR T cells in autoimmune diseases, extending this therapeutic strategy, including to children with pediatric onset severe autoimmune conditions, will be critical. Thus, future studies should comprehensively evaluate biologic correlates and toxicity profiles to enhance our understanding of how to continue to optimally leverage the potential role of CAR T cells in autoimmune diseases and beyond.

Conflict-of-interest disclosure: C.L.B. has pending and awarded patents in the field of engineered cell therapies. N.N.S. receives research funding from Lentigen, Vor Bio, and Cargo Therapeutics; has attended advisory board meetings (no honoraria) for Vor Bio, ImmunoACT, and Sobi; and receives royalties from Cargo Therapeutics.